The pressure overloaded right ventricle: a deformation imaging study

Patients with pulmonary hypertension (PH) have a poor prognosis, with pulmonary
arterial hypertension (PAH) having a 3-year survival in the current medical era
ranging from 58.2-72.1%. The main reason for death in PH patients is failure of
the chronically pressure overloaded right ventricle (RV). In patients that have
a chronically pressure overloaded right ventricle due to congenital heart
disease (CHD), however, time to RV failure is much longer, generally occurring
in the 3rd to 5th decade of life depending on the underlying pathology.
Apparently, the possibility to adapt to an increased afterload is less for a RV
that has been subject to normal afterload for years, than for a RV that has
never known a normal low afterload. A logical explanation for this difference
would be that a structurally different composition of the myocardial wall is
present, which gives rise to different contraction patterns and different
endurance to the high afterload. A second possible explanation would be a
difference in metabolic response of the myocardium and a difference in
ventilatory capacity between these different patient groups.
Over the last years, imaging studies and anatomical studies have provided
indications that the RV contraction pattern changes in response to high
pressure, from a longitudinal to a more circumferential contraction pattern.
Furthermore, it was also found that the myocardial wall is structurally
different for right ventricular hypertrophy (RVH) seen in Tetralogy of Fallot
(ToF) patients. However, whether this is true in all patients with chronically
pressure overloaded right ventricles due to congenital heart disease, let
alone, in patients with PH, is as yet unknown. Recently, several new imaging
techniques to evaluate RV myocardial structure and contraction have emerged,
such as tagging on Magnetic Resonance Imaging (MRI) and three-dimensional (3D)
speckle tracking on echocardiography. Furthermore diffusion tensor imaging
(DTI) on MRI is being applied in hearts and has been validated in both
ventricles, ex vivo and, in experimental setting, in vivo. This will not yet be
part of the current protocol because the abilities to do this in vivo are still
in under development and would vastly prolong the scan time. Using MR tagging,
lung perfusion scanning, gadolinium late enhancement and spectroscopy, we thus
aim to describe the RV myocardial structure, RV contraction pattern, proximal
pulmonary vasculature, and lung perfusion in patients with PH, in patients with
a pressure overloaded RV due to CHD, and in healthy volunteers. Conceivably,
following comparison of parameters derived from these new techniques between
the patients groups, differences in RV structure and contraction may be
unveiled. All imaging modalities reflect the function of the heart in a resting
condition. However it is also important compare how the heart reacts to stress,
as this does not always correlate to cardiac function in rest. Therefore
patients will be asked to participate in a cardiopulmonary exercise testing
(CPX). Also we can use these results to investigate the correlation of cardiac
function during exercise to the echocardiographic and MR derived functional
parameters (in rest).
More insight in to the underlying RV pathophysiology may help in better
understanding the course of the disease, adaptive abilities of the heart as
well as generate new insight into treatment.

Secondly, even though many studies have attempted to find prognosticators in PH
patients. Up to now no good early and non-invasive predictors for a more rapid
deteroriation are available. Only a few two dimensional (2D) echocardiographic
prognostic markers have been identified so far: Tricuspid annular plane
systolic excursion (TAPSE) < 20 mm, Indexed right atrial area and pericardial
effusion.18 But these parameters are also markers that arise late in the
disease course. This study will focus on 2D and 3D speckle tracking, as these
techniques have proven, in other patient groups, to be able to detect subtle
and subclinical RV dysfunction more sensitively than the above mentioned
parameters.
CPX, measuring: maximum oxygen uptake (VO2max), relation between ventilation
and carbon dioxide production (Ve/VCO2), anaerobic threshold, stroke volume and
rate of pressure rise (dP/dt), can also detect subtle deterioration in
different patient categories. These measurements have shown predictive value in
patients with congenital heart disease, heart failure and a recent review
recognized that this technique can provide valuable information in patients
with PH and that further prognostic research is needed in this field.19-22
The PH patients - group 1 or 4 - will therefore be followed during two years,
using the endpoint *clinical worsening* as defined in the statistics section,
to determine which echocardiographic parameters and which parameters derived
from cardiopulmonary exercise testing have (additive) predictive value. And as
important: to determine the prognostic significance of deterioration in these
parameters. Known predictors will be recorded in our database, derived from the
patient*s file: 6 Minute Walking Test (6MWT), hemodynamic parameters (when
measured) and NYHA class and NT-proBNP.

