Journal of Cardiovascular Translational Research

https://doi.org/10.1007/s12265-020-09997-0

ORIGINAL ARTICLE

Exercise Training Attenuates Cirrhotic Cardiomyopathy

Sérgio Luiz Borges de Souza 1 & Gustavo Augusto Ferreira Mota 1 & Cristina Schmitt Gregolin 2 & Milena do Nascimento 2 &
Renata Azevedo Melo Luvizotto 2 & Silmeia Garcia Zanati Bazan 1 & Mário Mateus Sugizaki 2 & Luis Fernando Barbisan 3 &
Antonio Carlos Cicogna 1 & André Ferreira do Nascimento 2

Received: 25 October 2019 / Accepted: 25 March 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Cirrhotic cardiomyopathy is a condition where liver cirrhosis is associated with cardiac dysfunction. Triggers and
blockers of cirrhotic cardiomyopathy are poorly understood, which might compromise the prognosis of chronic liver
disease patients. We tested whether exercise training would reduce liver damage induced by thioacetamide and prevent
liver cirrhosis-associated cardiomyopathy. Wistar rats were divided into three groups: control, thioacetamide (TAA), or
TAA plus exercise. Thioacetamide increased liver weight and serum alanine aminotransferase and aspartate aminotrans-
ferase levels. Also, TAA treatment was involved with hepatic nodule formation, fibrotic septa, inflammatory infiltration,
and hepatocyte necrosis. The exercise group presented with a reduction in liver injury status. We found that liver injury
was associated with disordered cardiac hypertrophy as well as diastolic and systolic dysfunction. Exercise training
attenuated cirrhosis-associated cardiac remodeling and diastolic dysfunction and prevented systolic impairment. These
results provided insights that exercise training can mitigate cirrhotic cardiomyopathy phenotype.

Keywords Exercise training . Cirrhotic cardiomyopathy .

ALT Alanine aminotransferase
Cardiac dysfunction . Thioacetamide . Liver cirrhosis
AST Aspartate aminotransferase
C Control
CC Cirrhotic cardiomyopathy
E Peak early transmitral flow velocity
Abbreviations E’ Early diastolic velocity of mitral annulus
A Peak late transmitral flow velocity ET Exercise training
A’ Late diastolic velocity of mitral annulus EFS Endocardial fractional shortening
AO Aorta FE Ejection fraction
HE Hematoxylin eosin
Associate Editor Domingo A. Pascual-Figal oversaw the review of this HR Heart rate
article
IVRT Isovolumetric relaxation time
Sérgio Luiz Borges de Souza, Gustavo Augusto Ferreira Mota, Cristina IS Inflammation score
Schmitt Gregolin, Milena do Nascimento are Graduate student. LA Left atrium
LFS Liver fibrosis score
* André Ferreira do Nascimento LV Left ventricle
nascimentoaf@yahoo.com.br
LVDD Left ventricle diastolic diameter
1
Department of Internal Medicine, Botucatu School of Medicine, São LVSD Left ventricle systolic diameter
Paulo State University (UNESP), Botucatu, São Paulo, Brazil PWSV Posterior wall shortening velocity
2
Institute of Health Sciences, Federal University of Mato Grosso S′ TDI of the systolic velocity of the
(UFMT), Avenida Alexandre Ferronato, n°1200, Setor Industrial, mitral annulus
Sinop, Mato Grosso 78.556-267, Brazil TAA Thioacetamide
3
Department of Morphology, Institute of Biosciences, TAA + EX Thioacetamide plus exercise training
Sao Paulo State University (UNESP), Botucatu, TDI Tissue Doppler imaging
São Paulo, Brazil TET Treadmil exercise testing

