Trial-Based Hemolysis Modeling to Investigate Operating Modes of Continuous-Flow LVADs.

Over the last 2 decades, numerous advancements in medical therapies have improved patient outcomes in heart failure (HF). However, a significant number of patients still progress to end-stage HF, in which treatment options are largely limited to cardiac transplantation. As patient demands for transplant continue to exceed the supply of available organs, mechanical assist devices—specifically, the left ventricular assist device (LVAD)—were initially introduced as a bridge to cardiac transplantation. LVADs have 2 important beneficial effects. First, LVADs are placed in parallel to the native left ventricle (LV), causing pressure and volume unloading of the LV. Second, LVADs restore cardiac output and subsequent perfusion to the organs. As a result of these 2 effects, it became evident that some patients had actual improvement in LV function after LVAD placement. The term reverse remodeling was used to describe the improvement in myocardial function that was observed in patients with a seemingly end-stage disease. With reverse remodeling, a new hope for the treatment of HF was born—using LVADs as a bridge to recovery; however, to date, this promise has largely been unrealized. This probably is reflective of the fact that the sequela of mechanical ventricular unloading are quite complex and appear to involve the engagement of competing biological pathways including regression of cardiomyocyte hypertrophy as well as progressive cell atrophy. Although the promise of ventricular recovery still persists, its actualization will await a more comprehensive dissection of these competing biological processes. This review will discuss the beneficial clinical effects of LVAD support as well as review what is known about the cellular and molecular response to mechanical unloading and mechanisms of reverse remodeling. Key research findings have been summarized in the Table. View this table: Table. Summary of Research of LVAD Support on Clinical Effects and the Cellular and Molecular Changes That May Contribute to Reverse …

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In this issue of Circulation, Birks et al 1 report their recent experience using the combination of continuous-flow (CF) circulatory support and pharmacological therapy to treat advanced heart failure in patients requiring left ventricular assist device (LVAD) support. Thirty-three patients underwent HeartMate II (HMII) LVAD implantation at Harefield hospital during the 3-year study period. Twenty-three patients (70%) with nonischemic cardiomyopathy were considered appropriate for the recovery protocol at the time of HMII LVAD implantation, and 20 patients (61%) who survived LVAD implantation formed the study cohort. With their strategy of aggressive neurohormonal blockade (phase I) followed by high-dose clenbuterol (phase II), 12 (60%) of the study cohort met criteria for LVAD explantation, and all 10 (50%) who survived the perioperative period demonstrated sustained recovery over 56 to 1112 days of follow-up. Therefore, 30% of all patients and 43% of all nonischemic patients undergoing HMII implantation could be managed to long-lasting recovery. In an era in which transplant waiting times have blurred the distinction between bridge-totransplant and destination therapy for some patients, this single-center experience is intriguing and offers hope for a new strategy for select patients supported with CF LVADs. Article see p 381 Reports in the literature regarding rates of cardiac recovery during pulsatile LVAD support are quite varied (Table 1). The Columbia University group reported a 1% rate of sustained cardiac recovery in 111 patients with both ischemic and nonischemic etiology of heart failure. 2 In contrast, the German Heart Institute reported that 13% of patients with nonischemic heart failure demonstrated sustained recovery (minimum follow-up of 36 months) after LVAD explantation. 3 The LVAD Working Group was the first multicenter, prospective initiative to study recovery.4 Sixty-seven LVAD patients (only 1 CF LVAD) with both ischemic and nonischemic causes underwent serial echocardiograms at reduced flow to seek recovery. Six percent of the whole cohort and 7% of all nonischemic patients could undergo LVAD explantation. None of these reports described the consistent use of pharmacological therapy during LVAD support, and it was not until the first Harefield recovery study 5 that data regarding combined pharmacological and mechanical support were available. In the first Harefield study, 15 LVAD patients (1 CF LVAD) received maximal doses of heart failure medications, followed by high-dose clenbuterol. All patients had a nonischemic etiology, and most (80%) had heart failure for 6 months. The authors reported that 75% of patients receiving clenbuterol could undergo LVAD explantation and 46% of all patients with nonischemic heart failure presenting for LVAD could be managed successfully to recovery in this way. These data from Harefield represented the most successful reported recovery strategy to date, and prompted a multicenter study in the United States (to replicate the Harefield recovery protocol) called the Harefield Recovery Protocol Study (HARPS). HARPS has now completed enrollment of 17 patients with the HMI pulsatile LVAD, 13 of whom received both maximal neurohormonal blockade and high-dose clenbuterol. Results from the US HARPS study will be presented in the near future. With the approval of the HMII LVAD for both bridge-to

Abstract. Objectives. This study sought to evaluate the use of a continuous-flow rotary left ventricular assist device (LVAD) as a bridge to heart transplant Background LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. Methods In a prospective multicenter study, 281 patients urgently listed (United Network for Organ Sharing status 1A or 1B) for heart transplant underwent implant of a continuous-flow LVAD. Survival and transplant rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. Results Of 281 patients, 222 (79%) underwent transplant or LVAD removal for cardiac recovery or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval, 65%–79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-minute walk test results (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-minute walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. Conclusions A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplant, with improved functional status and quality of life.

