Treatment Strategies for Myocardial Recovery in Heart Failure Andrew J. Lenneman, MD * Emma J. Birks, MD, PhD, FRCP

Curr Treat Options Cardio Med (2014) 16:287 DOI 10.1007/s11936-013-0287-9 Heart Failure (W Tang, Section Editor) Treatment Strategies for Myocardial Recovery in Heart Failure Andrew J. Lenneman, MD * Emma J. Birks, MD, PhD, FRCP Address *Division of Cardiovascular Medicine, University of Louisville, Rudd Heart and Lung Center, 201 Abraham Flexner Way, Suite 1001, Louisville, KY 40202, USA Email: andrew.lenneman@louisville.edu Email: emma.birks@louisville.edu Published online: 4 February 2014 * Springer Science+Business Media New York 2014 This article is part of the Topical Collection on Heart Failure Keywords Heart failure I Treatment I Ventricular assist device I Recovery I LVAD Opinion statement Heart failure is a progressive disorder characterized by adverse left ventricular remodeling. Until recently, this has been thought to be an irreversible process. Mechanical unloading with a left ventricular assist device (LVAD), particularly if combined with neurohormonal blockade with heart failure medications, can lead to a reversal of the heart failure phenotype, a process called reverse remodeling. Reverse remodeling refers to the regression of pathologic myocardial hypertrophy and improvement in LV chamber size that can occur in response to treatment. Myocardial recovery is the sustained normalization of structural, molecular, and hemodynamic changes sufficient to allow explant of the LVAD. Despite the fact that reverse remodeling is commonly seen in LVAD patients in clinical practice, myocardial recovery sufficient to allow device explantation is still rare. Previous experience suggests that young patients with short duration of heart failure and less myocardial fibrosis may be more likely to recover. Alternatively, it may just be that clinicians make a greater effort to recover these subgroups. A combined approach of mechanical unloading with LVADs and pharmacological management, together with regular testing of underlying myocardial function with the pump reduced to a speed at which it is not contributing, can increase the frequency of sustained recovery from heart failure. The goal is to achieve optimal unloading of the myocardium, combined with pharmacologic therapy aimed at promoting reverse remodeling. Myocardial recovery must be considered as a therapeutic target. Clinical variables such as pump speed and blood pressure must be optimized to promote maximal unloading, leading to reverse remodeling and myocardial recovery. Frequent echocardiographic and hemodynamic evaluation of underlying myocardial function must be performed. The combination of LVAD therapy with optimal neurohormonal blockade appears promising as an approach to myocardial recovery. In addition,

287, Page 2 of 9 Curr Treat Options Cardio Med (2014) 16:287 there is a growing body of translational research which, when combined with LVADs, may further promote more durable recovery. Strategies to thicken the myocardium to enhance the durability of recovery prior to explantation, such as clenbuterol (which induces physiological hypertrophy ), or intermittently reducing the pump speed to increase myocardial load may be beneficial. Emergence of cardiac stem cells and alternative biologic agents, when added to current therapies, may have a complementary role in promoting and maintaining myocardial recovery. This review will summarize both current strategies and emerging therapies. Introduction Heart failure (HF) is a major cause of morbidity and mortality worldwide. The central feature in the pathologic progression of heart failure is left ventricular remodeling [1], which refers to the adverse structural, molecular, and cellular changes that occur. These changes are expressed clinically as increases in end-diastolic and end-systolic volumes, myocyte hypertrophy, interstitial fibrosis, and changes in LV chamber geometry to a more spherical shape, usually leading to a decline in ejection fraction [2, 3]. Heart failure treatments are aimed at stopping the progression and reversing the maladaptive remodeling process. Neurohormonal modulation