Introduction
Cirrhosis is the end-stage of many types of chronic liver dis-
eases, such as alcoholism, chronic hepatitis C virus infection,
and nonalcoholic fatty liver disease, which has become a lead-
ing cause of chronic liver disease in Western countries. Under
repeated insults, the liver undergoes degeneration and necrosis
of hepatocytes, replacement of liver parenchyma by fibrotic
tissues and regenerative nodules, and loss of liver function [1].
Cirrhosis is not a single disease but has serious complications
which exacerbate the patient’s prognosis. Patients with cirrho-
sis have a high risk of developing irreversible liver failure,
hepatocellular carcinoma, esophageal variceal bleeding, asci-
tes, hepatic encephalopathy, renal failure, and cardiac distur-
bances [1, 2].
For many years, cardiac function abnormalities in cirrhosis
were attributed to the direct toxic effects of alcohol on the
heart. However, it has been known for over 60 years that
patients with end-stage liver disease have distinct cardiovas-
cular pathology; patients develop cirrhotic cardiomyopathy,
which denotes a condition characterized by a blunted contrac-
tile responsiveness to stress, diastolic dysfunction, and elec-
tromechanical abnormalities, all of which occur in the absence
of any other cardiac disease [2–4]. Cardiac changes have been
reported to occur in up to 40–50% of patients with liver cir-
rhosis [5, 6] independent of etiology. Also, it has been with
changes recorded even in children with various liver diseases
[7, 8]. Cardiac dysfunction might negatively affect the prog-
nosis of patients with cirrhosis, impair survival, and is impli-
cated in the development of other severe complications such
as renal failure [9, 10].
Accumulating evidence indicates that malnutrition, obesi-
ty, alcohol, smoking habits, and sedentary lifestyle can in-
crease the risk of progression of cirrhosis [11]. Some of these
factors are linked to higher risk of cardiac dysfunction
[12–14]. Lifestyle-related factors can be largely corrected,
and as such they represent an attractive approach to preventing
cirrhosis and its cardiac complications. Exercise training (ET)
is a useful strategy indicated to prevent various diseases, in-
cluding cardiovascular [15, 16]. Whether ET can prevent
cirrhosis-related cardiac dysfunction is unknown. However,
this nonpharmacological intervention represents an attractive
strategy to improve cardiac prognosis of patients with cirrho-
sis. In the present study, we used an animal model to investi-
gate whether exercise training would prevent liver cirrhosis-
associated cardiac dysfunction.
For creating liver injury and fibrosis/cirrhosis in a clinically
relevant manner, we used experimental administration of
thioacetamide (TAA) in rats. Thioacetamide is metabolized
into TAA-sulfoxide by CYP2E1 or by the FAD-
monooxygenase, and is further transformed into intermediates
and other polar molecules that induce hepatic necrosis [17,
18]. Subsequent covalent binding of TAA metabolites to liver
J. of Cardiovasc. Trans. Res.
macromolecules and increased reactive oxygen species pro-
duction then occurs [19]. Free radicals generated by the
bioactivation of TAA can deplete glutathione (GSH) and other
antioxidant defenses in hepatocytes and cause lipid peroxida-
tion [17, 18, 20]. It has been shown that TAA administration
does not directly produce alterations in the heart [21]. Thus,
models of cardiac alterations associated with toxic liver injury
induced by TAA may be useful to evaluate the effects of
candidate cardio/hepatoprotectants, including exercise.
Materials and Methods
Animals and Experimental Model
Male Wistar rats (250–300 g) were supplied by São Paulo
State University Animal Center - UNESP – Botucatu/SP and
kept in collective polypropylene cages in a climate-controlled
environment on a reverse 12 h light/dark cycle. The animals
received water and food ad libitum. The animals (n = 45) were
divided randomly into three groups: control (C),
thioacetamide (TAA), or TAA plus exercise training (TAA +
EX). The TAA was administered in a 100 mg/kg intraperito-
neal dose twice weekly for 8 weeks [22]. The control group
underwent the same procedure but received saline. After
8 weeks of experimental treatment, the animals were submit-
ted to in vivo and post mortem analyses.
Exercise Training Protocol
The ET protoctol was adapted from previous studies [23, 24].
Briefly, rats were submitted to run sessions 5 days/week
(Monday to Friday), running at a speed equivalent to 60% of
maximal speed, achieved during the treadmill exercise testing
(TET) described below. The TET was performed in the first,
third, fifth, and last week of experiment. In the first, third, and
fifth weeks, TET was used to adjust the running speed; in the
final week, TET was to demonstrate the effectiveness of exer-
cise protocol. The duration of exercise was increased by
10 min per week beginning in the third week until it reached
60 min/day. Exercise was then maintained from the fourth to
the eighth week.
Treadmill Exercise Testing
Exercise tolerance was estimated by maximal speed, total
time, and distance using graded TET as described previously
[25, 26]. Briefly, TET began at 6 m/min and increased by 3 m/
