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Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with clinical outcome
EJINME-03033; No of Pages 5 European Journal of Internal Medicine xxx (2015) xxx–xxx
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with clinical outcome☆ Calogero Falletta a,1, Daniela Filì b,1, Cinzia Nugara c,⁎, Gabriele Di Gesaro a, Chiara Minà a, Cesar Mario Hernandez Baravoglia a, Giuseppe Romano a, Cesare Scardulla a, Fabio Tuzzolino d, Giovanni Vizzini b, Francesco Clemenza a a Cardiology Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy b Hepatology Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy c Division of Cardiology A.O.U.P. Paolo Giaccone, Palermo, Italy d Research Office, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy
a r t i c l e
i n f o
Article history: Received 16 May 2015 Received in revised form 25 August 2015 Accepted 14 October 2015 Available online xxxx Keywords: Cirrhosis Diastolic dysfunction Tissue Doppler imaging
a b s t r a c t Background: Cirrhotic cardiomyopathy has been characterized by impaired contractile response to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease. However, the clinical significance of diastolic dysfunction (DDF) in cirrhotic patients has not been clarified. Methods: We studied 84 cirrhotic patients with normal systolic function to evaluate the prevalence of DDF using tissue Doppler imaging, and to investigate the possible correlation of DDF with outcomes (hospitalization, death) and with the specific causes of death. Results: The mean follow-up was 10 ± 8 months. DDF was diagnosed in 22 patients (26.2%). Patients with DDF more frequently had ascites (90.9% vs. 64.5 %; p = 0.026), lower levels of albumin (OR: 5.39; p = 0.004), higher NT-proBNP levels, and longer QTc interval (464 ± 23 ms vs. 452 ± 30 ms; p = 0.039). At follow-up, patients with DDF did not have a higher incidence of adverse events in terms of hospitalization and death. Conclusions: The presence of diastolic dysfunction has not been found to be clearly associated with outcome, and prognosis has been determined primarily by the severity of liver disease. © 2015 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Cirrhotic cardiomyopathy has been defined by the World Congress of Gastroenterology as a cardiac dysfunction in patients with cirrhosis, and characterized by impaired contractile responsiveness to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease [1,2]. Diastolic dysfunction (DDF) in cirrhosis is due to an increased stiffness of the myocardial wall secondary to myocardial hypertrophy, fibrosis, and subendothelial edema [1]. Studies in the field of cirrhotic cardiomyopathy have reported a prevalence of diastolic dysfunction that ranges from 40% to 50%, and increases in patients with severe ascites [3–7]. In these reports, DDF was identified on the basis of the evidence of an E/A ratio ≤ 1 ☆ Financial support: This study received no financial support in the way of corporate sponsorship or industry funding. ⁎ Corresponding author at: Division of Cardiology, A.O.U.P. Paolo Giaccone, Via del Vespro, 90127, Palermo, Italy. Tel./fax: +39 09121 92 478,+39 091 21 92 411. 1 Daniela Filì and Calogero Falletta made equal contributions and share first authorship.
and/or a prolonged DT interval. The echocardiographic criteria for diagnosing diastolic dysfunction have changed over time. While initially the presence of abnormal mitral flow velocities obtained by pulsed wave Doppler echocardiography [8] was accepted as evidence of diastolic dysfunction, in their more recent recommendations [9] echocardiography societies have come to underline the need to use more robust and specific criteria, such as those derived from pulsed wave tissue Doppler imaging. Moreover, the clinical significance of DDF in cirrhotic patients is still a matter of debate. The aim of this study was to define the prevalence of diastolic dysfunction in our population using tissue Doppler imaging (TDI), and to investigate the possible correlation of DDF with outcomes (hospitalization, death), and with the specific causes of death. 2. Methods Between March, 2012 and March, 2014, all patients evaluated and listed for liver transplantation at our institute were assessed for
http://dx.doi.org/10.1016/j.ejim.2015.10.009 0953-6205/© 2015 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009
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C. Falletta et al. / European Journal of Internal Medicine xxx (2015) xxx–xxx
enrollment in the study. Patients affected with valvular or ischemic heart disease, arrhythmias or pulmonary hypertension were excluded. Patients listed for causes different from cirrhosis were also excluded. The diagnosis of cirrhosis was established through a combination of biochemical, clinical and instrumental findings. Eighty-four cirrhotic patients agreed to participate in the study. They underwent clinical examination, laboratory tests, 12-lead electrocardiogram, and echocardiogram on the same day. Specifically, at admission, we recorded clinical data such as age, gender, body mass index (BMI), etiology of liver disease, heart rate, systolic and diastolic blood pressure, and QTc interval. Laboratory parameters, including natriuretic peptides, were also collected. Based on these data we calculated liver-specific prognostic scores, such as the Child-Pugh class and score, and