has been the foundation of heart failure treatment for the past two decades. In clinical practice, medical treatment alone has frequently been shown to promote reverse remodeling, leading to myocardial recovery. Spontaneous myocardial recovery is seen in some clinical settings, such as acute myocarditis, peripartum cardiomyopathy, and tachycardia-induced cardiomyopathy, among others. Myocardial recovery is thought to be more common under the above-mentioned clinical conditions partly as a result of lower burden of myocardial fibrosis, and thus many of the pharmacologic, mechanical, and biologic heart failure therapies are aimed at altering the degree of myocardial fibrosis. Excessive scarring and fibrosis may limit the capacity for myocardial recovery [4]. An increasing body of evidence suggests that LVAD unloading can reverse the pathologic molecular, cellular, and structural changes associated with chronic heart failure [5]. This process of reverse remodeling can lead to myocardial recovery, i.e., the sustained normalization of myocardial structure and function following the removal of mechanical support. While reverse remodeling can occur in response to pharmacologic therapy alone, it is often a marked response to LVAD mechanical unloading, and combining the two is likely to lead to increased incidence of recovery. Despite these favorable molecular changes, myocardial recovery sufficient to allow device explant varies widely in clinical practice (Table 1). The myocardial changes seen in response to LVAD unloading in patients with chronic HF demonstrate the plasticity of the molecular structure and function in cardiomyopathies. LVADs provide a unique opportunity to study the process of reverse remodeling and how it relates to myocardial recovery. LVAD support allows administration of HF therapies at high doses that are often not tolerated prior to pump implant due to hypotension and renal dysfunction. Once good flow is restored using the VAD, these advanced heart failure patients are able to tolerate these medications at much higher doses. LVADs also provide a relatively safe platform for the delivery of promising novel biologic and cell-based therapies. Treatment Diet and lifestyle Exercise training has been shown to improve quality of life in patients with heart failure [6, 7]. The role of exercise training in myocardial recovery, however, is less well defined. Exercise training has been shown to be safe in

Curr Treat Options Cardio Med (2014) 16:287 Page 3 of 9, 287 Table 1. Summary of myocardial recovery trial results Study Year Number Recovery overall, N (%) Recovery nonischemic, N (%) Mancini et al. [36] 1998 111 5 (4.5) 4 (8) Farrar et al. [37] 2002 271 22 (8.1) 22 (8.1) Birks et al. [23] 2006 15 11 (73.3) 11 (73) Dandel et al. [38] 2008 188 35 (18.5) 35 (18.5) Birks et al. [24 ] 2011 19 12 (63.2) 12 (63.2) Patel et al. [39] 2013 21 3 (14.3) 3 (23.1) LVAD patients, and a recent study demonstrated that exercise training showed a trend toward greater improvement in exercise capacity and quality of life when compared to a control group [8]. Pharmacologic treatment Neurohormonal blocking medications are used in high doses to promote reverse remodeling. HF medications have been shown to reverse pathologic hypertrophy and normalize cellular metabolic functions, as well as to improve mortality and functional status. Many advanced heart failure patients are unable to tolerate high doses of HF medications due to hypotension and renal failure. Following LVAD implant, patients are better able to tolerate high doses of these medications. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the rate of adverse LV remodeling and slow or prevent progressive LV dilation, both following acute myocardial infarction (MI) [9] and in nonischemic cardiomyopathies [10, 11]. Similar findings have been demonstrated upon administration of angiotensin receptor blockers (ARBs) [12]. ACE inhibitors (ACEi) and ARBs are used in combination to promote reverse remodeling and myocardial recovery in patients supported with an LVAD [11]. ACE inhibition has been associated with decreased myocardial collagen content decreased LV mass, and reduced myocardial stiffness [11, 13] in LVAD patients. Combining ACEi and ARBs leads to full blockade of the receptors and enhanced endothelial function due to increased concentrations of bradykinin. However, clinical trials of dual renin-angiotensin-aldosterone system (RAAS) blockade in heart failure patients have reported mixed results. Notably, in all of the ARB add-on trials, addition of an ARB to an ACE inhibitor led to increased rates of hypotension, renal dysfunction, and hyperkalemia [14, 15]. In LVAD patients, however, both renal function and blood pressure are supported by the VAD, so this is an ideal population to tolerate both ACEi and ARBs, particularly as maximal doses of both are administered [16]. In patients where myocardial recovery is the treatment goal, ARBs are added to ACEi to achieve maximum receptor blockade to promote reverse remodeling [16]. Goal dosage lisinopril, 40 mg daily losartan, 150 mg daily

287, Page 4 of 9 Curr Treat Options Cardio Med (2014) 16:287 Contraindications Main drug interactions Main side effects Cost/cost effectiveness hyperkalemia, renal failure, angioedema, previous reactions antihypertensive actions potentiated by volume depletion; use with caution in hyperkalemia cough (ACEi), renal insufficiency inexpensive Beta-adrenergic receptor (β-ar) blockers Several large randomized trials have demonstrated a survival benefit with beta-blocker therapy in symptomatic heart failure [17], which is when heart failure results in activation of the sympathetic nervous system. High catecholamine levels are not only a marker of disease, but are a direct contributor to heart failure progression. Beta-blockers can induce reverse remodeling in heart failure by improving myocyte contractility, contractile reserve, and calcium handling. Beta-blockers improve LV systolic function and reduce LV dimensions. Goal dosage Contraindications Main drug interactions Main side effects Cost/cost effectiveness carvedilol, 25 50 mg three times daily metoprolol succinate, 200 mg daily bisoprolol, 10 mg daily symptomatic bradycardia antiarrhythmic drugs, calcium channel blockers bradycardia, increased airway resistance, hypoglycemia, fatigue, depression inexpensive Aldosterone antagonists Aldosterone receptors are upregulated in heart failure and may contribute to adverse myocyte hypertrophy and fibrosis. Multiple randomized trials have demonstrated a mortality benefit in heart failure patients treated with spironolactone [18]. Treatment with aldosterone antagonists also reduces fibrosis and improves cardiac function in patients with nonischemic cardiomyopathy and following acute myocardial infarction. Standard dosage spironolactone, 25 mg daily Contraindications hyperkalemia, renal failure Main drug interactions: Main side effects hyperkalemia, renal failure Cost/cost effectiveness inexpensive Assistive devices Left ventricular assist devices Myocardial changes associated with mechanical unloading with LVADs Mechanical unloading with an LVAD promotes reverse remodeling. The marked unloading of the ventricle with an LVAD leads to regression of cellular hypertrophy, improved calcium handling, improved beta-receptor

Curr Treat Options Cardio Med (2014) 16:287 Page 5 of 9, 287 Table 2. Clinical therapies that reverse LV remodeling Beta-adrenergic-receptor blockers ACE inhibitors and angiotensin-receptor blockers Aldosterone antagonists Biventricular pacing LV assist devices density, and improved collagen handling [1, 19, 20 ]. Clinically, LVAD unloading can lead to reduced LV dimensions and LV end-diastolic pressure (LVEDP) as well as improvement in LV ejection fraction (LVEF) [21]. In published studies, a strategy combining LVAD mechanical unloading with specific pharmacologic interventions has been shown to maximize the incidence and promote the durability of myocardial recovery [21, 22, 23, 24 ]. We designed a strategy in which pharmacologic medications known to promote reverse remodeling are started early after LVAD implant and uptitrated to maximum target doses (see Table 2). Additionally, LVAD mechanical pump speed is optimized to promote maximal mechanical unloading of the LV; using echocardiographic