min every 3 min until exhaustion. Exhaustion was defined by
non-maintenance at the proposed speed for 5 s. Furthermore,
exercise testing was used to determine the run speed during
exercise training protocol. The TET was performed on a mo-
torized treadmill for rats (AVS Projetos – São Carlos, SP,
J. of Cardiovasc. Trans. Res.
Brazil) after 1 week of adaptation to treadmill environment
under low speed and duration run (5 m/min/day).
Systolic Blood Pressure
At the end of the experimental protocol, the systolic blood
pressure was assessed by using the noninvasive tail-cuff meth-
od with a Narco BioSystems® Electro-Sphygmomanometer
(International Biomedical, Austin, TX, USA). The average of
two pressure readings was recorded for each animal.
Echocardiography
Cardiac function and morphology were measured in vivo by
echocardiography at the end of protocol experiment (Vivid
S6, General Electric Medical Systems, Tirat Carmel, Israel),
using a 5.0 ± 11.5 MHz multi-frequency transducer, in accor-
dance with previous studies [27, 28]. Briefly, rats were anes-
thetized by intraperitoneal injection of a mixture of ketamine
(50 mg/kg) and xylazine (0.5 mg/kg). A two-dimensional
parasternal short-axis view of the left ventricle (LV) was ob-
tained at the level of the papillary muscles [29]. M-mode trac-
ings were obtained from short-axis views of the LV at or just
below the tip of the mitral valve leaflets, and at the level of the
aortic valve and the left atrium. M-mode images of the LV
were printed on a black-and-white thermal printer (Sony UP-
890MD) at a sweep speed of 100 mm/s. All LV structures
were measured by the same observer according to the
leading-edge method of the American Society of
Echocardiography [30]. Measurements reported are the aver-
age of at least five cardiac cycles from the M-mode tracings.
The following structural parameters were evaluated: left ven-
tricle diastolic diameter (LVDD), left ventricle systolic diam-
eter (LVSD), mass index of the left ventricle, relative wall
thickness of the left ventricle, left atrium (LA), and aorta
(AO) diameter. Diastolic function was assessed by peak early
and late diastolic transmitral flow velocity (E and A waves), E/
A ratio, tissue Doppler imaging (TDI) of early (E’) and late
(A’) diastolic velocity of mitral annulus, and E/TDI E’ ratio
and isovolumetric relaxation time (IVRT). Systolic function
was assessed based on the heart rate (HR), fractional ejection
(FE), endocardial fractional shortening (EFS), posterior wall
shortening velocity (PWSV), systolic velocity of the mitral
annulus (S′), and Tei index.
Biochemical Measurements
At the end of the treatment, all animals underwent a 12- to 15-
h fast and were subsequently anesthetized with sodium pen-
tobarbital (40 mg/kg/i.p.) and sacrificed by decapitation. The
serum was separated from total blood by centrifugation for
10 min. Enzymatic kits were used to measure serum alanine
aminotransferase (ALT) (k049, Bioclin, Belo Horizonte,
Minas Gerais, Brazil), aspartate aminotransferase (AST)
(k048, Bioclin, Belo Horizonte, Minas Gerais, Brazil), and
albumin (k040-1, Bioclin, Belo Horizonte, Minas Gerais,
Brazil). Glucose was measured in vivo before euthanasia
using handheld glucometer (ACCU-CHEK®GO, Roche
Diagnóstica Brasil Ltda, Brazil).
Hepatic Histopathology
Paraffin-embedded liver samples were sliced into 5-μm-thick
sections and stained with hematoxylin eosin (HE) for histo-
logical analysis or with Picrosirius red for collagen fiber anal-
ysis. Liver sections stained for HE and Picrosirius red were
evaluated for liver fibrosis (LFS) and inflammation (IS)
scores, both classified on a scale of 0–3, and an average liver
injury score that was calculated as follows: (LFS + IS)/2 [31].
Nodule formation and the presence of fibrotic septa were in-
cluded in the fibrosis score (0–3). The inflammation score (0–
3) was measured by Inflammatory infiltration and the break-
ing up of the hepatocellular limiting plates in the portal tracts.
Statistical Analysis
Data are expressed as the mean and standard deviation or
median and percentiles. Comparisons between groups were
made using one-way analysis of variance (ANOVA) and
Student Newman-Keuls or Kruskal-Wallis and Dunn. The sta-
tistical analyses were performed using SigmaPlot 12.0 (Systat
Software, Inc., San Jose, CA, USA). The level of significance
for all variables was 5%.
Results
General Characteristics
General characteristics are shown in Table 1. As expected,
weight gain was lower in groups under the thioacetamide ad-
ministration and was not aggravated by exercise training.
Thioacetamide increased liver weight and serum ALT and
AST levels while reducing left ventricle weight and systolic
arterial pressure. Exercise training was able to significantly
prevent the increase in AST levels and LV weight reduction,
and partially prevent systolic arterial pressure decline. There
were no differences between the right ventricle weight, fasting
glucose, or serum albumin for all groups.
Exercise Attenuates Thioacetamide-Induced Liver
Injury
Histopathologic examination showed significant nodule for-
mation, fibrotic septa, inflammatory infiltration, and hepato-
cyte necrosis in the liver of TAA group animals, compatible
 J. of Cardiovasc. Trans. Res.

