Subclinical Myocardial Dysfunction in Patients With Hepatic Cirrhosis
Condition: Cirrhosis; Cardiomyopathy
MeSH terms: Liver Cirrhosis; Cardiomyopathies; Fibrosis
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): echocardiography
Intervention type(s): Other
Intervention description(s): The patients and controls will be investigated by echocardiography, biomarkers, and ECG. After 1 year investigators will assess 1year mortality.
Other intervention name(s): biomarkers
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: hepatic cirrhosis; subclinical myocardial dysfunction; echocardiography; specific biomarkers; vascular assessment