EACVI project
Prognostic indices of Right heart dysfunction in patients
undergoing CABG (RH-CABG study)

EACVI study – RV-CABG

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Summary of the study
Title

Prognostic indices of Right heart dysfunction in patients
undergoing CABG (RH-CABG study)

Joint collaboration

EACVI HIT - HoT

Principal Investigator

Julia Grapsa MD, PhD, Erwan Donal MD, PhD, Julien

Local Coordinator

Magne MD, PhD, Gilbert Habib MD, PhD

Participating Centers

Estimation of 30 centers X 30 patients: 900 patients

Aims

Right ventricular dysfunction plays a fundamental role inheart failure pathophysiology and significantly impairs
patients outcome. Nonetheless, there is currently scarseknowledge on clinical correlates and predictors of rightventricular failure.
With the present multicenter prospective observational
study we aim therefore to:a) define correlates of right ventricular involvement,
among several clinical variables, in an unselected large
cohort of patients undergoing CABG;
b)identify predictors of future development of rightventricularsystolic

dysfunctioninpatients

withsignificant coronary artery disease who are undergoing
CABG operation.
Study design

Multicenter, prospective observational

Patients population

Patients who admitted for CABG from different European
Countries will be enrolled in the study.

Inclusion criteria- Patients will be distributed into two groups: a) patientswith normal ejection fraction (EF LV > 50%) and b)
patients with reduced ejection fraction (EF LV ≤ 50%)EACVI study – RV-CABG

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- Patients will be also distributed in two groups: a) those
who have CAD including severe RCA disease and b)
those who have LAD, Cx or LMS disease- Age >18 yrs;
- Ability to provide informed consent.
Exclusion criteria- Pulmonary embolism within the previous 6 months;- Known pulmonary hypertension- Need for inotropic support or for ventricular assist
device implantation;- Congenital heart disease;- Constrictive/restrictive/hypertrophic cardiomyopathy- Malignancy.
- Patients with redo or who had to be re-operated in thesame setting

Sample size

900 patients (≈ 30 patients/center)

Study duration

Enrolment: 9 months
Follow-up: 1 year

Power analysis

The power of the study was calculated by Dr.Bernard
North (Consultant in Statistical Genomics, Medical
Statistics, Imperial College of Science, Technology andMedicine). There is a justification of the sample size to be
employed as 200 patients for each group in order toachieve 95% power with significance α = 0.01 to detect a
difference of 15% in RV EDV with a standard deviationof the difference as 8%.

Statistical analysis

The value measurement will be performed with thestatistical model SPSS 13.0 and mean values of groups
will be compared with 2 tailed t test: standard deviations
between groups will be measured with the use of test chisquare. Correlations will be examined by multiple linear
regression. All data are expressed as mean ± SEM. A

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value of p<0.05 is considered statistically significant.
Very important is the study of reproducibility index
betweenthemeasurementsofintraobserver

andinterobserver. An observer should measure two values
and variability is defined as the mean value and thedifference between the standard deviation through thesegroups of values. Variability between two different
observers is described as the difference between pairs ofvalues and the mean value of these.
The assessment of RV will include: two dimensional
echocardiography,

real

time

three

dimensional

echocardiography and speckle tracking of LV and RV.
We will also measure routine blood and biochemical tests,
measurement of NT-proBNP, BNP in patients bloodplasma.
For a better estimation of life quality, the use of Kansas
City Cardiomyopathy quality of life questionnaire issuggested.
Blood tests for the measurement of biochemical values
should be taken every 6 months.
Furthermore, we will monitor intra-operative parameterssuch as cardiopulmonary by pass time or total time ofoperation.

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Workflow
Mandatory

Baseline

Follow-up

Visit

√

√

ECG

√

√

Echocardiography√√

Blood sampling√√

Cardiopulmonary exercise test√√

Spirometry√√

Cardiac magnetic resonance√√

Optional

List of abbreviations
CRF, care report formEF, ejection fracionFA, fractional area
HF, heart failure
LV, left ventricle
NYHA, New York Heart Association
PAP, pulmonary artery pressure
PSV, peak systolic velocity
RV, right ventricle
TAPSE, tricuspid annular plane systolic excursion
TDI, tissue Doppler imaging

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Prognostic indices of Right heart dysfunction in patients undergoing CABG
(RH-CABG study)