Table 1 General characteristics Exercise Improves Functional Capacity

Variables Groups
Treadmill exercise testing at the beginning of the experiment
Control TAA TAA + EX showed that all groups displayed equal functional capacity
prior to the exercise protocol, as verified by exhaustion speed,
Weight gain (g) 122 ± 25.3a 69.4 ± 24.6b 64.9 ± 23.4b
total time, and distance (data not shown). As expected, ET
Macroscopic morphology
improved exercise tolerance in the TAA + EX group regard-
Liver (g) 11.2 ± 0.85a 12.7 ± 1.93b 13.7 ± 1.71b
less of the TAA treatment, as demonstrated by a higher ex-
RV (g) 0.21 ± 0.02 0.20 ± 0.03 0.21 ± 0.02
haustion speed (Fig. 3).
LV (g) 0.76 ± 0.08a 0.64 ± 0.10b 0.73 ± 0.06a
SBP (mmHg) 129 ± 5.79a 110 ± 13.8b 119 ± 6.95c Exercise Prevents TAA-Induced Pathological Cardiac
Serum biochemical Structural Remodeling
ALT (U/L) 59.6 ± 15.0a 183 ± 73.2b 152 ± 83.2b
AST (U/L) 196 ± 36.9a 377 ± 146b 255 ± 62.4a Figure 4 shows the cardiac structural parameters assessed by
Glucose (mg/dL) 95.5 ± 9.30 87.9 ± 15.3 94.3 ± 13.9 echocardiogram. Thioacetamide treatment was associated
Albumin (g/dL) 2.71 ± 0.30 2.63 ± 0.17 2.90 ± 0.21 with pathological cardiac hypertrophy, while exercise training
Data expressed as mean ± standard deviation. Different letters indicate a
displayed a substantial attenuation of this disorder by
statistically significant difference between groups. P < 0.05. (n = 14 to 15 preventing LVDD, LVSD, LA, and RWT alterations.
each group)
TAA thioacetamide, TAA + EX thioacetamide plus exercise, RV right Exercise Prevents TAA-Induced Cardiac Dysfunction
ventricle, LV left ventricle, SBP systolic blood pressure
Left ventricular diastolic and systolic functions assessed by
with a condition of cirrhosis. Exercise training was able to echocardiogram are shown in Figs. 5 and 6, respectively.
reduce liver injury score and nodule formation, indicating that Thioacetamide treatment reduced heart rate regardless of sed-
liver damage was alleviated in trained animals (Figs. 1 and 2). entary or exercised condition. The diastolic function was

