Off-pump left ventricle reconstruction using the Revivent Myocardial Anchoring System in patients with severe ischemic cardiomyopathy.

In western countries, heart failure is a major health issue. The combination
of an aging population and more effective treatment of its precursor - MI -
make heart failure (HF) a growing health problem. Improved reperfusion therapy,
by means of catheterization (PCI), in the acute stage of myocardial infarction
(MI) and standardized use of post-infarction cardioprotective medication has
led to a sharp decline in mortality. As a result, the incidence of patients
with ischaemic cardiomyopathy (ICM) has increased. In the western world, the
prevalence of HF can be estimated at 1-2% and its incidence is 5-10 per 1000
persons per year. Left ventricular remodelling, a pathological process that
follows MI, occurs in more than 30% of patients treated with acute
reperfusion therapies and cardioprotective medications. Cardiac remodelling is
a process which leads to alteration in the size, shape, structure and function
of the ventricles. Remodelling in non-infarcted myocardium is initiated and
sustained by chronic haemodynamic stresses on the heart. As a result, the
failing heart becomes less elliptical and more spherical. The heart enlarges to
increase ventricular volume which leads to greater systolic volume and higher
cardiac output despite reduced ejection fraction (EF). Remodelling is also
characterized by gradual accumulation of DMF in non-infarcted myocardium. Left
ventricular remodelling is associated with progression of HF and a poor
prognosis. Another adverse effect of LV enlargement is mitral valve
regurgitation. Ischaemic mitral valve insufficiency is a ventricular problem
and is associated with progression to heart failure.

The gold standard modality used to quantify the extent of postischaemic
scarring, DMF and remodelling, is cardiovascular magnetic resonance imaging
(CMR). Various parameters that are used to evaluate heart failure are measured
using CMR. A powerful marker of LV remodelling is the left ventricular (LV)
end-systolic volume indexed to body surface area (ESVI). An LVESVI >60ml/m2
(normal =25ml/m2) is associated with a fivefold increase in mortality. It is
a valuable predictor of hospitalization for heart failure, even in patients
with a normal ejection fraction (EF) . The most commonly used index for left
ventricular function, is the EF. Two important mechanisms underlying heart
failure with reduced EF are: poor contractile function due to extensive
myocardial damage and LV dilatation caused by infarct expansion and stretching
of the myocardial scar. A left ventricular EF < 40% is associated with
impaired LV function.The alternative for CMR is the cardiac CTA. The cardiac
CTA has a good correlation with MRI in measurement of LV volume, LVEF and
extent of postischaemic scar. Most of the patients who meet the inclusion
criteria of this study, have a cardiac device. Ischaemic mitral valve
insufficiency, which affects 25% of patients after MI, results from annular
dilatation and remodelling of the subvalvular apparatus. The presence of even
mild mitral insufficiency is associated with reduced survival rates.

The N-terminal prohormone of brain natriuretic peptide (NT-proBNP), troponin I
(trop I), galectin-3 (Gal-3) and creatinine are important biomarkers of heart
failure. The biomarker profile of a patient has prognostic importance and
correlates with the severity of heart failure. Furthermore, diastolic
dysfunction can be found in a heart failure population with normal or
preserved left ventricular EF .
Patients with ischaemic heart failure are at high long-term risk for morbidity
and mortality. Heart failure leads to shortness of breath, fatigue and reduced
exercise capacity as a result of LV dysfunction. Pulmonary congestion,
dysrhythmia and peripheral oedema occur as HF progresses. The elderly are
primarily affected by this chronic disease and it is one of the main causes of
hospitalization in this group of patients . Among this population, the 5-year
mortality is 50-77%, with sudden cardiac death or uncontrolled symptoms of
heart failure being the predominant cause of death. Recent HF guidelines
accentuated the importance of the early identification of high risk patients
for morbidity and mortality from HF, not only for prevention and effective
treatment but also for regulation of healthcare costs associated with treatment
of this group of patients.

The medical management of ischaemic HF includes: heart failure medications,
cardiac-assist devices, heart transplantation and left ventricular assist
devices (LVADs). These are important therapies for ischaemic HF, but are beyond
the scope of this study and will not be discussed in detail.

1. Surgical Ventricular Reconstruction
Surgical ventricular reconstruction (SVR) can be used to treat ischaemic heart
failure due to systolic dysfunction following anterior MI and LV dilatation. By
excluding the MI scar, the relationship between function and structure is
restored. SVR rebuilds the failing heart to reconstruct the natural elliptical
configuration from the dilated spherical form. This procedure is often
performed concomitantly with an intervention on vessels and valves. The early
and late benefits of SVR have been consistently reported in various studies.
Although refuted in randomized trials, this procedure results in definitive
improvements in QoL .