MELD score. All echocardiographic examinations were done with Vivid System Seven (GE/Vingmed, Milwaukee, USA) at 3.5 MHz. Echocardiograms were recorded with patients in left lateral decubitus, and the evaluation was made through parasternal long and short axes, and apical fourchamber views according to European guidelines [10]. Left ventricular end-diastolic diameter, interventricular septal thickness, and left atrial diameter were measured with the 2D method in the parasternal long axis. Left atrial volume and area were calculated in the apical four-chamber views. Left ventricular volumes and ejection fraction were estimated using Simpson's biplane method. A left ventricular ejection fraction above 50% was considered normal. Spectral Doppler measurements were obtained with the transducer in the apical four-chamber view and the Doppler beam aligned perpendicularly to the plane of the mitral annulus. The sample volume was placed between the tips of the mitral leaflets. Three consecutive beats during quiet respiration were used for calculation of the Doppler variables. Tricuspid regurgitation (TR) and mitral regurgitation (MR) severity were quantified using color flow imaging and vena contracta width, and graded as none, mild, moderate and severe in a numeric scale from 0 to 3. Pulmonary artery systolic pressure (PASP) was obtained as the sum of pressure gradient between right atrium and right ventricle obtained from TR jet peak velocity, plus right atrial pressure estimation made with the use of inferior vena cava size and collapsibility. Tricuspid annular plane systolic excursion (TAPSE) was interpreted based on accepted guidelines [10]. TDI was obtained from the four-chamber apical view. The pulsed TDI measurements included the myocardial systolic and diastolic velocity acquired from the interventricular septum and left lateral wall at the valve annulus level. It was used the average e′ velocity obtained from the septal and lateral sides of the mitral annulus for the prediction of left ventricular filling pressures. According to current recommendations, using the average E/e′ ratio, a ratio ≤ 8 is associated with normal filling pressure. Diastolic dysfunction was diagnosed in cases of a ratio ≥ 13; when the value was between 9 and 13, left atrial volume ≥ 34 ml/mq was used to identify patients with diastolic dysfunction [9]. During the period of observation we recorded the occurrence of liver transplant, hospitalization, and death. The study was approved by our institute's Ethic Committee, and informed written consent was obtained from all patients. The study was carried out in accordance with the Declaration of Helsinki. 2.1. Statistical methods Data were collected using Excel 2007 (Microsoft, Richmond, WA, USA). Clinical, laboratory, and echocardiography characteristics were analyzed through descriptive statistical analysis and expressed as the mean value ± standard deviation or percentage and absolute values. Fisher's exact test was applied for categorical variables; two-sample t test, or Wilcoxon rank–sum test were used for continuous variables
when appropriate. The odds ratio was estimated by logistic regression. Survival analysis was applied with the Kaplan–Maier estimator, and comparison between groups was assessed with the log–rank test. The level of significance was determined for p values of less than 5%. Statistical analysis was done with STATA 13.1 software. 3. Results One hundred ten patients were listed for liver transplantation at our institute between March, 2012 and March, 2014, and 84 were enrolled in the study. The remaining 26 patients were excluded for the following reasons: 3 had coronary or valvular heart disease, 1 had pulmonary hypertension, 3 died before enrollment, 4 were transplanted before enrollment, and 5 were listed for causes different from cirrhosis; 10 had an inadequate echocardiographic window. Fifty-six patients were male (67%). Mean age was 53 ± 10.9 years, and mean BMI was 27 ± 3.6 kg/m2. The etiology of cirrhosis was viral in 57 patients (68%), alcohol in 8 (9%), and other (autoimmune, cryptogenic, NASH) in 19 (23%). Most of the patients (70; 83%) were in the Child-Pugh B–C class; the mean MELD score was 13.9 ± 4.9. The mean follow-up was 10 ± 8 months. During this period, 36 patients underwent liver transplantation. Twenty-one patients (25%) died during the study. The causes of death were hepatic failure in 6 patients (28.6%), hepatocellular carcinoma in 2 (9.5%), sepsis in 4 (19 %), cerebral hemorrhage in 2 (9.5%), complications related to the transplant in 4 (19 %), and other in 3 (14.4 %). In the remaining 63 patients, 50 were hospitalized at least once. DDF was diagnosed in 22 (26.2%) patients. Clinical and laboratory characteristics of the cirrhotic patients with and without diastolic dysfunction are reported in Table 1. Age, gender, BMI, systolic and diastolic blood pressure, heart rate, causes of liver disease, and cause of death did not differ significantly between patients with and without DDF. Patients with DDF more frequently had ascites (90.9% vs. 64.5%; p = 0.026), lower levels of albumin (OR:5.39; p = 0.004), NT-proBNP level N 125 pg/ml (45.4% vs. 13.6%, p = 0.005) and longer QTc interval (464 ± 23 vs. 452 ± 30; p = 0.039). There was no difference in INR, total bilirubin, and creatinine values. No significant difference was observed in the MELD score and Child-Pugh score between