Advances in Mechanical Circulatory Support Bridge to Recovery Understanding the Disconnect Between Clinical and Biological Outcomes Stavros G. Drakos, MD, PhD; Abdallah G. Kfoury, MD; Josef Stehlik, MD; Craig H. Selzman, MD; Bruce B. Reid, MD; John V. Terrovitis, MD, PhD; John N. Nanas, MD, PhD; Dean Y. Li, MD, PhD L eft ventricular (LV) assist devices (LVADs) are increas- ingly used in everyday clinical practice either as a bridge for end-stage heart failure (HF) patients to heart transplanta- tion or as a permanent (destination) therapy. 1,2 Yet, there is still significant uncertainty about the consequences of this intervention both at the level of the detailed myocardial biology (ie, biological outcomes) and at the functional car- diovascular response of the patient at the organ level (ie, clinical outcomes). The LVAD patient population presents a series of signifi- cant advantages as far as research is concerned. First, LVAD therapy offers the ability to acquire paired human myocardial tissue at LVAD implantation and again on LVAD removal. The ability to obtain human tissue and the possibility for its serial examination before and after any therapeutic investi- gational therapy combined with LVADs provide an important opportunity for in-depth study of the changes in the structure and function of the diseased human heart caused by the specific investigational therapy. Second, this population rep- resents a relatively safe investigational platform because the hemodynamic support provided by VADs makes these pa- tients significantly less vulnerable to any arrhythmic 3 or hemodynamic adverse events potentially associated with new aggressive investigational therapies. Third, the volumes of potential study subjects for these investigations (ie, patients who receive LVADs) are rapidly increasing; because of a lack of donor organs and incremental progress in device design and durability, the number of advanced HF patients with LVADs has been continuously increasing. 1,2 These 3 research advantages create an ideal setting for various new HF therapies to test their potential efficacy in LVAD patients. Fourth, this population offers an opportunity to investigate the effects of the LVAD-induced removal of excess mechan- ical load, which drives the vicious cycle of myocardial remodeling and eventually leads to the clinical HF syn- drome. 4 Increasing evidence suggests that a significant degree of improvement in myocardial structure and function can be observed after LVAD-induced mechanical unloading, 5 to the point that some of these advanced HF patients can eventually be weaned from mechanical support and achieve sustained myocardial recovery. 6,7 These important research advantages may transform this LVAD patient population into a precious translational re- search vehicle for investigating new antiremodeling and regenerative therapies for HF. However, for these promises to be fulfilled, we must first establish the baseline and better understand the fundamental impact of LVAD-induced un- loading on the failing human heart. LVAD Bridge to Recovery: Clinical Outcomes Witnessing a chronically sick, almost moribund, end-stage HF patient achieve sustained myocardial recovery after LVAD weaning is one of the most fascinating and rewarding experiences in the contemporary treatment of heart disease (Figure 1). The main results of key clinical outcome studies investigating LVAD bridge to recovery are summarized in Table 1. 8 –20 Except for 3 recent studies from Berlin, 21 Harefield, 12 and Vancouver, 14 the majority of the devices used in the bridge-to-recovery studies have so far included first-generation, pulsatile-flow LVADs. As shown in Table 1, the most effective approach aiming at recovery of myocardial function reported so far is the Harefield protocol, which tested mechanical unloading combined with aggressive anti- remodeling drug therapy and the -2 agonist clenbuterol in nonischemic cardiomyopathy patients. 11–13,22 The Harefield protocol was also tested in the Harefield Recovery Protocol Study (HARPS) multicenter study. 23 Of 13 patients, only 1 met explantation criteria, with the authors attributing their inability to reproduce the recovery rates of prior Harefield protocol reports potentially to differences in the patient characteristics of the population studied or modifications of the Harefield protocol done in the HARPS study. 23 Repro- ducibility of the Harefield protocol results in larger patient cohorts and in a randomized fashion is of great importance. Similarly, as evident from Table 1, the success of LVAD weaning and of achieving sustained myocardial recovery varied significantly across the reported studies. This variabil- ity may have been caused by a variety of factors such as From the Divisions of Cardiology, Cardiothoracic Surgery, and Molecular Medicine, University of Utah School of Medicine, Salt Lake City (S.G.D., A.G.K., J.S., C.H.S., B.B.R., D.Y.L.); Cardiovascular Department, Intermountain Medical Center, Salt Lake City, UT (S.G.D., A.G.K., B.B.R.); UTAH Cardiac Transplant Program, Salt Lake City (S.G.D., A.G.K., J.S., C.H.S., B.B.R.); and Third Division of Cardiology, University of Athens, Athens, Greece (S.G.D., J.V.T., J.N.N.). Correspondence to Stavros G. Drakos, Heart Failure Program (Division of Cardiology) and Molecular Medicine Program (Eccles Institute of Human Genetics), University of Utah, 15 N 2030 E, Bldg 533, Room 4450, Salt Lake City, UT, 84132. E-mail stavros.drakos@u2m2.utah.edu (Circulation. 2012;126:230-241.) © 2012 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.040261 230 by guest on December 31, 2016 http://circ.ahajournals.org/ Downloaded from