Fig. 1 Histological analysis of liver sections. Lesion score (a), expressed as mean ± SD or median (min to max). Different letters
inflammation score (b), and average liver injury score (c). indicate a statistically significant difference between groups. P < 0.05.
Thioacetamide (TAA), thioacetamide plus exercise (TAA + EX). Data (n = 6 to 7 each group)
J. of Cardiovasc. Trans. Res.

Fig. 2 Representative macroscopic images of the liver and microscopic (TAA + EX). Thioacetamide (TAA), thioacetamide plus exercise (TAA +
sections stained by hematoxylin eosin (HE) (d, e, and f) or Picrosirius red EX). (n = 6 to 7 each group)
(g, h, and i). a, d, and g (control); b, e, and h (TAA); and c, f, and i

deteriorated in the TAA group as verified by changes in all
analyzed variables, except Mitral A and E. Exercise training
was useful to attenuate diastolic dysfunction by reducing E/A
and IVRT increase, and partially TDI E’, mitral E/TDI E’
ratio, E/TDI E, and TDI E/TDI A’ alterations (Fig. 5).
Concerning left ventricular contraction, thioacetamide de-
creases systolic function, which was characterized by lower
levels of ejection fraction, fractional endocardial shortening,
posterior wall shortening velocity (PWSV), tissue Doppler
imaging of systolic velocity of the mitral annulus, and elevat-
ed myocardial performance index. All systolic function
indicators in the exercise group were maintained in the same
levels of control group, indicating that exercise program was
able to prevent TAA-induced cardiac systolic dysfunction.
Discussion
Cardiac abnormalities are the leading cause of morbidity and
mortality in patients with end-stage liver cirrhosis [32, 33]. In
this study, we report that thioacetamide was effective in pro-
moting liver cirrhosis, which reproduced essential features of

Fig. 3 Exercise tolerance test.

Thioacetamide (TAA),
thioacetamide plus exercise
(TAA + EX). Data expressed as
mean ± SD. Different letters
indicate a statistically significant
difference between groups. P <
0.05. (n = 8 to 14 each group)