patients with and without DDF. However, we observed a higher prevalence of Child-Pugh Class C in patients with diastolic dysfunction, though it did not reach statistical significance. Table 2 shows echocardiographic characteristics of our population. In particular, no differences were found between patients having diastolic dysfunction or not, in terms of ejection fraction (EF), left ventricular end-diastolic diameter, left ventricular end-diastolic indexed volume, and interventricular septal thickness. In patients with DDF we found higher PASP (32.2 ± 6.8 vs. 26.9 ± 5.5 mmHg; p b 0.001) and TAPSE (30.3 ± 5.2 vs. 26.7 ± 4.6 mm; p = 0.003). Diastolic dysfunction was associated with a higher degree of tricuspid (1.18 ± 0.1 vs. 0.79 ± 0.1; p = 0.015) and mitral regurgitation, though only the first reached statistical significance. We found no significant association in terms of rate of hospitalization and mortality in patients with DDF (Fig. 1, Table 3). The same analysis was done by dividing the population into two subgroups based on the occurrence of liver transplantation or not, with no change in outcome (Table 4). The only factors associated with a worse outcome were albumin level (3.2 ± 0.2 vs. 2.7 ± 0.1, p = 0.029; OR = 0.29, p = 0.008), Child-Pugh class (A 57.1% vs. B 82.7% vs. C 87.8%, p = 0.047, OR 2.2, p = 0.027), and MELD score (11.8 ± 1.4 vs. 14.5 ± 0.6, 1-sided p = 0.025; OR = 1.93, p = 0.053) (Fig. 2). 4. Discussion It is well known that cirrhotic patients have an altered hemodynamic profile [11], but the nosological entity defined as cirrhotic
Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009
C. Falletta et al. / European Journal of Internal Medicine xxx (2015) xxx–xxx Table 1 Clinical and laboratory characteristics of cirrhotic patients with and without diastolic dysfunction. Variable
With DDF n = 22; 26.2%
Without DDF n = 62; 73.8%
p
Gender, male (%) Age (years) BMI (kg/m2) Etiology of liver disease, n (%) Viral Alcoholic Other Hepatocellular carcinoma, n (%) Child-Pugh class, n (%) A B C Child-Pugh score ≥7, n (%) MELD score Ascites, n (%) Systolic artery pressure (mmHg) Diastolic artery pressure (mmHg) Heart rate (pulse/min) QTc interval INR Total bilirubin (mg/dl) Albumin (g/dl) NT-proBNP N125 pg/ml Creatinine (mg/dl)
12 (21.4) 54.7 ± 14.1 27.1 ± 3.2
44 (78.6) 52.4 ± 9.6 27 ± 3.7
0.192 0.490 0.942 0.053
11 (50) 2 (9.1) 9 (40.9) 10 (45.4)
46 (74.2) 6 (9.7) 10 (16.1) 26 (41.9)
1 (4.6) 6 (27.2) 15 (68.2) 21 (95) 14.6 ± 3.6 20 (90.9) 118.3 ± 11.3 70. 1 ± 13.5 70.1 ± 13.5 464 ± 23 1.4 ± 0.2 3.8 ± 2.8 2.5 ± 0.9 10 (45.4) 0.94 ± 0.3
13 (21) 23 (37) 26 (42) 49 (79) 13.7 ± 5.3 40 (64.5) 117.9 ± 15.9 64.7 ± 11.3 70.4 ± 12.6 452 ± 30 1.3 ± 0.3 3.4 ± 3.7 2.9 ± 0.8 8 (13.6) 0.97 ± 0.3
3
2.00
1.50
1.00
0.50 p = 0.345 0.806 0.066
0.00 0
3
6
9 Months No DDF
0.101 0.393 0.026 0.907 0.451 0.908 0.039 0.836 0.640 0.0003 0.005 0.658
cardiomyopathy is still controversial. From a pathophysiological point of view, cirrhosis determines marked arterial vasodilatation, with consequent reduction of systemic vascular resistance. Redistribution of the circulating blood volume results in a central hypovolemia [2,12]. The activation of renin–angiotensin–aldosterone system (RAAS) and of sympathetic nervous system (SNS), as compensatory mechanisms, determines a hyperdynamic circulation, which is characterized by an increased cardiac output and heart rate that ensures an adequate peripheral organ perfusion [13]. It has been postulated, therefore, that cirrhosis may be associated with cardiac dysfunction, even if the mechanism is not completely understood. Studies that support this hypothesis led to the definition of cirrhotic cardiomyopathy as a condition characterized by impaired contractile responsiveness to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease [1,2]. Biomarkers such as natriuretic peptide and troponin I play a central role in diagnosing and risk-stratifying heart failure patients [14]. In patients affected with cirrhosis, BNP and pro-BNP levels were found to be correlated with severity of disease, incidence of cardiac dysfunction, and survival [12,15,16]. Troponin I is increased in patients with cirrhosis and subclinical myocardial damage [12,17]; atrial natriuretic peptide (ANP) levels are also increased in patients with cirrhosis, and associated with a poorer prognosis [12]. Recent studies suggest that a new biomarker, galectin-3, is overexpressed in human fibrotic liver disease [18]. Galectin-3, activated by tissue damage, promotes fibrosis and is associated with a worse prognosis in patients with heart failure [19–21]. Table 2 Echocardiographic characteristics of cirrhotic patients with and without diastolic dysfunction. Variable
With DDF n = 22; 26.2%
Without DDF n = 62; 73.8%
p
EF (%) Left ventricular EDD (mm) Interventricular septal thickness (mm) Left ventricular EDVI (ml/mq) Left atrial volume (ml) TAPSE (mm) Pulmonary artery pressure (mmHg)
65.4 ± 4.9 47.8 ± 45.6 10.3 ± 1.7 54.9 ± 15.6 86.4 ± 77.4 30.3 ± 5.2 32.2 ± 6.8
63.6 ± 4.5 46.2 ± 45.0 10.1 ± 1.5 52.5 ± 10.8 63.5 ± 57.4 26.7 ± 4.6 26.9 ± 5.5
0.132 0.189 0.675 0.505 b0.001 0.003 b0.001
12
15
18
DDF
Fig. 1. DDF was not associated with hospitalization and/or death. The cohort was divided into patients with and without DDF, and the prevalence of the outcome of interest was plotted against time. There was no significant difference between the two subgroups.