Background
Despite recent advances in pharmacological and non-pharmacological therapy, heart failure (HF)
still holds a poor prognosis and represents a major global burden in terms of morbidity andmortality. Left and right ventricular functions are strictly linked in HF pathophysiology and in thedevelopment of the HF clinical syndrome. The right ventricle (RV) can be indeed primarily
involved, for example as a consequence of RV infarction or following right sided valvular disease.
Most commonly, RV dysfunction occurs following the increase in right side pressures due toalterations in the systolic and/or diastolic properties of left ventricle (LV).
Patients with coronary artery disease who are undergoing CABG have a significant degree ofdiastolic impairment. Depending on several factors – which have not been clearly documented. Few
patients with a normal RV before CABG, may develop pulmonary hypertension and impaired RV
post CABG. The mechanism of development of RV dysfunction is still unknown and this will be
the aim of this study: to explore the mechanism of RV dysfunction development.
Imaging of the right ventricle
The difficult approach of right ventricle is an important factor, concerning the surveillance ofpulmonary hypertensives. It is the most anteriorly situated cardiac chamber, since it is locatedimmediately behind the sternum.21,22 It also marks the inferior border of the cardiac silhouette. In
contrast to the near conical shape of the left ventricle, the right ventricle is more triangular inshape when viewed from the front and it curves over the left ventricle. When seen from the apex,
the right edge of the right ventricle is sharp, forming the acute margin of the heart. In cross section
the cavity appears like a crescent. Thus, the curvature of the ventricular septum places the rightventricular outflow tract antero-cephalad to that of the left ventricle’s resulting in a characteristic“cross-over” relationship between right and left ventricular outflows. Two are the anatomic
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components that make right ventricle difficult to be examined in detail, especially when using two
dimensional echocardiography, the irregular shape of the cavity and the heavy trabeculation whichmakes difficult the identification of right ventricular borders.
Nowadays, the accuracy of measuring the right heart impairment due to the disease is offered by
two new methods, real time three dimensional echocardiography and cardiac magnetic resonanceimaging.

3-dimensional echocardiography
The most recent introduction of real time 3D echocardiography (RT3DE) has revolutionizedechocardiography as images may be obtained in just one beat. This has resulted in improved image
resolution, higher penetration and harmonic capabilities that may be used for both grey scale andcontrast imaging. The major advantage is that volumetric analysis does not rely on geometricassumptions, as has been the case with two dimensional echocardiography. Quantifications of LV
volumes and mass have successfully been performed and a similar approach can be applied for RV
remodeling in pulmonary hypertension.

Cardiac magnetic resonanceWith CMR, RV function can be evaluated in the short axis. This technique can also be used formeasurement of flow velocity and volume by phase velocity mapping.32,33 Phase velocity mappingis based on gradient – echo pulse sequences in combination with ECG triggering. The phase
contrast allows velocity encoding and therefore flow measurements. Despite the excellent image
quality and reproducibility, MRI has some disadvantages: the data acquisition and analysis israther time consuming, and some patients groups (for example, pacemaker patients) cannot
undergo MRI.

Speckle tracking
The speckle pattern can be used to track myocardial motion due to two facts about the speckle
pattern. The randomness of the speckle pattern ensures that each region of the myocardium has its
own unique speckle pattern: that can differentiate a region from other regions. It resembles mmode because the speckles follow the myocardial motion. By this, defining a region (kernel) in
one frame, this kernel can be identified as region in the next frame with the same size and shapeEACVI project RV-CABG

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with the most similar speckle pattern, and the motiuon of the kernel can be tracked from frame toframe. From this accumulation of regions, the search algorithm derives.
The algorithm for this seach is simple, it simply searches for the area with the smallest differencein the total sum of pixel values, the smallest sum of absolute differences (SAD). This has beenshown to be as effective as cross correlation. However, the speckle pattern will not repeat perfectly.
This is due to both true out of plane motion (rotation and torsion relative to apical planes andlongitudinal deformation relative to short axis planes) and to small changes in the interference
pattern. But the frame to frame change is small, and the approach to recognition is statistical. Thismeans, however, that the search should be done from frame to frame, the changes over longer timeintervals

will

be

to

great.