Fig. 4 Echocardiographic analysis of the cardiac structure.
Thioacetamide (TAA), thioacetamide plus exercise (TAA + EX), left
ventricle diastolic and systolic diameter (respectively, LVDD and
LVSD), left atrium (LA), left atrium to aorta ratio (LA/AO), mass index
cirrhotic cardiomyopathy observed in human cirrhotic cardio-
myopathy, including diastolic and systolic dysfunction as well
as heart rate modification and left ventricular hypertrophy.
Exercise training prevented TAA-induced pathological cardi-
ac structural remodeling and cardiac dysfunction. These re-
sults provide insight into the influence of regular exercise
programs to attenuate cardiac complications in patients under-
going to liver cirrhosis.
Individuals with cirrhosis and portal hypertension frequent-
ly develop hyperdynamic circulation. During cirrhosis, de-
creased metabolism of vasodilators leads to systemic vasodi-
lation and lower systemic vascular resistance and consequent
hypotension [34, 35]. Increased systemic vasodilatation lead-
ing to higher pre-load may result in LV chamber dilatation
J. of Cardiovasc. Trans. Res.
of the LV (LVMI), relative wall thickness of the LV (RWT). Data
expressed as mean ± SD or median (min to max). Different letters
indicate a statistically significant difference between groups. P < 0.05.
(n = 13 to 15 each group)
[36]. Recently, in the same TAA-induced cirrhosis model,
our group demonstrated that TAA reduced arterial pressure,
which was associated with decreased contractile response in
the aorta. In this study, the results support our previous blood
pressure data (Table 1) and show that TAA-induced cirrhosis
is also involved with left ventricular eccentric remodeling,
characterized by increased LV end diastolic dimension and
LV mass index (Fig. 4) similar to cardiomyopathy in human
liver fibrosis. Exercise training attenuated arterial blood pres-
sure decline (Table 1) and pathologic cardiac hypertrophy
(Fig. 4), indicating that circulatory imbalance may be
prevented in part by a regular exercise program. It is plausible
that exercise prevented cardiac remodeling by indirectly con-
trolling cardiac pre-load associated with cirrhosis-involved
J. of Cardiovasc. Trans. Res.
Fig. 5 Echocardiographic analysis of the diastolic cardiac function.
Thioacetamide (TAA), thioacetamide plus exercise (TAA + EX), peak
early and late transmitral flow velocity (Mitral E and Mitral A wave,
respectively), mitral E to mitral A ratio (E/A), tissue Doppler imaging
of early (E’) and late (A’) diastolic velocity of mitral annulus (TDI E’ and
systemic vasodilation. In this sense, lower liver injury (Figs. 1
and 2) and reduced serum AST levels (Table 1) induced by
exercise training may have a significant impact. Increasing
amounts of hepatic fibrosis during the cirrhotic process lead
to deterioration of liver function followed by a reduced capac-
ity of hepatic metabolic functions. Liver failure is an excretory
dysfunction resulting in increased circulatory levels of biliru-
bin and bile acids [37]. Bile acids may cause toxic effects on
the heart and suppress myocardial function [38, 39]. Bile acids
also affect the beta-adrenoceptor density and membrane fluid-
ity in the myocardium and may be involved in the pathogen-
esis of CC [38], a mechanism observed in animal models [40,
41]. Thus, by attenuating liver injury and dysfunction,
TDI A’), mitral E to TDI E ratio (E/TDI E’), isovolumetric relaxation
time (IVRT). Data expressed as mean ± SD or median (min to max).
Different letters indicate a statistically significant difference between
groups. P < 0.05. (n = 13 to 15 each group)
exercise may have improved the hemodynamic and humoral
conditions of the heart.
As expected, TAA-induced cirrhosis decreased heart rate in
comparison with controls (Fig. 6). Several studies show that
cirrhosis leads to QT interval prolongation with an underlying
mechanism that has not been fully elucidated, although cardi-
ac exposure to cardiotoxins [42] and beta-adrenergic hyperac-
tivity [43] have been described. This alteration was not
prevented or exacerbated by exercise training. However, the
exercised group presented normal levels of ejection fraction
and fractional endocardial shortening, while the untrained
TAA group showed a decline of these parameters. These re-
sults suggest that ET can improve myocardial capacity