Based on this evidence, Pellicori et al. [22] suggest that galectin-3 could be a biological link between cardiac fibrosis and liver cirrhosis. Prolonged QTc interval is also frequent in cirrhotic patients (up to 50%) [12]. This finding is correlated with the severity of liver disease, and negatively affects prognosis [23], though some studies have found the opposite [24]. Finally, cardiac dysfunction, mainly diastolic, as it appears earlier, might negatively affect the prognosis in cirrhotic patients [3,4]. According to the literature, diagnosis of cirrhotic cardiomyopathy is based principally on the following criteria: 1. systolic dysfunction (blunted increase in cardiac output with exercise, volume challenge or pharmacological stimuli, resting EF b 55%); 2. diastolic dysfunction (E/A ratio b 1.0, prolonged deceleration time N 200 ms, prolonged isovolumetric relaxation time N 80 ms); 3. supportive criteria (electrophysiological abnormalities, abnormal chronotropic response, electromechanical uncoupling/dyssynchrony, prolonged QTc interval, enlarged left atrium, increased myocardial mass, increased BNP and pro-BNP, and increased troponin I) [1]. Based on these criteria, previous data showed a prevalence of DDF between 40% and 50% in patients affected with liver cirrhosis, with a higher incidence in patients with decompensated cirrhosis and severe ascites [1–7]. Nevertheless, in the current recommendations [9], a diagnosis of diastolic dysfunction in patients with normal ejection fraction is based primarily on TDI parameters. More recently, these criteria have been utilized in studies on cirrhotic cardiomyopathy [25,26]. The aim of our study was to determine the prevalence of DDF according to the most recent criteria [9] in a group of cirrhotic patients on the waiting list for transplantation and with no relevant heart disease, and to investigate the association with prognosis. With the new accepted criteria, in our population we found a prevalence of DDF of 26%. This rate is lower than previously reported [1–7], probably due to the use of less specific criteria in the past, which could have led to an overestimation of the prevalence of this entity. Consonant with previous data [25,27,28], in our population DDF was associated with higher incidence of ascites (90.9% vs. 64.5 %; p = 0.026), higher NT-proBNP level, and longer QTc interval (464 ± 23 vs. 452 ± 30; p = 0.039). Moreover, we observed an association Table 3 Incidence of events (death, hospitalization) in cirrhotic patients with and without diastolic dysfunction. Variable
With DDF
Without DDF
p
Death, n (%) Hospitalization, n (%)
8 (36.4) 13 (92.9)
13 (21) 37 (75.5)
0.164 0.265
Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009
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C. Falletta et al. / European Journal of Internal Medicine xxx (2015) xxx–xxx
Table 4 Incidence of events (death, hospitalization) in cirrhotic patients with and without diastolic dysfunction, separated for occurrence of liver transplantation (Tx). Variable
With DDF
Without DDF
p
Tx, death, n (%) Tx, hospitalization, n (%) No Tx, death, n (%) No Tx, hospitalization, n (%)
3(37.5) 3 (60) 5 (35.7) 8 (88.9)
7(25) 16 (76.2) 6 (17.7) 20 (71.4)
0.658 0.588 0.258 0.403
between DDF and lower level of albumin (OR: 5.39; p = 0.004), higher degree of tricuspid (1.18 ± 0.1 vs. 0.79 ± 0.1; p = 0.015), and mitral regurgitation, though only the first was statistically significant. In our population, patients with DDF showed a more severe liver disease measured with the Child-Pugh score, without reaching statistical significance. This may be related to the relatively small sample size. The relationship between the degree of liver dysfunction and the evidence of cirrhotic cardiomyopathy is controversial. Merli et al. [29] have found no direct relationship between the severity of liver disease and cardiac dysfunction, while others [12,16,30] have reported a more pronounced cardiac dysfunction in patients with decompensated cirrhosis. Moreover, several studies [4,25,31,32] have evaluated the correlation between cirrhotic cardiomyopathy and outcomes, though the results are still a matter of controversy. Recently, Raevens et al. [31] observed that tricuspid regurgitation severity on echocardiography is predictive of survival in cirrhotic patients who have undergone liver transplantation. On the basis of these findings, they suggest that patients with a degree of TR higher than mild should be followed more closely. In our study, patients had a mean follow-up of 10 ± 8 months. In the period of observation, no association was found between evidence of diastolic dysfunction and outcome, defined as hospitalization or mortality. QTc interval and NT-proBNP levels were not associated with outcome. However, these results may be influenced by the relatively short duration of the follow-up and low number of patients, which are limitations of our study. In agreement with the literature, in our population we found that severity of liver disease was associated with hospitalization and mortality.
MELD
5. Conclusions Echocardiography is currently the gold standard for assessing myocardial systolic and diastolic function. Indeed, based on current echocardiographic statements, TDI is considered the most reliable tool for diagnosing diastolic dysfunction. Current recommendations for identifying the nosological entity known as cirrhotic cardiomyopathy are still based on outdated echocardiographic criteria, with lower specificity. In the past, this may have led to an overestimation of the prevalence of this entity. In addition, in the more recent literature, the presence of diastolic dysfunction has not been found to be clearly associated with outcome, and prognosis has been determined primarily by the severity of liver disease. The results of our study on a population of cirrhotic patients are consonant with these findings. Further studies on larger cohorts of patients are needed to evaluate the role of the DDF in the long-term prognosis of cirrhotic patients. Learning points Current recommendations for identifying cirrhotic cardiomyopathy are based on outdated echocardiographic criteria. This may have led to an overestimation of the prevalence of this entity in the past. We studied a cohort of cirrhotic patients enlisted for liver transplant. The prevalence of diastolic dysfunction diagnosed with TDI was lower than previously reported and has not been found to be clearly associated with outcome. Authorship C. Falletta: designed and performed the study, collected and analyzed data, and helped draft the paper. D. Filì: designed and performed the study, collected and analyzed data, and helped draft the paper. C. Nugara: collected and analyzed data, and helped draft the paper. G. Di Gesaro: collected data. C. Minà: collected data. CM Hernandez Baravoglia: collected data. G. Romano: collected data. C. Scardulla: contributed to study design. F. Tuzzolino: analyzed data. G. Vizzini: contributed to study design. F. Clemenza: designed and performed the study, analyzed data, and helped draft the paper. Conflict of interests The authors state that they have no conflicts of interest.
Child-Pugh
References DDF
Albumine 0.00
2.00
4.00 6.00 odds ratio
8.00
10.00
Fig. 2. Only 3 clinical variables were found to be associated with hospitalization and/or death in our cohort. Among the studied variables, MELD score, Child-Pugh class and albumin were found to be significantly associated with the outcome of interest. DDF was not associated with hospitalization and/or death. The odds ratio for the MELD score was calculated using 5-point increments, the odds ratio for the INR was calculated using 0.1 unit increments.