There are various approaches to SVR but these will not be discussed as they
are beyond the scope of this study.

2. Revivent Myocardial Anchoring System
The Revivent device was developed by BioVentrix and obtained the CE mark in
2012. This device has been developed to reconstruct the LV in a minimally
invasive way in patients with ischaemic cardiomyopathy. The study performed in
order to obtain the CE mark for this new technique has already shown favourable
results. The Revivent System has been implanted in 60 patients with ischaemic
HF. Results obtained after 1 year showed a reduction of 35% in LVESVI, a 15%
improvement in LVEF, a one grade reduction in NYHA classification, a 20%
improvement in 6-minute walking scores, and a 32% improvement in quality of
life scores.

To study patients with severe HF who would benefit from off-pump SVR using
the Revivent Myocardial Anchoring System. To investigate the characteristics of
the ischaemic heart using CMR or cardiac CT in order to verify patient
eligibility for the Revivent System. To analyze the characteristics of
patients with severe ICM who would profit from the less-invasive SVR with
Revivent System.

The study will be a prospective, non-randomized , single-armed cohort study of
patients with ischaemic HF. It is designed to investigate the new less-invasive
technique for LV reconstruction. During a follow-up period of 1 year, patient
outcomes after the Revivent System implantation will be monitored. Patients
giving informed consent agree to the implantation of the Revivent System and
will undergo clinical tests at certain intervals (prior to the operation,
during the procedure and hospital admission, at discharge, 30 days, 6 and 12
months after the surgery). Patients will also consent to the collection of
clinical data at these intervals. This study will have no control group.

The Revivent device will be used for surgical restoration of left ventricle.
This device can be used to place permanent cardiac implants into the heart for
the reduction of the LV volume in patients with ischaemic heart failure. The
system utilizes anchors that are implanted into the scarred area of the heart,
which, when deployed, exclude some of the scarred area from the ischaemic
event. This procedure is performed in a surgical setting without the use of
cardiopulmonary bypass. The Revivent components consist of a series of
catheters and anchors that are deployed under fluoroscopic imaging and TEE. The
implantation of the Revivent device can be performed as a stand-alone procedure
through sternotomy or in combination with other cardiac surgery.

This technique needs no cardiac incision and allows major reconstruction of
the LV on a beating heart in a short time span.


The Revivent System consists of implantable components and a series of anchors.
The anchor pairs are connected to each other by an adjustable *length Tether.
The distance between anchors is variable and determined by the position of the
Locking Anchor on the Tether. The Hinged Anchor is hinged to facilitate
low-profile passage through a catheter that is inserted perpendicularly to the
septum, after which it can be pivoted 90° to lie flat on the septum; the
Locking Anchor houses a cam-based reversible locking mechanism allowing
apposition of the two anchors at a continuum of positions. Once the proper
distance between the two is established, excess Tether length is cut and
removed.