Thirdly, 3D speckle tracking of the right ventricle is a novel technique which
has not been validated satisfactorily. Nor has it been used in studies large
enough to establish reference values. Therefore, we aim to validate this new
technique through comparison with MR tagging as a reference and to establish
its clinical utility - by means of feasibility and reproducibility - in healthy
controls and patients with right ventricular pathology. Furthermore we will use
Ventripoint, a system using 2D echocardiography in a 3D magnetic space to
determine anatomic landmarks and reconstruct RV volumes and EF, will be
validated against MR data.

1. To characterize and compare RV myocardial structure, contraction patterns,
and functional capacity of (A) PH patients (group 1 or 4, the latter are to be
inoperable), (B) patients with pressure overloaded RV due to CHD and (C)
healthy controls.
2. To evaluate the prognostic value of 2D and 3D echocardiographic parameters
(emphasizing on deformation imaging) and of cardiopulmonary exercise
parameters, for time to clinical worsening in PAH patients.
3. To validate RV 3D speckle tracking against MR tagging in healthy controls
and patients with RV dysfunction and to asses its clinical utility by means of
feasibility and reproducibility.
4. To establish reference values for the novel 3D speckle tracking of the RV
and to provide the first data on 3D speckle tracking in RV dysfunction.

Observational study, partly cross sectional (CHD patients and healthy controls)
and partly follow-up (PH patients).

The risk associated with participation is considered to be very low. Gadolinium
is considered a safe contrast medium with very low complication rate (< 1 on
10.000 with serious adverse event).26 The risk associated with insertion of an
intravenous (i.v.) catheter is negligible. Furthermore a very small risk of
complication was reported during and directly after a symptom-limited maximal
cardiopulmonary exercise test. A trial evaluating over 6000 exercise test
reported no serious adverse events. During a safety trial in heart failure
patients (over 4000 tests), both ventricular tachycardia and fibrillation
occurred once and were successfully converted. However this test is also part
of standard follow-up in PH patients and CHD patients.
For all participants the major burden will be time-related. For healthy
controls this will be a one-time visit of 2 hours. This will consist of; 15-30
minutes for short physical examination, history and ECG, 45 minutes for
echocardiogram and 60 minutes for MRI.
For the congenital heart disease group this will also be a one-time visit with
an additional cardiopulmonary exercise test, cumulating to about 2.5 hours
(excluding travelling time).
The PH patient group will be asked to pay two visits to the UMCU, the first
visit will be approximately 2.5 hours (MRI, echocardiogram, exercise test), the
second visit 1 hour (only echocardiogram). Note that only the first 17 patients
with PAH associated with connective tissue disease (CTD), the first 17 CTEPH
and the first 17 with Eisenmenger's syndrome will be asked to undergo MRI.
For CHD patients and, partly, PH patients the results of echocardiogram, MRI
and cardiopulmonary exercise test are also part of the regular patient care and
will be available for treating physicians and recorded in the patient file. All
investigations will be planned in consensus with the patients to minimize the
burden as much as possible.
Patients and healthy controls have no benefit for participating in this study.
The results are mostly important for scientific purposes; to gain more insight
into the adaptive mechanisms of the heart and a better understanding of the
various disease processes. Furthermore there is a possible advantage for future
PAH patients as these new insights might yield new focus areas for therapy.
Prognostic parameters are also very important since they aid physicians in
making decisions for the individual patient (therapeutic/diagnostic).
Even though there are no direct advantages for participants, we believe the
burden of participation is rather minimal, thereby justifying participation.