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Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with clinical outcome☆ Calogero Falletta a,1, Daniela Filì b,1, Cinzia Nugara c,⁎, Gabriele Di Gesaro a, Chiara Minà a, Cesar Mario Hernandez Baravoglia a, Giuseppe Romano a, Cesare Scardulla a, Fabio Tuzzolino d, Giovanni Vizzini b, Francesco Clemenza a a Cardiology Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy b Hepatology Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy c Division of Cardiology A.O.U.P. Paolo Giaccone, Palermo, Italy d Research Office, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy
a r t i c l e
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Article history: Received 16 May 2015 Received in revised form 25 August 2015 Accepted 14 October 2015 Available online xxxx Keywords: Cirrhosis Diastolic dysfunction Tissue Doppler imaging
a b s t r a c t Background: Cirrhotic cardiomyopathy has been characterized by impaired contractile response to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease. However, the clinical significance of diastolic dysfunction (DDF) in cirrhotic patients has not been clarified. Methods: We studied 84 cirrhotic patients with normal systolic function to evaluate the prevalence of DDF using tissue Doppler imaging, and to investigate the possible correlation of DDF with outcomes (hospitalization, death) and with the specific causes of death. Results: The mean follow-up was 10 ± 8 months. DDF was diagnosed in 22 patients (26.2%). Patients with DDF more frequently had ascites (90.9% vs. 64.5 %; p = 0.026), lower levels of albumin (OR: 5.39; p = 0.004), higher NT-proBNP levels, and longer QTc interval (464 ± 23 ms vs. 452 ± 30 ms; p = 0.039). At follow-up, patients with DDF did not have a higher incidence of adverse events in terms of hospitalization and death. Conclusions: The presence of diastolic dysfunction has not been found to be clearly associated with outcome, and prognosis has been determined primarily by the severity of liver disease. © 2015 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Cirrhotic cardiomyopathy has been defined by the World Congress of Gastroenterology as a cardiac dysfunction in patients with cirrhosis, and characterized by impaired contractile responsiveness to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease [1,2]. Diastolic dysfunction (DDF) in cirrhosis is due to an increased stiffness of the myocardial wall secondary to myocardial hypertrophy, fibrosis, and subendothelial edema [1]. Studies in the field of cirrhotic cardiomyopathy have reported a prevalence of diastolic dysfunction that ranges from 40% to 50%, and increases in patients with severe ascites [3–7]. In these reports, DDF was identified on the basis of the evidence of an E/A ratio ≤ 1 ☆ Financial support: This study received no financial support in the way of corporate sponsorship or industry funding. ⁎ Corresponding author at: Division of Cardiology, A.O.U.P. Paolo Giaccone, Via del Vespro, 90127, Palermo, Italy. Tel./fax: +39 09121 92 478,+39 091 21 92 411. 1 Daniela Filì and Calogero Falletta made equal contributions and share first authorship.
and/or a prolonged DT interval. The echocardiographic criteria for diagnosing diastolic dysfunction have changed over time. While initially the presence of abnormal mitral flow velocities obtained by pulsed wave Doppler echocardiography [8] was accepted as evidence of diastolic dysfunction, in their more recent recommendations [9] echocardiography societies have come to underline the need to use more robust and specific criteria, such as those derived from pulsed wave tissue Doppler imaging. Moreover, the clinical significance of DDF in cirrhotic patients is still a matter of debate. The aim of this study was to define the prevalence of diastolic dysfunction in our population using tissue Doppler imaging (TDI), and to investigate the possible correlation of DDF with outcomes (hospitalization, death), and with the specific causes of death. 2. Methods Between March, 2012 and March, 2014, all patients evaluated and listed for liver transplantation at our institute were assessed for
http://dx.doi.org/10.1016/j.ejim.2015.10.009 0953-6205/© 2015 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009
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C. Falletta et al. / European Journal of Internal Medicine xxx (2015) xxx–xxx
enrollment in the study. Patients affected with valvular or ischemic heart disease, arrhythmias or pulmonary hypertension were excluded. Patients listed for causes different from cirrhosis were also excluded. The diagnosis of cirrhosis was established through a combination of biochemical, clinical and instrumental findings. Eighty-four cirrhotic patients agreed to participate in the study. They underwent clinical examination, laboratory tests, 12-lead electrocardiogram, and echocardiogram on the same day. Specifically, at admission, we recorded clinical data such as age, gender, body mass index (BMI), etiology of liver disease, heart rate, systolic and diastolic blood pressure, and QTc interval. Laboratory parameters, including natriuretic peptides, were also collected. Based on these data we calculated liver-specific prognostic scores, such as the Child-Pugh class and score, and MELD score. All echocardiographic examinations were done with Vivid System