The Current Status of Continuous Flow Left Ventricular Assist Devices

In patients with severe heart failure, cardiac transplantation has been shown to provide considerable benefit. Since 1967, in excess of 88,000 total heart transplants have been performed and 1-year survival is 81%, the annual mortality is 4% per year thereafter. The supply of donor hearts is incredibly limited and much research has focused on mechanical means of improving myocardial function, and several such left ventricular assist devices (LVADs) have been developed through the National Institutes of Health artificialheart program. Several devices have been previously approved by the Food and Drug Administration as bridging therapy to transplantation, though none have been studied as long-term alternatives to transplantation. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) [1] trial explored whether a specific type of LVAD (a previous generation pulsatile device), when used in the long-term, would reduce mortality (Figure 1). The survival following severe heart failure was extremely poor in the optimally medically treated group in this trial (defined as End-stage heart failure was defined as New York Heart Association (NYHA) class IV symptoms for at least 90 days, left ventricular ejection fraction (LVEF) <25%, peak oxygen consumption <12 mL/kg/min or continued need for intravenous inotropes for symptomatic hypotension). In the optimally medically treated control arm of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial [1] which evaluated an externalized pulsation ventricular assist device, survival at one year was 28% and 6% at two years, underlying the poor prognosis of this clinical entity (Figure 1). Driving the need for mechanical circulatory support (MCS) is the relative paucity of donors and the unmet need for orthotopic heart transplantation in the general population. There has also been an increase in the number of patients who require mechanical circulatory support (MCS) as a bridge to transplantation [2]. This has been driven, particularly in the UK by limitation of the number of hearts for donation, and also to buy time on the transplant waiting list. This is due to an increase in the numbers of non-heart beating donors (DCDs), whereby retrieval takes place in a circulation arrested donor, and the increased survival of head injury patients and those with intracranial bleeds who are treated by a decompressive craniotomy, reducing the pool of donors who have raised intracranial pressure and who have coned, resulting in brain stem death. The net result is a retrieval rate for heart transplantation of around 19%. The risk of having preformed antibodies directed against the donor heart (sensitised patients) is increasingly likely and is particularly Abstract In this review, we hope to give a perspective of the new realities of cardiac mechanical circulatory assist devices. New iterations of devices are providing greater durability and freedom of complications. Work is near to provide internal batteries and transcutaneous energy transfer systems for completely implantable systems, avoiding the need for an externalized drive line.


Introduction
In patients with severe heart failure, cardiac transplantation has been shown to provide considerable benefit. Since 1967, in excess of 88,000 total heart transplants have been performed and 1-year survival is 81%, the annual mortality is 4% per year thereafter. The supply of donor hearts is incredibly limited and much research has focused on mechanical means of improving myocardial function, and several such left ventricular assist devices (LVADs) have been developed through the National Institutes of Health artificialheart program. Several devices have been previously approved by the Food and Drug Administration as bridging therapy to transplantation, though none have been studied as long-term alternatives to transplantation. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) [1] trial explored whether a specific type of LVAD (a previous generation pulsatile device), when used in the long-term, would reduce mortality ( Figure 1). The survival following severe heart failure was extremely poor in the optimally medically treated group in this trial (defined as End-stage heart failure was defined as New York Heart Association (NYHA) class IV symptoms for at least 90 days, left ventricular ejection fraction (LVEF) <25%, peak oxygen consumption <12 mL/kg/min or continued need for intravenous inotropes for symptomatic hypotension).
In the optimally medically treated control arm of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial [1] which evaluated an externalized pulsation ventricular assist device, survival at one year was 28% and 6% at two years, underlying the poor prognosis of this clinical entity ( Figure 1). Driving the need for mechanical circulatory support (MCS) is the relative paucity of donors and the unmet need for orthotopic heart transplantation in the general population. There has also been an increase in the number of patients who require mechanical circulatory support (MCS) as a bridge to transplantation [2]. This has been driven, particularly in the UK by limitation of the number of hearts for donation, and also to buy time on the transplant waiting list. This is due to an increase in the numbers of non-heart beating donors (DCDs), whereby retrieval takes place in a circulation arrested donor, and the increased survival of head injury patients and those with intracranial bleeds who are treated by a decompressive craniotomy, reducing the pool of donors who have raised intracranial pressure and who have coned, resulting in brain stem death. The net result is a retrieval rate for heart transplantation of around 19%. The risk of having preformed antibodies directed against the donor heart (sensitised patients) is increasingly likely and is particularly challenging as it may increase the risk of rejection and allograft vasculopathy. There has also been an increase in the number of patients requiring MCS as a bridge to transplantation [3]. This allows many severely ill adults and paediatric patients to survive until a suitable donor heart is available. Patients with MCS are at increased risk for rejection, infection, stroke, and bleeding. The need for transfusions also increases the risk of pre-sensitization [3][4][5]. Survival at 1 and 5 years is decreased in patients requiring MCS prior to transplantation, but still higher than 80% and 70%, respectively (ISHLT database) [2].