Fig. 6 Echocardiographic analysis of the systolic cardiac function.
Thioacetamide (TAA), thioacetamide plus exercise (TAA + EX), heart
rate (HR), ejection fraction (EF), endocardial fractional shortening
(EFS), posterior wall shortening velocity (PWSV), tissue Doppler
regardless of heart rate condition. Exercise is an important
mediator of sympathetic regulation to prevent sympathetic
toxicity [44], and can cause resting bradycardia in both ro-
dents [45, 46] and humans [47]. The underlying mechanism
that led to HR reduction may not have been the same for all
animals treated with TAA and TAA + EX.
Diastolic dysfunction after cirrhosis occurs due to myocar-
dial remodeling, which includes ventricular wall thickening
and progressive extracellular matrix exacerbation [48, 49].
This scenario entails a high filing pressure gradient and con-
sequent atrial enlargement, resulting in a decrease in cardiac
function [50, 51]. In agreement with the human study [52], our
J. of Cardiovasc. Trans. Res.
imaging of systolic velocity of the mitral annulus (TDI S′), myocardial
performance index (Tei index). Data expressed as mean ± SD or median
(min to max). Different letters indicate a statistically significant difference
between groups. P < 0.05. (n = 13 to 15 each group)
data showed that the TAA group had significant diastolic im-
pairment (increased E/A, E/E’, and prolongated IVRT), ac-
companied by larger atrial size in comparison with controls.
These data allow us to conclude the TAA group presented
with a decompensated cirrhosis stage [50]. Exercise training,
however, attenuated the cardiac cirrhotic status observed by a
reduction in diastolic dysfunction as well as abnormal atrial
growth prevention. Atrial enlargement is an essential marker
of illness magnitude [51] and has been widely reported
[53–55]. We can infer that exercise programs can reduce CC
severity. As mentioned above, the structural data suggest that
TAA treatment stimulated development of eccentric
J. of Cardiovasc. Trans. Res.
hypertrophy, evidenced by increased LVMI and LVDD and
decreased RWT; the exercise-trained group displayed a phe-
notypic status of physiological hypertrophy, which is charac-
terized by ventricular wall thickening without RWT change
and functional melioration. The TAA + EX group had signif-
icant attenuation of diastolic dysfunction, at least in part due to
near normal structural maintenance.
Echocardiographic results also showed that TAA-induced
liver injury is associated with significant systolic dysfunction,
similar to advanced disease in humans [56]. Our data, howev-
er, demonstrates that exercise is a preventive strategy that can
mitigate the myocardial contractile performance decline
which occurs during cirrhosis. Several mechanisms have been
proposed to explain how cirrhosis induces cardiac inotropic
abnormality, including upregulation of the cannabinoid sig-
naling pathway [57], beta-adrenergic receptors downregula-
tion [58], and nitric oxide production imbalance [59]; it should
be noted that both of these last effects have the ability to
compromise myocyte contraction. Moreover, pathological
structural remodeling contributes to systolic damage. We
found that ET induced cardiac physiological remodeling,
which can help prevent systolic dysfunction. Although no
molecular mechanism was investigated in this research, there
is a consensus in the literature about the efficacy of aerobic
exercise in provide nitric oxide signaling stability [60], con-
trolled neurohormonal activity [46, 47], and cardiac physio-
logical hypertrophy [61, 62].
Limitations
In our study, cardiomyopathy could be considered asymptom-
atic and mild. In addition, we used an exercise program for
preventing cardiac changes associated with progression of liv-
er cirrhosis. Despite the fact that exercise training prevents
pathological cardiac structural remodeling and reduction in
left ventricular diastolic and systolic function associated with
liver cirrhosis in rats, the present study does not provide evi-
dence that exercise training could be safe for cirrhotic cardio-
myopathy with severe cardiac dysfunction or heart failure. To
the best of our knowledge, there is no information that might
indicate an exercise program for this population. There are
also no clinical studies on the management of cirrhotic cardio-
myopathy, and the guidelines for the treatment of chronic
heart failure in non-cirrhotic patients have been followed [4].
Clinical Perspectives
Cardiac dysfunction might negatively affect the prognosis of
patients with cirrhosis [9, 10, 45, 57] and appears to be in-
volved in the development of cardiovascular complications
following liver transplantation [58, 59]. Patients with pre-
existing cardiac conditions are generally not listed for trans-
plantation. Since exercise training was demonstrated to be an
effective strategy in preventing a reduction in left ventricular
diastolic and systolic function associated with liver cirrhosis,
we may expect that exercise training is a potential strategy for
maintaining cardiac function during cirrhosis of the liver. This
study highlights some significant benefits generated by
nonpharmacological therapy based on regular exercise for
the prevention of cirrhotic cardiomyopathy, which may im-
prove prognosis, survival, and health status of patients with
liver disease.
Conclusion
In conclusion, this study provided insights into how exercise
training prevents cirrhotic cardiomyopathy, which was asso-
ciated with lower levels of liver injury.
Funding Information This work was funded by Fundação de Amparo à
Pesquisa do Estado de Mato Grosso - FAPEMAT (161,294/2014) and
Conselho Nacional de Desenvolvimento Científico e Tecnológico -
CNPq (442,979/2014-2).
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Ethical Approval The study protocol was approved by the Botucatu
School of Medicine Research Ethics Committee – UNESP (protocol
number 1257/2018), and all applicable institutional and international
guidelines for the care and use of animals were followed.
Human Subjects/Informed Consent No human studies were carried out
by the authors for this article.
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