Seven (GE/Vingmed, Milwaukee, USA) at 3.5 MHz. Echocardiograms were recorded with patients in left lateral decubitus, and the evaluation was made through parasternal long and short axes, and apical fourchamber views according to European guidelines [10]. Left ventricular end-diastolic diameter, interventricular septal thickness, and left atrial diameter were measured with the 2D method in the parasternal long axis. Left atrial volume and area were calculated in the apical four-chamber views. Left ventricular volumes and ejection fraction were estimated using Simpson's biplane method. A left ventricular ejection fraction above 50% was considered normal. Spectral Doppler measurements were obtained with the transducer in the apical four-chamber view and the Doppler beam aligned perpendicularly to the plane of the mitral annulus. The sample volume was placed between the tips of the mitral leaflets. Three consecutive beats during quiet respiration were used for calculation of the Doppler variables. Tricuspid regurgitation (TR) and mitral regurgitation (MR) severity were quantified using color flow imaging and vena contracta width, and graded as none, mild, moderate and severe in a numeric scale from 0 to 3. Pulmonary artery systolic pressure (PASP) was obtained as the sum of pressure gradient between right atrium and right ventricle obtained from TR jet peak velocity, plus right atrial pressure estimation made with the use of inferior vena cava size and collapsibility. Tricuspid annular plane systolic excursion (TAPSE) was interpreted based on accepted guidelines [10]. TDI was obtained from the four-chamber apical view. The pulsed TDI measurements included the myocardial systolic and diastolic velocity acquired from the interventricular septum and left lateral wall at the valve annulus level. It was used the average e′ velocity obtained from the septal and lateral sides of the mitral annulus for the prediction of left ventricular filling pressures. According to current recommendations, using the average E/e′ ratio, a ratio ≤ 8 is associated with normal filling pressure. Diastolic dysfunction was diagnosed in cases of a ratio ≥ 13; when the value was between 9 and 13, left atrial volume ≥ 34 ml/mq was used to identify patients with diastolic dysfunction [9]. During the period of observation we recorded the occurrence of liver transplant, hospitalization, and death. The study was approved by our institute's Ethic Committee, and informed written consent was obtained from all patients. The study was carried out in accordance with the Declaration of Helsinki. 2.1. Statistical methods Data were collected using Excel 2007 (Microsoft, Richmond, WA, USA). Clinical, laboratory, and echocardiography characteristics were analyzed through descriptive statistical analysis and expressed as the mean value ± standard deviation or percentage and absolute values. Fisher's exact test was applied for categorical variables; two-sample t test, or Wilcoxon rank–sum test were used for continuous variables
when appropriate. The odds ratio was estimated by logistic regression. Survival analysis was applied with the Kaplan–Maier estimator, and comparison between groups was assessed with the log–rank test. The level of significance was determined for p values of less than 5%. Statistical analysis was done with STATA 13.1 software. 3. Results One hundred ten patients were listed for liver transplantation at our institute between March, 2012 and March, 2014, and 84 were enrolled in the study. The remaining 26 patients were excluded for the following reasons: 3 had coronary or valvular heart disease, 1 had pulmonary hypertension, 3 died before enrollment, 4 were transplanted before enrollment, and 5 were listed for causes different from cirrhosis; 10 had an inadequate echocardiographic window. Fifty-six patients were male (67%). Mean age was 53 ± 10.9 years, and mean BMI was 27 ± 3.6 kg/m2. The etiology of cirrhosis was viral in 57 patients (68%), alcohol in 8 (9%), and other (autoimmune, cryptogenic, NASH) in 19 (23%). Most of the patients (70; 83%) were in the Child-Pugh B–C class; the mean MELD score was 13.9 ± 4.9. The mean follow-up was 10 ± 8 months. During this period, 36 patients underwent liver transplantation. Twenty-one patients (25%) died during the study. The causes of death were hepatic failure in 6 patients (28.6%), hepatocellular carcinoma in 2 (9.5%), sepsis in 4 (19 %), cerebral hemorrhage in 2 (9.5%), complications related to the transplant in 4 (19 %), and other in 3 (14.4 %). In the remaining 63 patients, 50 were hospitalized at least once. DDF was diagnosed in 22 (26.2%) patients. Clinical and laboratory characteristics of the cirrhotic patients with and without diastolic dysfunction are reported in Table 1. Age, gender, BMI, systolic and diastolic blood pressure, heart rate, causes of liver disease, and cause of death did not differ significantly between patients with and without DDF. Patients with DDF more frequently had ascites (90.9% vs. 64.5%; p = 0.026), lower levels of albumin (OR:5.39; p = 0.004), NT-proBNP level N 125 pg/ml (45.4% vs. 13.6%, p = 0.005) and longer QTc interval (464 ± 23 vs. 452 ± 30; p = 0.039). There was no difference in INR, total bilirubin, and creatinine values. No significant difference was observed in the MELD score and Child-Pugh score between patients with and without DDF. However, we