Speckle tracking has been validated by ultrasonomicrometry in the longitudinal direction as well as
for rotation. One great advantage is that it is angle independent and can be used to track in two
dimensions.
However, drop outs and reverberations will affect the tracking, and in the lateral direction low
lateral resolution will "smear" the speckles in the lateral direction, making tracing less perfect, as
can be seen above, where thacking in the inferior wall where lateral resolution is poorer, is lessperfect than in the septum where the sector is narrower and lines more dense, giving a better lateral
resolution.
Speckle tracking is frame rate sensitive:
1. Too low frame rate will result in too great changes from frame to frame, resulting in poor
tracking. This may also limit the use in high heart rates, as the motion and thus frame toframe change increases relative to the frame rate.
2. Too high frame rate is obtained by reduced lateral resolution, and thus resulting in poorer
tracking at least in the transverse direction.
Regarding RV dysfunction and heart failure
The presence of RV dysfunction in HF has been associated with adverse modifications inhaemodynamics and humoral response (Spinarova L et al, 2005). Preserved RV systolic function isa more potent predictor of event free survival in advanced HF than peak oxygen consumption (DiSalvo TG et al, 1995; Dokainish H et al, 2007). Several studies have demonstrated that impairment
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of RV systolic function has a profound impact on patients outcome and can predict death or cardiac
transplantation. Ghio and Colleagues have shown, for example, that in patients with severe LV
dysfunction (LV ejection fraction, LVEF, <35%) of either ischemic and non-ischemic etiology bothmean pulmonary artery pressure (PAP) and RVEF are be independent predictors of survival (Ghio S
et al, 2001).
To date, the largest set of data on the prognostic role of RV failure has been obtained from a
post-hoc analysis of the BEST trial (Beta-blocker Evaluation of Survival trial). In this study, RV
systolic function was estimated in more than two thousands patients with severe HF by means ofradionuclide ventriculography (Meyer P et al, 2010), and RVEF <20% was independently
associated with the combined end-point of HF mortality and hospitalisation, after adjustment forother co-variables including LVEF. More recently, Gulati has confirmed the predictive value of RV
function on all-cause mortality and cardiac transplantation in 250 patients with non ischemic dilated
cardiomyopathy (Gulati A et al, 2013). Noteworthy, in this study assessment of RV systolic
function was performed by means of cardiac magnetic resonance imaging, currently representing
the gold standard for the morphological and functional evaluation of RV. Nonetheless the majorityof the evidence for the prognostic role of RV failure originates from studies in which RV systolic
function has been evaluated with echocardiography. Some of them have used RV fractional area
(RVFA) or tricuspid annular plane systolic excursion (TAPSE) obtained with bidimensional or Mmode echocardiography, respectively, as an estimate of RV systolic function (Di Salvo TG et al,
1995; de Groote P et al, 1998; Kjaergaard J et al, 2007; Dini FL et al , 2007; Dini FL et al, 2008),
while some others relied on echocardiographic markers of RV systolic function based on tissue
Doppler imaging (TDI) (Dokainish H et al, 2007; Meluzin J et al, 2003; Meluzin J et al, 2005;
Bistola V et al, 2010). Damy and Colleagues have compared the prognostic value of different
echocardiographic indices of RV systolic function, including RVFA, TAPSE, peak systolic (PSV)
and integral systolic wave velocity of tricuspid annulus, in a cohort of 136 patients with severe HF(LVEF <35%). The Authors report (after adjustment for other clinical, biohumoral andechocardiographic variables) that PSV (threshold value: 9.5 cm/sec) was the only independent
predictor of the composite end-point of death, urgent heart transplantation or LV assist device
implantation and acute heart failure. Currently, TAPSE represents the most widespread estimate of
RV systolic function and, although it assumes that displacement of the basal RV segment is