guidance, pump speed is adjusted, with the goal of decreasing LV chamber dimensions while maintaining the LV septum in the midline with closure of the aortic valve and minimizing mitral regurgitation. Optimal blood pressure control must be achieved in parallel with increasing pump speed. Continuous-flow LVADs are afterload-dependent, and hence increased afterload will decrease pump flow and reduce LV unloading. Therefore, the afterload reduction provided by the above-described medications will also increase pump flow and further unload the heart. In order to truly assess the underlying myocardial function, evaluations must then be conducted at regular intervals with the pump speed reduced to a level at which no net forward or reverse flow is provided [22 ]. LV function is assessed by echocardiography and exercise and hemodynamic studies, all performed at no net forward or reverse flow. Table 4 summarizes our algorithm for the clinical evaluation of myocardial recovery. Clenbuterol as adjuvant therapy At Harefield hospital near London, researchers developed a strategy of LVAD unloading with specific pharmacological interventions. The strategy was di- Table 3. Target doses of heart failure medications used in combination with LVAD unloading Lisinopril 40 mg daily Carvedilol 25 mg tid or 50 mg bid Spironolactone 25 mg daily Digoxin 0.125 mg daily Losartan 150 mg daily

287, Page 6 of 9 Curr Treat Options Cardio Med (2014) 16:287 Table 4. Algorithm for promoting and testing for myocardial recovery following LVAD implantation Immediately post-op, following LVAD Early addition of HF medications (as soon as inotropes are weaned) to induce implant "reverse remodeling" with rapid uptitration of HF meds to high target doses Before discharge or first clinic visit post 2D Echo with LVAD at full support to maximize pump speed for unloading implant Starting at 6 weeks after implantation "Low-speed" Echo is performed, goal EF 945 % with pump down and regularly repeated 6-minute walk With LVAD at "low speed"(as part of the echo test) Goal: distanced walked is greater than 450 m and LVEF 945 % at low speed Cardiopulmonary exercise testing LVAD at full support LVAD at "low speed" Goal: peak VO2 916 ml/kg/min Right heart catheterization LVAD at full support LVAD at "low speed for 15 min Goal: PCWP G15, Cardiac Index92.5 L/min/m 2 Low speed is the pump speed at which there is no forward or reverse flow 22 vided into two phases. The first phase consisted of maximal unloading of the myocardium using LVADs combined with high-dose reverse-remodeling HF medications. Once maximal reverse remodeling was achieved, patients were switched to β1-selective beta-blockers, with the addition of clenbuterol to promote physiologic hypertrophy [23, 24, 25] (Tables 3 and 4). Clenbuterol is a selective β-2 adrenergic receptor agonist and a potent synthetic analog to epinephrine. It has been shown to induce a physiologic myocyte hypertrophy in rat models [26, 27]. The goal here is to induce physiologic hypertrophy after reverse remodeling has occurred to enhance the durability of myocardial recovery. Explantation Another important aspect of the myocardial recovery strategy is to use a careful explant technique aimed at minimizing any trauma to the explanted heart while it is fragile (i.e., while it is being loaded again after a long period of unloading). This can be achieved in one of two ways. The first is an explant technique that uses a short period of femoral cardiopulmonary bypass with minimal mobilization, i.e., as minimally invasive a technique as possible [28, 29]. The second method uses a felt plug rapidly inserted into the hole when the inlet cannula is removed, which avoids cardiopulmonary bypass altogether [30]. Heart failure medications are restarted following explantation and again uptitrated to maximal doses [23, 24 ]. Cardiac resynchronization therapy (CRT) Many patients with HF also have electric conduction abnormalities leading to ventricular dyssynchrony. Cardiac resynchronization therapy (CRT) involves biventricular pacing to reduce dyssynchrony and improve ventricular function, leading to reduction of LV dilation and hypertrophy [31, 32].