observed a higher prevalence of Child-Pugh Class C in patients with diastolic dysfunction, though it did not reach statistical significance. Table 2 shows echocardiographic characteristics of our population. In particular, no differences were found between patients having diastolic dysfunction or not, in terms of ejection fraction (EF), left ventricular end-diastolic diameter, left ventricular end-diastolic indexed volume, and interventricular septal thickness. In patients with DDF we found higher PASP (32.2 ± 6.8 vs. 26.9 ± 5.5 mmHg; p b 0.001) and TAPSE (30.3 ± 5.2 vs. 26.7 ± 4.6 mm; p = 0.003). Diastolic dysfunction was associated with a higher degree of tricuspid (1.18 ± 0.1 vs. 0.79 ± 0.1; p = 0.015) and mitral regurgitation, though only the first reached statistical significance. We found no significant association in terms of rate of hospitalization and mortality in patients with DDF (Fig. 1, Table 3). The same analysis was done by dividing the population into two subgroups based on the occurrence of liver transplantation or not, with no change in outcome (Table 4). The only factors associated with a worse outcome were albumin level (3.2 ± 0.2 vs. 2.7 ± 0.1, p = 0.029; OR = 0.29, p = 0.008), Child-Pugh class (A 57.1% vs. B 82.7% vs. C 87.8%, p = 0.047, OR 2.2, p = 0.027), and MELD score (11.8 ± 1.4 vs. 14.5 ± 0.6, 1-sided p = 0.025; OR = 1.93, p = 0.053) (Fig. 2). 4. Discussion It is well known that cirrhotic patients have an altered hemodynamic profile [11], but the nosological entity defined as cirrhotic
Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009
C. Falletta et al. / European Journal of Internal Medicine xxx (2015) xxx–xxx Table 1 Clinical and laboratory characteristics of cirrhotic patients with and without diastolic dysfunction. Variable
With DDF n = 22; 26.2%
Without DDF n = 62; 73.8%
p
Gender, male (%) Age (years) BMI (kg/m2) Etiology of liver disease, n (%) Viral Alcoholic Other Hepatocellular carcinoma, n (%) Child-Pugh class, n (%) A B C Child-Pugh score ≥7, n (%) MELD score Ascites, n (%) Systolic artery pressure (mmHg) Diastolic artery pressure (mmHg) Heart rate (pulse/min) QTc interval INR Total bilirubin (mg/dl) Albumin (g/dl) NT-proBNP N125 pg/ml Creatinine (mg/dl)
12 (21.4) 54.7 ± 14.1 27.1 ± 3.2
44 (78.6) 52.4 ± 9.6 27 ± 3.7
0.192 0.490 0.942 0.053
11 (50) 2 (9.1) 9 (40.9) 10 (45.4)
46 (74.2) 6 (9.7) 10 (16.1) 26 (41.9)
1 (4.6) 6 (27.2) 15 (68.2) 21 (95) 14.6 ± 3.6 20 (90.9) 118.3 ± 11.3 70. 1 ± 13.5 70.1 ± 13.5 464 ± 23 1.4 ± 0.2 3.8 ± 2.8 2.5 ± 0.9 10 (45.4) 0.94 ± 0.3
13 (21) 23 (37) 26 (42) 49 (79) 13.7 ± 5.3 40 (64.5) 117.9 ± 15.9 64.7 ± 11.3 70.4 ± 12.6 452 ± 30 1.3 ± 0.3 3.4 ± 3.7 2.9 ± 0.8 8 (13.6) 0.97 ± 0.3
3
2.00
1.50
1.00
0.50 p = 0.345 0.806 0.066
0.00 0
3
6
9 Months No DDF
0.101 0.393 0.026 0.907 0.451 0.908 0.039 0.836 0.640 0.0003 0.005 0.658
cardiomyopathy is still controversial. From a pathophysiological point of view, cirrhosis determines marked arterial vasodilatation, with consequent reduction of systemic vascular resistance. Redistribution of the circulating blood volume results in a central hypovolemia [2,12]. The activation of renin–angiotensin–aldosterone system (RAAS) and of sympathetic nervous system (SNS), as compensatory mechanisms, determines a hyperdynamic circulation, which is characterized by an increased cardiac output and heart rate that ensures an adequate peripheral organ perfusion [13]. It has been postulated, therefore, that cirrhosis may be associated with cardiac dysfunction, even if the mechanism is not completely understood. Studies that support this hypothesis led to the definition of cirrhotic cardiomyopathy as a condition characterized by impaired contractile responsiveness to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease [1,2]. Biomarkers such as natriuretic peptide and troponin I play a central role in diagnosing and risk-stratifying heart failure patients [14]. In patients affected with cirrhosis, BNP and pro-BNP levels were found to be correlated with severity of disease, incidence of cardiac dysfunction, and survival [12,15,16]. Troponin I is increased in patients with cirrhosis and subclinical myocardial damage [12,17]; atrial natriuretic peptide (ANP) levels are also increased in patients with cirrhosis, and associated with a poorer prognosis [12]. Recent studies suggest that a new biomarker, galectin-3, is overexpressed in human fibrotic liver disease [18]. Galectin-3, activated by tissue damage, promotes fibrosis and is associated with a worse prognosis in patients with heart failure [19–21]. Table 2 Echocardiographic characteristics of cirrhotic patients with and without diastolic dysfunction. Variable
With DDF n = 22; 26.2%
Without DDF n = 62; 73.8%
p
EF (%) Left ventricular EDD (mm) Interventricular septal thickness (mm) Left ventricular EDVI (ml/mq) Left atrial volume (ml) TAPSE (mm) Pulmonary artery pressure (mmHg)
65.4 ± 4.9 47.8 ± 45.6 10.3 ± 1.7 54.9 ± 15.6 86.4 ± 77.4 30.3 ± 5.2 32.2 ± 6.8
63.6 ± 4.5 46.2 ± 45.0 10.1 ± 1.5 52.5 ± 10.8 63.5 ± 57.4 26.7 ± 4.6 26.9 ± 5.5
0.132 0.189 0.675 0.505 b0.001 0.003 b0.001
12
15
18
DDF
Fig. 1. DDF was not associated with hospitalization and/or death. The cohort was divided into patients with and without DDF, and the prevalence of the outcome of interest was plotted against time. There was no significant difference between the two subgroups.
