LV flow patterns in systolic heart failure: A new aspect elucidated by high-frame rate echocardiography (PHRAsE study)

Despite improvements in the treatment of virtually all cardiac disorders,
prevalence of systolic and diastolic heart failure (HF) is still rising.
According to a recent report of the *Rijksinstituut voor Volksgezondheid en
Milieu*, approximately 130.000 people in The Netherlands are diagnosed with HF
in 2012 and this number is expected to increase to 195.000 in 2025. The current
treatment of patients with heart failure consists of optimal medical treatment
and in selected patients cardiac resynchronisation therapy (CRT).
The enthusiasm for the striking effectiveness of cardiac resynchronisation
therapy (CRT) in patients with heart failure and ventricular conduction
disturbance has been tempered by the observation that a variable proportion of
eligible patients fail to benefit from this treatment, the so-called *non-
responders*. The commonly mentioned percentage of non-responders is about 30%
and might be higher compared to the response to drugs. For a treatment that
involves a relatively expensive therapy and that requires essentially life-long
implantation of a device and leads, an almost perfect response would be
desired.
The problem of non-response to CRT is increasingly important, because it is
anticipated that larger groups of heart failure patients are indicated to the
therapy, due to inclusion of patients with New York Heart Association (NYHA)
functional class I or II, as according to the European guidelines.
Today, according to these guidelines, the selection criteria for CRT in patient
with heart failure heavily rely on the initially QRS duration and the present
of a left bundle branch block configuration on the ECG indicating the severity
of conduction disturbance.
With the problematic prediction of indicators of mechanical dyssynchrony in
mind,
echocardiographic indicators might serve to further support the assessment of a
LBBB-like
conduction disturbance and predict if a patient is a responder or not. In this
regard, not all-mechanical dyssynchrony indicates a substrate that is amenable
to CRT.

Current experience with contrast echocardiography and vortex imaging
Feinstein initially described the use of contrast-enhanced ultrasound of the
left ventricular opacification.(ref) The ASE and EAE guidelines have
recommended CE to improve LV endocardial visualisation. Beside this option
there is a growing interest in vortex imaging of the left ventricle by using
the micro particles of the echo contrast. Intraventricular fluid dynamics can
be assessed clinically using echocardiography. With the newer techniques like
particle image velocimetry (PIV) adapted to echocardiography (Echo-PIV) would
increase the evaluation of the blood flow in the left ventricle. Previous in
vitro study of Wong et al described the importance of LV vortex in preventing
of flow stasis. Blood flow in a healthy human left ventricle forms an
energetically efficient vortex. This vortex facilitates inflow into the
ventricle, minimizes the dissipation of energy, preserves momentum, and
redirects the flow toward the left ventricular outflow. Valvular heart disease
and ischemic heart disease change the vortex configuration and increase
dissipative energy loss. Several intracardiac flow visualization technologies
have emerged recently, among which is LV flow mapping with high-frame rate
echocardiographic technology. The present study is designed to implement a
novel method for analysis LV flow pattern with high frame rate echocardiography
and intend to improve patient selection and reduce the proportion of
non-responders to CRT.

This will be a prospective and observational study.

Primary Objective:
* To explore the value of LV flow pattern with high-frame rate echocardiography
in patients with systolic heart failure and relate the flow patterns to CRT
response.
* To assess if LV flow pattern provide insight into the hemodynamic mechanism
of LV failure and disease progression
* To obtain individual quantitative metrics of global and regional vortex flow
measurements in the LV.

Secondary objective:
* To determine the difference in LV flow patterns in patients before and after
resynchronization therapy (CRT).
* To assess LV flow patterns in the settings of the biventricular pacemaker for
optimal cardiac output.

Tertiary objectives:
* To obtain LV myocardial perfusion with contrast and high-frame rate
echocardiography.

Prospective and observational cohort study.

Duration: 36 months.

Setting: Outpatient clinic of an academic hospital. The additional measurements
proposed in this protocol are a minor extension to the conventional
echocardiographic exam for which the patients are visiting the outpatient
clinic.

Methods
A. Pilot study:
The pilot study will consist of 20 patients with reduced LV systolic function
(ejection fraction <40%) at baseline echocardiography. Patients with
significant atrial or ventricular arrhythmia, significant valvular disease (of
greater than moderate severity), or inability to obtain adequate
echocardiographic examination will be excluded. All patients are regularly seen
at the outpatients clinic of Erasmus MC.

B. Consecutive study:
The consecutive study will include 100 patients The study population consists
of 30 patients with heart failure and CRT, 30 patients with heart failure and
no CRT, who also undergo cardiac MRI for clinical indication, and 40 patients
with heart valve pathology. All patients are regularly seen at the outpatients
clinic of Erasmus MC. Patients with acute coronary syndrome, or coronary
revascularization within 6 months before CRT were excluded.

Protocol pilot study: During a regularly outpatients visit, a standard Doppler
echocardiographic examination, including real-time 3-dimensional
echocardiographic study and intra-cardiac blood flow velocity will be assessed
during biventricular pacing, only right ventricular pacing and if there is an
adequate escape rhythm the echocardiographic examination will also be performed
with no pacing of the CRT. Patients will be asked if clinical data from the
clinical interview and physical examination may be retrieved from the medical
files. The study is an observational diagnostic study, physical and
physiological discomfort for the patients is limited.

Protocol consecutive study:
The consecutive study will include 100 patients. A standard Doppler
echocardiographic examination, including real-time 3-dimensional
echocardiographic study will be performed. To obtain the high-frame rate images
of the LV intra-cardiac blood flow velocity and LV myocardial perfusion,
contrast will be injected. High-frame rate echocardiographic images with
contrast will be obtained. For the 30 patients with heart failure and CRT,
high-frame rate echocardiographic images will be obtained during three fases:
1. during biventricular pacing, 2. only right ventricular pacing and 3. if
possible during no pacing. Every fase will take approximately 10 minutes. The
differences in LV intra-cardial flow velocity and LV myocardial perfusion will
be assessed in all different fases.
The first part of the study is explorative. We will develop a scoring system to
assess LV vortex flow and velocity parameters. This scoring system will be used
to evaluate the differences between de pacing settings and between de
nonresponders and responders for CRT.

The burden of the study procedures consists of extension of the
echocardiographic study which the patient undergoes during the regular visit to
the outpatient clinic. Patients will be invited to
participate and with permission of the patient clinical data from the clinical
interview and
physical examination may be retrieved from the medical files. The study is an
observational
study, physical and physiological discomfort for the patients is very limited.
The
ultrasound contrast agent is safe and registered for the use during
echocardiography.(ref.)
There is a small risk of an allergic reaction after administration of
ultrasound contrast agent
(0.01%).20 During all examinations a medical doctor will be present to react
immediately in
case of an allergic reaction. Additional blood tests will not be required. The
risks associated with participation can be considered negligible and the burden
can be considered minimal.