Cirrhosis Clinical Trial
Official title:
An Integrated Approach of Subclinical Myocardial Dysfunction in Patients With Hepatic Cirrhosis: Echocardiography, Specific Biomarkers, and Vascular Assessment
The prevalence of hepatic cirrhosis in Romania is very high, with a 10-year mortality of
34-66%. Upward trend of mortality is observed. It is known that cirrhosis is associated with
cardiac abnormalities. These can induce several complications of cirrhosis, and increase
postoperative mortality. Therefore, it is a major public health issue and research in this
field should be a priority.
Few studies evaluated the cardiac function in cirrhotic patients, using only conventional
echocardiography. However, this allows only the late diagnosis of cardiac dysfunction, which
might be already irreversible. Consequently, description of new parameters, which could
detect early dysfunction, becomes essential. There is no study designed to estimate
intrinsic myocardial properties in cirrhosis. New methods (Tissue Doppler and
Speckle-tracking echocardiography) could be essential to detect early cardiac dysfunction.
The exact role of biological markers in the diagnosis of cardiac dysfunction remains to be
clarified. Impaired cardiac function coupled with augmented vascular function could be the
model for cirrhotic patients. This type of ventriculo-arterial interaction has never been
described.
The main objectives of our project are:
1. to investigate the mechanisms which lead to cardiac dysfunction;
2. to describe new parameters for the early diagnosis of cirrhotic cardiomyopathy;
3. to describe the type of ventriculo-arterial interaction;
4. the association between biological markers and echo parameters.
Scientific context and motivation:
Cirrhosis is the end stage of chronic damage to the liver. The prevalence is estimated to be
very high in Romania, more than 1000/100.000 inhabitants, with 10-year mortality of 34-66%.
Upward trends of mortality are observed in a few countries, including Romania, which had
extremely high mortality rates. The cost in terms of hospital costs and lost productivity is
high. Therefore, hepatic cirrhosis represents a major public health in Romania.
It is known that hepatic cirrhosis is associated with cardiovascular abnormalities. These
abnormalities have been suggested to induce/aggravate several complications of cirrhosis,
and also to increase postoperative mortality after major surgery or liver transplantation.
Few studies documented the existence of a hyperdynamic circulation, with increased cardiac
output and reduced systemic vascular resistance. Despite this hyperkinetic circulation, some
patients have abnormal ventricular function unmasked by physiologic/pharmacologic stress.
There are few studies of cardiac function in cirrhosis, although contractile function
disorders found in nonalcoholic cirrhosis in animal models suggested that this is
independent from alcohol intake. These issues are complicated by the fact that, alcohol use
represents one of the commonest causes of both cirrhosis and cardiomyopathy. There are
reasons to believe that cirrhosis per se may be associated with subtle contractile
dysfunction. First, hyperkinetic circulatory changes may induce a high-output cardiac
failure resembling a chronic volume overload of the heart. Second, cirrhosis is associated
with high serum catecholamine levels, and long-term exposure to elevated catecholamines
results in cardiomyopathy. Third, necropsy series of patients with alcoholic/nonalcoholic
cirrhosis show similar cardiac pathologic findings: diffuse fibrosis, subendocardial edema,
nuclear and cytoplasmic vacuolation.
Despite the increased cardiac output, ventricular inotropic and chronotropic responses to
stimuli are blunted, a condition known as "cirrhotic cardiomyopathy". These include systolic
and diastolic dysfunction, electrophysiological changes, and structural changes. There are
no clear consensus definition for this condition. Cardiac function was evaluated by classic
echocardiography, 2D and color/spectral Doppler: cardiac dimensions, left ventricular
ejection fraction (LVEF), systolic and diastolic timings. All of these changes are dependent
on load conditions, and cirrhosis has major variability of preload conditions. However,
these conventional measurements allow only the late diagnosis of cardiac dysfunction, which
might be already irreversible.
Moreover, the cardiac dysfunction is very frequently subclinical and it can appear from
early stages (even in chronic hepatitis). Consequently, early diagnosis of subclinical
cardiac dysfunction are essential in the management of such patients. There is no study
designed to estimate intrinsic myocardial properties in cirrhosis. Tissue Doppler Imaging
(TDI) and speckle-tracking echocardiography (STE) could be very useful in this field, and
this is the major point of the project.
In cirrhosis, different humoral substances enter directly in the systemic circulation. The
following factors are involved as possible mediators for cardiac dysfunction and vascular
changes: increased NO and CO production, endocannabinoids, TNF-α, IL-1, IL-6. Increased NO
production is the major factor involved in the peripheral arterial vasodilation in
cirrhosis.
In conclusion, impaired cardiac function coupled with augmented vascular function could be
the model for cirrhotic patients. This type of ventriculo-arterial interaction has never
been described. This could be the second important point of our research.
Unresolved questions: Consensus definition criteria, specific diagnostic tests, the exact
prevalence of this syndrome, and appropriate management strategies are all unresolved
questions. To date, there is no single diagnostic test that can identify cirrhotic patients
with cardiac dysfunction. Level of natriuretic peptide (proBNP) is elevated due to increased
cardiac release and not because of impaired hepatic extraction. Similarly, troponin I was
reported to be elevated. The exact role of these markers in the diagnosis of cirrhotic
cardiomyopathy, remains to be clarified. We intend to analyze all these markers, in order to
describe the existence of pro-inflammatory status, impairment of oxidative stress and
presence of myocardial fibrosis. The association between these markers and different
parameters of cardiac dysfunction will also be described in our study, for the first time.