Curr Treat Options Cardio Med (2014) 16:287 Page 7 of 9, 287 Global cardiac function improvement and the reverse remodeling effects of CRT are greater in patients with nonischemic cardiomyopathy. There is a small group of patients, called super responders, whose LV function improves to normal or near-normal values [33]. Those with QRS duration greater than 150 ms with left bundle branch block (LBBB) morphology are most likely to benefit from CRT. The precise role of CRT in promoting myocardial recovery in patients supported with an LVAD is not well-defined, and this is an area in need of further investigation. Emerging therapies Phosphodiesterase type 5 (PDE5) inhibitors PDE5 inhibitors are widely used as an adjunctive therapy in heart failure patients with pulmonary hypertension. PDE5 inhibition enhances NO signaling by increasing the cyclic guanosine monophosphate (cgmp) availability, and has been shown to improve diastolic function in patients with heart failure [34]. Further study is needed to define its role, if any, in myocardial recovery. Stem cells Novel biologic agents Recent studies of stem cell-based therapies for heart failure indicate that current techniques have the potential to improve LV function. Stem cells offer the possibility of cardiac tissue regeneration through repair or replacement of damaged or lost myocytes. Clinical trial results have been encouraging, but further study is needed to determine optimal cell types and delivery methods to maximize results. Combining LVAD mechanical unloading with stem cell regeneration could lead to more durable myocardial recovery from HF. Other novel biological agents may have a future role in myocardial recovery. MicroRNAs, for example, have been proven to be powerful modifiers in many cardiovascular disease states, including heart failure. They have been shown to play an important role in cardiac development and myocyte proliferation, and likely play an important role in the remodeling process [35]. The growth factor neuregulin (NRG) has been shown to play a role in cardiac remodeling, and evidence from early clinical trials indicates that treatment with recombinant NRG improves LV systolic functions. These promising discoveries represent important potential therapeutic targets which, when combined with mechanical unloading with an LVAD, may increase the incidence and durability of myocardial recovery. Compliance with Ethics Guidelines Conflict of Interest Dr. Andrew J. Lenneman declares no potential conflicts of interest relevant to this article. Dr. Emma J. Birks has received grants.

287, Page 8 of 9 Curr Treat Options Cardio Med (2014) 16:287 Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Birks EJ, George RS. Molecular changes occurring during reverse remodelling following left ventricular assist device support. J Cardiovasc Transl Res. 2010;3:635 42. 2. Mann DL, Burkhoff D. Is myocardial recovery possible and how do you measure it? Curr Cardiol Rep. 2012;14:293 8. This is a good discussion of myocardial recovery in heart failure and how reverse remodeling relates to myocardial recovery. 3. Frazier OH, Myers TJ. Left ventricular assist system as a bridge to myocardial recovery. Ann Thorac Surg. 1999;68:734 41. 4. Segura AM, Frazier OH, Demirozu Z, Buja LM. Histopathologic correlates of myocardial improvement in patients supported by a left ventricular assist device. Cardiovasc Pathol. 2011;20:139 45. 5. Mann DL, Burkhoff D. Myocardial expression levels of micro-ribonucleic acids in patients with left ventricular assist devices signature of myocardial recovery, signature of reverse remodeling, or signature with no name? J Am Coll Cardiol. 2011;58:2279 81. 6. Belardinelli R, Georgiou D, Cianci G, Purcaro A. 10- year exercise training in chronic heart failure: a randomized controlled trial. J Am Coll Cardiol. 2012;60:1521 8. 7. O'Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. Jama. 2009;301:1439 50. 8. Hayes K, Leet AS, Bradley SJ, Holland AE. Effects of exercise training on exercise capacity and quality of life in patients with a left ventricular assist device: a preliminary randomized controlled trial. J Heart Lung Transplant. 2012;31:729 34. 9. St John Sutton M, Lee D, Rouleau JL, et al. Left ventricular remodeling and ventricular arrhythmias after myocardial infarction. Circulation. 2003;107:2577 82. 10. Greenberg B, Quinones MA, Koilpillai C, et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation. 1995;91:2573 81. 11. Klotz S, Danser AH, Foronjy RF, et al. The impact of angiotensin-converting enzyme inhibitor therapy on the extracellular collagen matrix during left ventricular assist device support in patients with end-stage heart failure. J Am Coll Cardiol. 2007;49:1166 74. 12. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772 6. 