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representative of the function of the entire ventricle, it is a simple, reproducible method, lessdependent on optimal image quality.
This amount of evidence-base supports a role for RV function, independently from LV
systolic and diastolic impairment, in the identification of HF patients at higher risk for
cardiovascular events. Despite the significant pathophysiological and clinical implications of RV
involvement and its key prognostic value in patients with HF, the current clinical guidelines for HF
management and recommendations for pharmacological and non pharmacological therapeutical
approaches, are not substantially influenced by the coexistence of RV dysfunction, according tocurrent guidelines on HF management (McMurray JJ et al, 2012). In this view, the identification ofclinical correlates of RV dysfunction may help to clarify pathophysiological mechanisms
undelrlying the development of RV dysfunction. This may help to delineate the profile of thepatient with biventricular failure with the possibility of tailoring therapy in the future.
Although few retrospective single-center studies have investigated determinants of RV
failure in selected cohorts of HF - describing associations with pulmonary capillary wedge pressure,anemia (Guglin M et al, 2012), LV diastolic dysfunction, tricuspid regurgitation (Berkowitz R et al,2010), pulmonary artery pressure (Grose R et al, 1983), ventricular dyssynchrony (Gupta S et al,2008) or NYHA functional class (Ereminiene E et al, 2012) - clear data are currently lacking.
Similarly, despite the prognostic relevance of RV involvement in HF, informations on predictors of
future development of RV systolic dysfunction are limited to patients with acute myocardial
infarction or those implanted with a ventricular assist device (Azevedo PS et al, 2012; Drakos SG etal, 2010).
Aims
With the present study we aim therefore: to define prognostic indices of RV dysfunction in a large cohort of CABG patients;
 to associate echocardiographic predictors with clinical/hemodynamic data.
Study design
Patients admitted for CABG from 30 centers between December 2015 and August 2016 will beenrolled in this multicenter prospective observational study, according to the following criteria.

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Inclusion criteria- Patients will be distributed into two groups: a) patients with normal ejection fraction (EF LV >50%) and b) patients with reduced ejection fraction (EF LV ≤ 50%)
- Patients will be also distributed in two groups: a) those who have CAD including severe RCA
disease and b) those who have LAD, Cx or LMS disease- Age >18 yrs;
- Ability to provide informed consent.

Exclusion criteria
Pulmonary embolism within the previous 6 months;- Known pulmonary hypertension- Need for inotropic support or for ventricular assist device implantation;- Congenital heart disease;- Constrictive/restrictive/hypertrophic cardiomyopathy- Malignancy.
- Patients with redo or who had to be re-operated in the same setting
Patients will receive an extensive clinical examination, including history, anthropometriccharacteristics, symptoms, pharmacological and non-pharmacological therapy. All subjects will also
be submitted to transthoracic echocardiography, with assessment of RV systolic function by meansof a multiscoring system. Patients data will be used for the purpose of the study only if obtained
within 30 days. Anonymisation of data will be obtained.
Clinical and echocardiographic characteristics of patients with impaired RV function will be thencompared to those of patients with preserved RV systolic function. Clinical correlates of RV
dysfunction will be identified among all mandatory variables assessed at baseline evaluation.
A follow-up clinical, electrocardiographic and echocardiographic evaluation will be performed at 6
and 12 months after CABG operation in order to verify changes in RV systolic function. Predictorsof future development of RV failure will then be identified among variables considered at baseline
evaluation.
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Data acquisistion
Patients clinical, biohumoral and istrumental data will be collected through CRF.
Accuracy of data will be verified and CRF will be filled by investigators in each center.

Exit criteria
At any time during the protocol patients may choose to leave the study without any penalty or lossof benefits to which they are otherwise entitled and will continue to receive standard of medical
care.

Sample size estimation and statistical analysis
Assuming 30 participating Centers all over Europe and 30 patients recruited by each center in the 9months enrolment period, the estimated size of the study population is ≈900.
Variable distribution will be reported as mean and standard deviation (normally distributed
variables), median and interquartile range (non-normally distributed variables) or as percentage(cathegorical variables). Comparison between groups will be performed with Student T test for
unpaired data or with analysis of variance and Bonferroni correction. Categorical variables will becompared with Chi-square test (with Yates correction) or with Fisher test.

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Correlates and predictors of right ventricular dysfunction will be identified by means on logistic
univariate analysis. Univariate correlates/predictors will then enter a multivariable model. All
statistical tests will be 2-tailed. A p value of <0.05 will be considered as statistically significant.
Expected value of results
The study will have a great input in predicting the patients who will develop RV dysfunction post
CABG. Therefore, it may have a great impact on their management (percutaneous intervention or
CABG consideration beforehand) or even pharmacological management afterwards (for example
initiation of ACE inhibitors).
Confidentiality
Patients data will be collected in a central electronic database under the responsibility of EACVI.
All data will be anonymized and access to the database will be protected by a personal password
provided to principal investigators.

Centers participating to the study
The following Centers will participate to the study by recruiting patients:
1.
2.
3.
4.
5.
Steering committeeIntellectual property

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The property of study data will be shared among participating centers. Data will be published (inform of presentation in nationa/international meetings or as full paper) after anonymization,
statistical analysis, and independently from results.

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