Advances in Donor Allocation and Selection
Recipient criteria for heart transplantation include, severe symptoms despite maximal medical management, the absence of reversible or surgically amenable heart disease, and where estimated 1-year survival is less than 50% [6]. An estimate of functional capacity in ambulatory patients can be best quantified by measurement of peak O 2 consumption (VO 2 max). Patients with low VO2max (<12 ml/min/kg) have high mortality even if treated with beta blockers and transplantation should be considered for these patients. In addition, heart failure prognosis scores to estimate survival, such as the Heart Failure Severity Score may be used.
This calculates a survival probability on the basis of the presence of ischaemic cardiomyopathy, resting heart rate, left ventricular ejection fraction, mean blood pressure, interventricular conduction delay, VO 2 max and serum sodium concentration [7]. Transplantation eligibility is always considered with regard to risk factors, especially, pulmonary hypertension ( Figure 2). Right heart catheterization must be performed in all potential candidates for heart transplantation in order to quantify pulmonary vascular resistance [7]. Right heart failure is a substantial cause of mortality. 110 left ventricular end diastolic pressure with elevated left atrial and pulmonary venous pressures. This is a reactive form of pulmonary hypertension and may fall when the cardiac output is increased with inotropes or unloaded with nitrate infusions [7].
The transpulmonary gradient is calculated by subtracting the left atrial filling pressure from the mean pulmonary artery pressure. A fixed transpulmonary gradient in excess of 14 mmHg is associated with greatly elevated risk, and thus this cut off is used in the UK [8].
In such patients a destination therapy strategy may be used with continuous flow LVADS.

Mechanical Circulatory Assist Devices
In recent years, the use of MCS device in treating patients with end-stage heart disease has increased significantly, as bridge to transplantation and as destination therapy for transplant ineligible candidates. This increase is based on the accumulated experience with new second-generation continuous-flow devices which show significant improvements in survival, functional capacity and quality of life [9,10]. On the basis of the Heart Mate II Registry experience (1300 patients), guidelines for the clinical management of patients treated with continuous-flow devices have been published [11].
Risk scoring systems, such as the Seattle Heart Failure Model [12] and the Cumulative Risk Score for 90-Day in-Hospital Mortality [13] and the Destination Therapy Risk Score have been investigated to stratify patients who might benefit from LVAD support [14].
Right ventricle failure is a leading cause of morbidity and death after LVAD implant (incidence of about 35%), and can be very difficult to predict [15,16]. Various means to assess right ventricle function both pre-and postoperatively have been assessed (10). Right ventricular failure risk scores have been created that stratify the risk of right ventricular failure (RVFRS) and death after LVAD implantation ( Figure 3). One such RVFRS found independent predictors of right ventricular failure to include vasopressor requirement, aspartate aminotransferase >80 IU/L, bilirubin >2.0mg/dL and creatinine >2.3mg/dL [15]. Another study developed a score to predict RVAD need after LVAD placement, which included factors of cardiac index, right ventricular stroke work index, severe preoperative right ventricular dysfunction, creatinine, previous cardiac surgery and systolic blood pressure [16]. More recently the presence of severe TR and a tricuspid annulus

Conclusion
Heart transplantation is associated with excellent long-term outcomes and is the gold standard solution for intractable end stage heart failure in eligible patients. What limits its impact, overall, is the limited availability of donor organs. The development of ventricular assist devices has mitigated against this, to some extent. Subsequent device iterations with further miniaturisation and continuous flow have resulted in effective bridge to transplant solutions. The presence of an externalized drive line exposes the VAD recipient to infections, however, which may precipitate urgent listing for heart transplant in the bridge to transplant candidate and may limit the life span of the destination therapy candidate. Fully implantable driveline free systems will definitely enhance the utility of these systems in these settings. As our knowledge of molecular medicine increases, manipulation of key proteins implicated in the pathophysiology of heart failure such as SERCA2a may allow some recovery of the myocardium in patients with heart failure to the extent that transplantation may be deferred or the LVAD explanted