Introduction
Heart Failure (HF) is one of the leading causes of death
worldwide.1According to the National Health and Nutrition Examination Survey data
from the United States, an estimated 6.2 million adults presented with
HF between 2013 and 2016 compared to 5.7 million between 2009 and
2012.1While various treatment strategies have been implemented to improve
symptoms and decrease mortality, cardiac transplantation remains the
treatment of choice for patients with advanced refractory
HF.2
Over the last two decades, the number of suitable donor hearts has
plateaued while the demand for organs continues to
increase.3This has motivated strategies to expand the donor pool such as the
utilization of hearts procured through donation after circulatory death
(DCD). The main burden to donor heart harvesting after DCD is the warm
ischemia occurring between the withdrawal of life sustaining treatment
and reperfusion or
cardioplegia.4Although cold ischemic storage is the universally accepted method of DCD
heart preservation, it is not ideal. Low levels of anaerobic metabolism
continue in the background with subsequent depletion of adenosine
triphosphate (ATP) stores and an increase in
acidosis.5 Combined
with the warm ischemic insults already impacting DCD donor hearts, this
may significantly decrease organ function after
transplant.6Therefore, it is critical in this scenario to improve myocardial
preservation and reperfusion prior to transplantation.
Ex situ heart perfusion (ESHP) has been introduced as a technique with
the potential to improve heart transplant outcomes by reducing cold
ischemic time and supporting aerobic metabolism, thereby allowing better
and longer allograft preservation between retrieval and
implant.7,8The Organ Care System (OCS) is currently the only available system for
clinical human ESHP. It allows the preservation of a donor heart in
Langendorff (LM) or resting mode. LM consists of delivering perfusate in
a retrograde fashion from the aortic root to the coronary arteries
without loading the left ventricle (LV) and relies solely on metabolic
parameters such as lactate extraction to determine if the heart is
suitable for
transplant.9Given the lack of ventricular loading, the OCS is not suitable to assess
myocardium function at this
time.10As a result, several groups are in the process of developing new ESHP
systems to assure more physiological allograft perfusion with
ventricular loading to allow functional assessment and quantification of
cardiac mechanics in order to predict organ suitability for
transplant.11,12
Heart function is determined by a complex interaction between preload,
afterload, heart rate and the inotropic state of the myocardium. Our
group has developed and validated a novel modular ESHP system to allow
functional donor heart evaluation with biventricular loading (working
mode).13–15This novel modular ESHP system can produce physiological hemodynamic
characteristics and evaluate contractile parameters in both the left and
right ventricles of adult-sized porcine hearts in three different modes:
LM, biventricular Pump Supported Working mode (Bi-SAM) and biventricular
Passive Afterload Working Mode (Bi-PAM). During LM, oxygenated perfusate
is pumped retrograde by a centrifugal pump into the aorta at a constant
pressure of 50 mmHg that results in aortic valve closure and perfusate
flow into the coronary vessels. The perfusate drains into the coronary
sinus and through the right ventricle it is ejected back to the
reservoir through a cannula into the pulmonary artery. In this mode, the
LV is not loaded and cannot be functionally evaluated.
The working mode allows for LV loading and functional assessment. During
diastole, SAM enables both antegrade flow to the left atrium and
retrograde flow into the aorta. The retrograde flow is provided by a
pump allowing coronary perfusion. In systole, the same retrograde flow
acts as aortic resistance. However, the LV must overcome the aortic
backpressure which can cause an uncontrolled rise in aortic systolic and
diastolic pressure. PAM is an alternative to SAM that may simulate
systemic vascular resistance more closely by connecting the ascending
aorta to a Windkessel-based afterload module. In an electrical system,
the Windkessel module comprises a circuit containing lumped elements of
resistance, capacitance, and inductance. Here, the governing equations
of an electric circuit are applied to a fluid system, where fluid
pressure, fluid volume and volumetric flow rate directly parallel
voltage, electrical charge and electrical current,
respectively.16 A physical Windkessel module can
possibly provide more realistic and predictable vascular impedances for
in-vitro flow experiments.17 It is used for
computational fluid dynamics validation and other investigations of the
cardiovascular system and medical devices.18 A
Windkessel module describes the hemodynamics of the arterial system in
terms of resistance and compliance.19 Increasing
resistance results in an increase in both systolic and diastolic
pressure. Increasing compliance results in a decrease in systolic
pressure and an increase in diastolic pressure. Through manipulation of
resistance and compliance, systolic and diastolic pressures can be
varied independently. In PAM, measured in vivo aortic, systolic and
diastolic pressures are targeted while in SAM, the diastolic pressure is
maintained at 30 mmHg and the systolic pressure is not controlled.
LV functional assessment has been traditionally achieved experimentally
using transduction catheters to obtain pressure-volume loops, allowing
quantification of ventricular elastance during LV loading on
ESHP.20The predictive value of these measurements for outcomes after
transplantation is still
unknown.21 In
addition, transduction catheters have several limitations: they are
costly, invasive and can only be placed in isolated
hearts. Echocardiography is the gold standard for the perioperative
assessment of cardiac function. However, in the setting of ESHP it has
only been reported as a marginal component of the overall cardiac
evaluation.22We developed a custom-made 3D-printed enclosure to support and protect
the donor heart during ESHP and permit epicardial imaging using a
standard transesophageal echocardiography (TEE)
probe.23 ESHP
with controlled loading may allow a standardized and non-invasive
assessment of the LV during working mode and may increase the early
identification of organ dysfunction prior to transplantation and thereby
improve patient outcomes.
Until now the validity of using SAM to assess the cardiac function is
controversial as the retrograde aortic flow is not physiological and
uncontrollable rises in systolic pressure may impact heart function. By
allowing a more physiological perfusion of the LV, PAM has been proposed
as an alternative to SAM that strives to improve the physiological
appropriateness of LV afterload during ESHP.14,15 A
standardized setting is fundamental for a reliable functional assessment
of the heart during ESHP and for determining if these hearts are usable
for transplantation. The relative feasibility and physiologic
significance of functional assessment under the two working modes is not
currently known. In this study, we sought to assess the feasibility of
performing a reliable and comprehensive functional assessment of LV
during ESHP using echocardiography in both afterload working modes.