13. Milting H, Kassner A, Arusoglu L, et al. Influence of ACE-inhibition and mechanical unloading on the regulation of extracellular matrix proteins in the myocardium of heart transplantation candidates bridged by ventricular assist devices. Eur J Heart Fail. 2006;8:278 83. 14. Lakhdar R, Al-Mallah MH, Lanfear DE. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensinconverting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. J Card Fail. 2008;14:181 8. 15. Lang CC, Struthers AD. Targeting the renin-angiotensin-aldosterone system in heart failure. Nat Rev Cardiol. 2013;10:125 34. 16. Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374:1840 8. 17. Domanski MJ, Krause-Steinrauf H, Massie BM, et al. A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS. J Card Fail. 2003;9:354 63. 18. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med. 1999;341:709 17. 19. Hall JL, Fermin DR, Birks EJ, et al. Clinical, molecular, and genomic changes in response to a left ven-

Curr Treat Options Cardio Med (2014) 16:287 Page 9 of 9, 287 tricular assist device. J Am Coll Cardiol. 2011;57:641 52. 20. Birks EJ. Molecular changes after left ventricular assist device support for heart failure. Circ Res. 2013;113:777 91. This comprehensive review describes the molecular and structural myocardial changes that occur in response to LVAD unloading. 21. George RS, Yacoub MH, Tasca G, et al. Hemodynamic and echocardiographic responses to acute interruption of left ventricular assist device support: relevance to assessment of myocardial recovery. J Heart Lung Transplant. 2007;26:967 73. 22. George RS, Sabharwal NK, Webb C, et al. Echocardiographic assessment of flow across continuousflow ventricular assist devices at low speeds. J Heart Lung Transplant. 2010;29:1245 52. This study describes the optimal LVAD speed at which to assess the native LV function and the physiologic response to speed reduction. 23. Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med. 2006;355:1873 84. 24. Birks EJ, George RS, Hedger M, et al. Reversal of severe heart failure with a continuous-flow left ventricular assist device and pharmacological therapy: a prospective study. Circulation. 2011;123:381 90. This study reports the clinical results of pharmacologic and mechanical unloading with continuous-flow LVAD to promote myocardial recovery, and reports clinical outcomes following device explant. 25. Yacoub MH. A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery. Eur Heart J. 2001;22:534 40. 26. Wong K, Boheler KR, Bishop J, Petrou M, Yacoub MH. Clenbuterol induces cardiac hypertrophy with normal functional, morphological and molecular features. Cardiovasc Res. 1998;37:115 22. 27. Soppa GK, Smolenski RT, Latif N, et al. Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle. Am J Physiol Heart Circ Physiol. 2005;288:H1468 76. 28. Tansley P, Yacoub M. Minimally invasive explantation of implantable left ventricular assist devices. J Thorac Cardiovasc Surg. 2002;124:189 91. 29. Haj-Yahia S, Birks EJ, Dreyfus G, Khaghani A. Limited surgical approach for explanting the HeartMate II left ventricular assist device after myocardial recovery. J Thorac Cardiovasc Surg. 2008;135:453 4. 30. Cohn WE, Gregoric ID, Radovancevic B, Frazier OH. A felt plug simplifies left ventricular assist device removal after successful bridge to recovery. J Heart Lung Transplant. 2007;26:1209 11. 31. St John Sutton M, Ghio S, Plappert T, et al. Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure. Circulation. 2009;120:1858 65. 32. Moss AJ, Hall WJ, Cannom DS, et al. Cardiacresynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361:1329 38. 33. Reant P, Zaroui A, Donal E, et al. Identification and characterization of super-responders after cardiac resynchronization therapy. Am J Cardiol. 2010;105:1327 35. 34. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011;4:8 17. 35. Matkovich SJ, Van Booven DJ, Youker KA, et al. Reciprocal regulation of myocardial micrornas and messenger RNA in human cardiomyopathy and reversal of the microrna signature by biomechanical support. Circulation. 2009;119:1263 71. 36. Mancini DM, Beniaminovitz A, Levin H, et al. Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation. 1998;98:2383 9. 37. Farrar DJ, Holman WR, McBride LR, et al. Long-term follow-up of Thoratec ventricular assist device bridgeto-recovery patients successfully removed from support after recovery of ventricular function. J Heart Lung Transplant. 2002;21:516 21. 38. Dandel M, Weng Y, Siniawski H, et al. Prediction of cardiac stability after weaning from left ventricular assist devices in patients with idiopathic dilated cardiomyopathy. Circulation. 2008;118:S94 S105. 39. Patel SR, Saeed O, Murthy S, et al. Combining neurohormonal blockade with continuous-flow left ventricular assist device support for myocardial recovery: a single-arm prospective study. J Heart Lung Transplant. 2013;32:305 12.