The optimum management of cirrhotic cardiomyopathy has not been established since there are
neither "gold standard" diagnostic criteria nor specific treatments at present. We consider
that our research could make progress in this field.
Objectives.
The main objectives are to detect, by new echocardiographic methods, early cardiac
dysfunction in cirrhotic patients, and to establish usefulness of different biomarkers in
diagnosis of this condition. This information will be coupled with data regarding
endothelial function, in order to describe new type of ventriculo-arterial interaction
(intrinsic myocardial dysfunction - augmented vascular function).
Main objectives:
1. to create a gold standard protocol of the early diagnosis of cardiac dysfunction, by
using new echocardiographic methods, and therefore to identify cirrhotic patients at
risk for developing heart failure;
2. to compare the effect of alcoholic vs. nonalcoholic cirrhosis on cardiac and vascular
function;
3. to assess the chronology of the cardiac abnormalities;
4. to define the type of ventriculo-arterial interaction in these patients;
5. to analyze different mechanisms involved in cardiac dysfunction, biological markers
(brain natriuretic peptide, troponins, markers of inflammation, cardiac fibrosis, and
oxidative stress);
6. to correlate the severity of hepatic disease (Child-Pugh score) with different
parameters of cardiac dysfunction and biological markers;
7. to test implication of some genetic disorders in the occurrence of cardiac dysfunction
in our patients;
8. to generate new research, by using stress echocardiography in cirrhotic patients in
order to find stress-induced subtle cardiac dysfunction, which can be absent at rest;
9. to create new opportunities for research in the management strategies of cirrhotic
patients with secondary cardiac dysfunction.
Methods. All patients and normal individuals will be assessed by:
1. General data: age, sex, IMC, blood pressure, heart rate, cardiac risk factors, clinical
stage of cirrhosis, Child-Pugh score, date of diagnosis and complications, previous
investigations.
2. Electrocardiogram (12 leads) and routine blood samples.
3. Specific biomarkers: proBNP, troponin, myocardial fibrosis (β cross laps and
procollagen type-1 amino terminal), and markers of inflammation (PCR-hs, IL1, IL6, IL
10, TNFα); oxidative stress: carbonyl in plasmatic proteins, and the antioxidant
capacity of plasma.
4. Comprehensive Echocardiography: VIVID 9 GE echo machine, with dedicated software
ECHOPAC BT11:
Conventional echocardiography:
- Structural parameters: thickness of the cardiac walls; diameters and volumes of
the cardiac cavities, aorta, and pulmonary artery; left ventricular (LV) mass;
wall stress.
- Functional parameters of systolic and diastolic function: LVEF, LV shortening
fraction, left/right cardiac output and index, tricuspid and mitral annular
excursions; parameters derived from the transmitral, transtricuspid, aortic or
pulmonary flow, different systolic/diastolic timings and ratios (LV/RV TEI index,
pre-ejection/ejection ratio, etc).
- Q analysis by TDI: measurements of isovolumic accelerations, systolic and
diastolic myocardial velocities and derived times, strain at the level of basal
and mid, LV/RV myocardial segments.
- STE - This method offers an alternative to techniques such as TDI (angle
dependent!!) for myocardial deformation (measured as strain and strain rate) in
radial, longitudinal, and circumferential directions, in order to assess LV/RV
systolic and diastolic function, LV torsion, and left and right atrial function.
- 3D echocardiography - precise evaluation of the cardiac chamber anatomy and
volume. 4D analysis enables post-processing of multi-plane imaging datasets,
allows multidimensional imaging acquired in parasternal bi-plane and apical
tri-plane views, and supports 2D, color, as well as, tissue Doppler modes
(including tissue synchronization imaging).
5. Measurement of endothelial function, parameters of arterial remodeling, and arterial
stiffness at the level of the common carotid artery (vascular remodeling and arterial
stiffness indices), and at the level of the brachial artery (endothelial function).
Assessment will be done using an ALOKA α10 ultrasound machine, equipped with an
"echo-tracking" system. Meanwhile, a dedicated new software (wave intensity analysis)
will be used to assess ventriculo-arterial coupling. Another system (Complior) will be
used in order to measure the pulse wave velocity between 2 arterial sites
(carotid-femoral and carotid-radial), as a measure of arterial stiffness.
The relevance of the proposal:
Investigators known that hepatic cirrhosis represents a major public health in Romania.
Because cardiac dysfunction induces/aggravates several complications of cirrhosis, it leads
to a significant increase in morbidity, mortality, and economical costs. Thus, by creation
of a gold standard protocol for detection of the early cardiac dysfunction, investigators
will be able to identify cirrhotic patients at risk for developing heart failure.
Investigators believe that the early identification of cardiac dysfunction is a health
problem of major interest. New imagistic and laboratory parameters might be essential to
identify patients at risk and to find treatment strategies in these patients. This could
generate new research projects in the treatment field, which is now an untouched field.
Our proposal will create knowledge in the medical field and generate important scientific
results, nationally and internationally competitive. It could define mechanisms of cardiac
dysfunction induced by cirrhosis, and describe new type of arterial-ventriculo interaction.
Moreover, it might be able to introduce into clinical practice a "gold standard" evaluation
for patients at risk for developing cardiac dysfunction, consequently leading to an
optimization of therapy. Therefore, the results of the project could be applicative also
from social and economic purposes.
;
Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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