Based on this evidence, Pellicori et al. [22] suggest that galectin-3 could be a biological link between cardiac fibrosis and liver cirrhosis. Prolonged QTc interval is also frequent in cirrhotic patients (up to 50%) [12]. This finding is correlated with the severity of liver disease, and negatively affects prognosis [23], though some studies have found the opposite [24]. Finally, cardiac dysfunction, mainly diastolic, as it appears earlier, might negatively affect the prognosis in cirrhotic patients [3,4]. According to the literature, diagnosis of cirrhotic cardiomyopathy is based principally on the following criteria: 1. systolic dysfunction (blunted increase in cardiac output with exercise, volume challenge or pharmacological stimuli, resting EF b 55%); 2. diastolic dysfunction (E/A ratio b 1.0, prolonged deceleration time N 200 ms, prolonged isovolumetric relaxation time N 80 ms); 3. supportive criteria (electrophysiological abnormalities, abnormal chronotropic response, electromechanical uncoupling/dyssynchrony, prolonged QTc interval, enlarged left atrium, increased myocardial mass, increased BNP and pro-BNP, and increased troponin I) [1]. Based on these criteria, previous data showed a prevalence of DDF between 40% and 50% in patients affected with liver cirrhosis, with a higher incidence in patients with decompensated cirrhosis and severe ascites [1–7]. Nevertheless, in the current recommendations [9], a diagnosis of diastolic dysfunction in patients with normal ejection fraction is based primarily on TDI parameters. More recently, these criteria have been utilized in studies on cirrhotic cardiomyopathy [25,26]. The aim of our study was to determine the prevalence of DDF according to the most recent criteria [9] in a group of cirrhotic patients on the waiting list for transplantation and with no relevant heart disease, and to investigate the association with prognosis. With the new accepted criteria, in our population we found a prevalence of DDF of 26%. This rate is lower than previously reported [1–7], probably due to the use of less specific criteria in the past, which could have led to an overestimation of the prevalence of this entity. Consonant with previous data [25,27,28], in our population DDF was associated with higher incidence of ascites (90.9% vs. 64.5 %; p = 0.026), higher NT-proBNP level, and longer QTc interval (464 ± 23 vs. 452 ± 30; p = 0.039). Moreover, we observed an association Table 3 Incidence of events (death, hospitalization) in cirrhotic patients with and without diastolic dysfunction. Variable
With DDF
Without DDF
p
Death, n (%) Hospitalization, n (%)
8 (36.4) 13 (92.9)
13 (21) 37 (75.5)
0.164 0.265
Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009
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C. Falletta et al. / European Journal of Internal Medicine xxx (2015) xxx–xxx
Table 4 Incidence of events (death, hospitalization) in cirrhotic patients with and without diastolic dysfunction, separated for occurrence of liver transplantation (Tx). Variable
With DDF
Without DDF
p
Tx, death, n (%) Tx, hospitalization, n (%) No Tx, death, n (%) No Tx, hospitalization, n (%)
3(37.5) 3 (60) 5 (35.7) 8 (88.9)
7(25) 16 (76.2) 6 (17.7) 20 (71.4)
0.658 0.588 0.258 0.403
between DDF and lower level of albumin (OR: 5.39; p = 0.004), higher degree of tricuspid (1.18 ± 0.1 vs. 0.79 ± 0.1; p = 0.015), and mitral regurgitation, though only the first was statistically significant. In our population, patients with DDF showed a more severe liver disease measured with the Child-Pugh score, without reaching statistical significance. This may be related to the relatively small sample size. The relationship between the degree of liver dysfunction and the evidence of cirrhotic cardiomyopathy is controversial. Merli et al. [29] have found no direct relationship between the severity of liver disease and cardiac dysfunction, while others [12,16,30] have reported a more pronounced cardiac dysfunction in patients with decompensated cirrhosis. Moreover, several studies [4,25,31,32] have evaluated the correlation between cirrhotic cardiomyopathy and outcomes, though the results are still a matter of controversy. Recently, Raevens et al. [31] observed that tricuspid regurgitation severity on echocardiography is predictive of survival in cirrhotic patients who have undergone liver transplantation. On the basis of these findings, they suggest that patients with a degree of TR higher than mild should be followed more closely. In our study, patients had a mean follow-up of 10 ± 8 months. In the period of observation, no association was found between evidence of diastolic dysfunction and outcome, defined as hospitalization or mortality. QTc interval and NT-proBNP levels were not associated with outcome. However, these results may be influenced by the relatively short duration of the follow-up and low number of patients, which are limitations of our study. In agreement with the literature, in our population we found that severity of liver disease was associated with hospitalization and mortality.
MELD
5. Conclusions Echocardiography is currently the gold standard for assessing myocardial systolic and diastolic function. Indeed, based on current echocardiographic statements, TDI is considered the most reliable tool for diagnosing diastolic dysfunction. Current recommendations for identifying the nosological entity known as cirrhotic cardiomyopathy are still based on outdated echocardiographic criteria, with lower specificity. In the past, this may have led to an overestimation of the prevalence of this entity. In addition, in the more recent literature, the presence of diastolic dysfunction has not been found to be clearly associated with outcome, and prognosis has been determined primarily by the severity of liver disease. The results of our study on a population of cirrhotic patients are consonant with these findings. Further studies on larger cohorts of patients are needed to evaluate the role of the DDF in the long-term prognosis of cirrhotic patients. Learning points Current recommendations for identifying cirrhotic cardiomyopathy are based on outdated echocardiographic criteria. This may have led to an overestimation of the prevalence of this entity in the past. We studied a cohort of cirrhotic patients enlisted for liver transplant. The prevalence of diastolic dysfunction diagnosed with TDI was lower than previously reported and has not been found to be clearly associated with outcome. Authorship C. Falletta: designed and performed the study, collected and analyzed data, and helped draft the paper. D. Filì: designed and performed the study, collected and analyzed data, and helped draft the paper. C. Nugara: collected and analyzed data, and helped draft the paper. G. Di Gesaro: collected data. C. Minà: collected data. CM Hernandez Baravoglia: collected data. G. Romano: collected data. C. Scardulla: contributed to study design. F. Tuzzolino: analyzed data. G. Vizzini: contributed to study design. F. Clemenza: designed and performed the study, analyzed data, and helped draft the paper. Conflict of interests The authors state that they have no conflicts of interest.
Child-Pugh
References DDF
Albumine 0.00
2.00
4.00 6.00 odds ratio
8.00
10.00
Fig. 2. Only 3 clinical variables were found to be associated with hospitalization and/or death in our cohort. Among the studied variables, MELD score, Child-Pugh class and albumin were found to be significantly associated with the outcome of interest. DDF was not associated with hospitalization and/or death. The odds ratio for the MELD score was calculated using 5-point increments, the odds ratio for the INR was calculated using 0.1 unit increments.
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Please cite this article as: Falletta C, et al, Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with cl..., Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.10.009