Cardiac CTA: balancing risks and benefits

Patients undergoing a cardiac CTA are exposed to a high radiation dose.
Radiation dose exposure has been associated to an increased risk of developing
a radiation-induced cancer 27,28. Therefore, the potential benefit of CTA for
assessment of cardiac function and shape have to be carefully weighed against
the potential risks.
Cardiac CTA is a non-invasive, patient-friendly imaging modality to investigate
LV geometry and function but require a high dose of radiation. For this
reason, in this study the cardiac CTA will be performed only by patients with
MRI incompatible ICD*s or CRT*s. Unlike the MRI group, the operation indication
will be determined by means of the already existing imaging. Due to potential
risk of cardiac CTA, all efforts will be made to ensure that the most eligible
candidates for the operation undergo the CTA. Basically, patients undergoing a
cardiac CTA will undergo the operation. Patients with a cardiac device and yet
meeting the inclusion criteria are at the end stage of heart failure. Though,
there is a potential risk attached to cardiac CTA, the surgical team believe
that they will benefit from the operation. The potential benefit of minimal
invasive SVR and potential risk of radiation will be assessed for each
individual patient. All efforts will be made to recruit patients with a
MRI-compatible cardiac device to avoid the use of ionizing radiation. In the
worst case, the cardiac CTA has to be performed by the whole study population
(n=10). The potential lifetime-attributable risk (LAR) of cancer for cardiac
CTA differs considerably with age and sex 28. The LAR is high for younger age,
women (due to risk of breast cancer in addition to lung cancer) and for
combined cardiac and aortic scanning. The risk is markedly lower for old
patients due to declined radiosensitivity of many organs and the long latency
period from radiation exposure to development of malignancy. It is important to
take the potential risk of dying from cancer in perspective relative to the
poor prognosis of advanced heart failure. Furthermore, most of the eligible
candidates with advanced heart failure are above the age of 60,which is a less
vulnerable group of patients for radiation-induced cancer. The standard
exclusion criteria for cardiac CTA like renal dysfunction, intolerance for
iodinated contrast, contraindication for *-blocker, rapid ventricular response
during atrial fibrillation and frequent atrial or ventricular arrhythmias will
be taken in account while selecting these patients.
To reduce radiation exposure, the CTA will be performed only at the beginning
and end of the study. Prior to the operation, it is significant to image the
function and dimension of the left ventricle. Accurate measurements of the
LV and localisation of the postischaemic scar are extremely important for the
LV reconstruction with the Revivent System. Due to rapid developments in
cardiac CTA technology, is the image quality and value of CTA almost
comparable to the MRI which is the gold standard. The echocardiogram is the
most often used method to measure LVEF. This technique has auditory, technical
and operator limitations. The LV volume measurement is based on assumption of
the LV shape. The measurement of LV volume is not accurate in case of patients
with altered LV geometry. Another imaging modality to measure the cardiac
function is the radionuclide techniques and invasive contrast
ventriculography (CVG). The nuclear imaging has technical limitations and CVG
is invasive test with low reliability. New developed and other methods to
measure LV volume and LVEF will not be discussed since they lack accuracy . As
mentioned earlier, the CTA will be repeated at the end of the study for
accurate assessment of the cardiac functional parameters after the
operation. We make every effort to avoid unnecessary repeating the CTA. At the
moment the radiation dose for cardiac CTA is about 10 millisieverts (mSv). From
July 2015, low dose cardiac CTA*s will be possible due the availability of the
new scans at AMC . Postoperative will all the patients receive cardiac CT with
low dose of radiation.


Risk and Benefit Analysis

Depending on the condition of the patient, the surgeon and the treating
cardiologist may recommend that a minimal invasive SVR with the Revivent System
be carried out. They believe that it is the most suitable treatment for the
patients with benefits which have already been proven. However, all cardiac
operations carry certain risks. Some serious complications may even result in
death. These complications are typical and anticipated. Although the majority
of the following events were not observed in previous studies, the following
are considered potential adverse events of the SVR with Revivent System:

* Risks associated with surgery, general anaesthesia, and median sternotomy
* As with any medical device, durability of the implant materials
* Device(s) implanted into the heart that may require removal
* Unintended perforation of the heart wall
* Damage to another structure, such as a valve or the conduction system
* Erosion of the device through adjacent tissue
* Infection due to the presence of a foreign body in the heart tissue
* Patient re-operation that is device-related
* Bleeding
* Embolism
* Mortality
*Radiation induced skin reaction

The risk of this technique is comparable with less-invasive cardiac surgery.
Patients who consent to participate will undergo operation and will be required
to attend hospital appointments and follow-up exams. MRI has no associated
health risks. MRI does not require ionizing radiation, and gadolinium contrast
is well tolerated with only very rare cases of gadolinium allergy reported in
the literature. For each individual study participant, the MRIs will yield
useful information that can be used for the patient*s clinical follow-up.
Further, the follow-up will include some routine exams and will be performed in
order to evaluate the clinical condition and cardiac function before, during
and after the operation. The follow-up period will be 1 year. Clinical
evaluation and tests performed during the follow-up period are non-invasive and
generally considered standard care for severe heart failure patients.
Therefore, there is no specific risk associated with these.

Prior to enrolment, the surgical team will clearly define the indications and
contraindications criteria to ensure that only appropriate patients enter the
study. The procedure will be performed by one experienced cardiac surgeon. He
will ensure that treatment and follow-up are consistent with current medical
practice. It is evident that every effort will be made by surgeon to minimize
the risks for the patient receiving the Revivent device. The follow-up will
allow careful monitoring of each patient, which may lead to prompt treatment
adjustments where necessary.
This study will introduce off-pump left ventricular reconstruction using the
Revivent System as a potential new treatment option for patients with ischaemic
HF. It is expected to reduce the need for implantable cardiac devices, LVADs
and heart transplantation, which will lead to decrease in healthcare costs in
this group of patients.