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Over the past two decades, left ventricular assist device (LVAD) support has emerged as standard therapy for adult patients with advanced, life-threatening heart failure. First-generation pulsatile devices have been replaced by rotary blood pumps that continuously unload the failing left ventricle. So-called continuous-flow LVADs (CF-LVADs) are smaller, more reliable, durable, and energy efficient, and less traumatic to implant than first-generation devices. Survival of 80% at one year and 70% at two years has been widely achieved (1). However, CF-LVADs have introduced a new, non-pulsatile physiology in which blood encounters supraphysiologic shear stress, and as a result, unforeseen consequences have emerged. CF-LVADs operate with an impeller that spins at thousands of revolutions per minute (RPM) to generate forward flow. Within current-generation devices, blood passes through narrow flow gaps (50 to 500 µm) at high velocity. Consequently, blood encounters shear stress that exceeds physiologic values by more than two orders of magnitude. Indeed, current-generation LVADs generate peak shear stress of up to 1,500 Pa (2). For reference, physiologic levels of intravascular shear stress in mammals are approximately two to eight Pa (2). Irrefutable evidence demonstrates that supraphysiologic shear stress from CF-LVADs causes blood trauma that contributes to adverse events. Pathologic degradation of von Willebrand factor (VWF) leads to an acquired bleeding diathesis, gastrointestinal angiodysplasia, and gastrointestinal bleeding in 20% to 40% of LVAD patients (3,4). Platelet activation and (at least subclinical) hemolysis cause a procoagulant state that contributes to LVAD thrombosis and thromboembolism (5). As a result, “LVAD hemocompatibility”, a term that characterizes the clinical impact of biophysical interactions and blood trauma at the blood-device interface, is gaining attention as a major area for improvement of future-generation LVADs. Lack of pulsatile blood flow has also raised concerns. Potential benefits of pulsatility include prevention of aortic valve thrombosis, leaflet fusion, de novo aortic insufficiency, favorable myocardial remodeling, avoidance of arterial stiffening, better end-organ function, reduced bleeding, and reduced stroke (6). Consequently, pulsation algorithms are being developed to generate pulsatility with CF-LVADs. Also problematic, CF-LVADs operate at fixed RPM, independent of patient physiology. These devices do not sense or adjust device parameters in response to dynamic changes in cardiac rate, rhythm, preload, afterload, intracardiac hemodynamics, or systemic metabolic demands. “Physiologic control”, a term used to describe automatic responsiveness to changes in patient physiology, is another focus for improvement of future-generation LVADs. Devices with physiologic control may sense and adjust to pathologic conditions such as exacerbation of heart failure, hypotension, hypovolemia, and malignant arrhythmia. Optimization of ventricular (un)loading may increase favorable myocardial remodeling and facilitate LVAD weaning and explantation in the setting of myocardial recovery. Finally, full sternotomy and cardiopulmonary bypass (CPB) deter referral of less sick patients for LVAD therapy. Minimally-invasive implantation strategies without CPB that include mini-thoracotomy, subxiphoid access, device placement in an infraclavicular pacemaker-like pocket, and percutaneous implantation may increase referral of earlier-stage heart failure patients and increase the public health impact of LVAD support. In summary, next-generation LVADs are needed to reduce adverse events and improve outcomes. Toroidal-flow is a novel LVAD flow strategy designed to improve hemocompatibility while providing pulsatility with physiologic device control. As such, the first-of-its-kind, toroidal-flow TORVAD is a disruptive technology with the potential to alter mechanical circulatory support therapy. TORVAD Windmill Cardiovascular Systems, Inc. (Austin, TX, USA) is developing the TORVAD (2,7-10), a positive-displacement, rotary LVAD (Figure 1). The toroidal-flow mechanism generates low shear stress (7), minimal blood trauma (2), pulsatile blood flow (9), and operates with physiologic control (8,10). Open in a separate window Figure 1 The Toroidal-Flow TORVAD, Device and Mechanism of Flow. (A) The toroidal-flow TORVAD consists of an inflow cannula with sewing ring, torus pumping chamber, and outflow graft. An epicardial ECG lead senses the patient’s native heart rhythm and triggers TORVAD support with asynchronous or synchronous pulsatile, counter-pulsatile, or co-pulsatile pumping modes. (B) To simultaneously fill and eject, the TORVAD spins two magnetic pistons (Pa and Pb) in sequence within the doughnut-shaped torus chamber. During support, each piston remains stationary while the other piston spins. While the first piston (Pa) is temporarily fixed as a virtual valve between the torus inflow and outflow, the second piston (Pb) rotates within the torus to eject 30 mL of blood. After one cycle, the pistons switch positions, and the first piston (Pa) spins while the second piston (Pb) remains stationary. The result is unidirectional, pulsatile blood flow with low shear stress and a high level of physiologic control. ECG, electrocardiogram.

Aortic regurgitation during continuous-flow left ventricular assist device support: An insufficient understanding of an insufficient lesion