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.