Bridge to Recovery
2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 2 Linguagem: Inglês
10.1161/circulationaha.111.040261
ISSN1524-4539
AutoresStavros G. Drakos, Abdallah G. Kfoury, Josef Stehlik, Craig H. Selzman, B.B. Reid, John Terrovitis, John N. Nanas, Dean Y. Li,
Tópico(s)Cardiac Structural Anomalies and Repair
ResumoHomeCirculationVol. 126, No. 2Bridge to Recovery Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBBridge to RecoveryUnderstanding 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 and Dean Y. Li, MD, PhD Stavros G. DrakosStavros G. Drakos 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.). , Abdallah G. KfouryAbdallah G. Kfoury 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.). , Josef StehlikJosef Stehlik 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.). , Craig H. SelzmanCraig H. Selzman 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.). , Bruce B. ReidBruce B. Reid 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.). , John V. TerrovitisJohn V. Terrovitis 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.). , John N. NanasJohn N. Nanas 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.). and Dean Y. LiDean Y. Li 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.). Originally published10 Jul 2012https://doi.org/10.1161/CIRCULATIONAHA.111.040261Circulation. 2012;126:230–241IntroductionLeft ventricular (LV) assist devices (LVADs) are increasingly used in everyday clinical practice either as a bridge for end-stage heart failure (HF) patients to heart transplantation 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 cardiovascular response of the patient at the organ level (ie, clinical outcomes).The LVAD patient population presents a series of significant 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 investigational 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 represents a relatively safe investigational platform because the hemodynamic support provided by VADs makes these patients significantly less vulnerable to any arrhythmic3 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 mechanical load, which drives the vicious cycle of myocardial remodeling and eventually leads to the clinical HF syndrome.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.6,7These important research advantages may transform this LVAD patient population into a precious translational research 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 unloading on the failing human heart.LVAD Bridge to Recovery: Clinical OutcomesWitnessing 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 antiremodeling drug therapy and the β-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 Reproducibility of the Harefield protocol results in larger patient cohorts and in a randomized fashion is of great importance.Download figureDownload PowerPointFigure 1. A through C, Serial chest radiographs and echocardiograms (M mode, parasternal long-axis view) from a 59-year-old patient with a multiyear history of idiopathic dilated cardiomyopathy and heart failure (HF) refractory to standard therapy, including inotropes (University of Athens, Greece). The patient underwent a combination of left ventricular assist device (LVAD) unloading and pharmacological therapy (Harefield protocol; see text for details) and was successfully weaned from the LVAD 6 months after implantation. He continued on standard HF pharmacological therapy and achieved sustained functional recovery with no signs or symptoms of HF over a 7-year follow-up period. EF indicates left ventricular ejection fraction; LVIDd, left ventricular end-diastolic diameter.Table 1. Left Ventricular Assist Device Bridge-to-Recovery StudiesStudyStudy DesignnAdjuvant Drug Therapy ProtocolMonitoring Heart Function ProtocolUnloading Duration, moRecovery,* n (%)Freedom From HF Recurrence, %/Follow-Up (Mean)US LVAD Working Group 20078P67Not standardizedYes4.56 (9)100/6 moBerlin 2008 and 20119,10R188Not standardizedYes435 (19)74 and 66/3 and 5 y, respectivelyHarefield 200611P15YesYes1111 (73)100 and 89/1 and 4 y, respectivelyHarefield 201112P20YesYes912 (60)83/3 yUniversity of Athens–Harefield 200713P8YesYes74 (50)100/2 yVancouver 201114P17Not standardizedYes74 (23)100/2 yGothenburg 200715P18Not standardizedYes73 (17)33/8 yPittsburgh 200316R18Not standardizedYes86 (33)67/1 yOsaka 200517R11Not standardizedNA155 (45)100/8–29 moPittsburgh 201018R102N/ANA514 (14)71/5 yMulticenter 200219R271N/ANA222 (8)77/3 yColumbia 199820R111N/ANA65 (4.5)20/15 moHF indicates heart failure; LVAD, left ventricular assist device; P, prospective; R, retrospective; and NA, not applicable.*Defined as LVAD explantation as a result of functional myocardial recovery.Similarly, as evident from Table 1, the success of LVAD weaning and of achieving sustained myocardial recovery varied significantly across the reported studies. This variability may have been caused by a variety of factors such as 1) nonstandardized heart function monitoring during LVAD support, 2) differences in medical therapy added to LVAD therapy, 3) variable duration of LVAD unloading, 4) divergences in LVAD weaning criteria, and 5) diversity of the populations studied in their propensity for recovery (type of HF, extent of pre-LVAD cardiac remodeling). These limitations were especially prominent in the multicenter LVAD trials focused on bridge-to-transplantation or destination therapy, which, for this reason, are not included in Table 1.24 As we discuss later, the wide range of results described in Table 1 might have contributed to the observed disconnect between clinical and biological outcomes of LVAD studies.Several studies described significant beneficial effects of LVAD unloading on specific parameters of cardiovascular function: LV and left atrial geometry and function, volume and pressure unloading, systemic hemodynamics, cardiopulmonary function, and exercise capacity.25–33 As reviewed in detail elsewhere,34 the impact of LVAD therapy on the arrhythmogenicity of the heart is controversial, with data from a recent small prospective study showing a significant decrease in premature ventricular contractions and ventricular couplets but no change in the incidence of nonsustained or sustained ventricular tachycardia.35 In terms of the cardiovascular functional effects of pulsatile- versus continuous-flow LVADs, several clinical studies that directly addressed this issue are summarized in Figure 2. It seems that pulsatile-flow LVADs might have some advantages over continuous-flow devices, which may be further translated to more favorable outcomes in terms of bridge to recovery.21 However, this issue warrants further investigation and remains to be proven in a properly designed prospective study. Moreover, with pulsatile-flow LVADs, the device ejection is not generally coordinated with ventricular contraction, and this device-heart dyssynchrony may paradoxically increase afterload. Continuous-flow LVADs are not subject to such dyssynchrony, and whether this theoretical advantage translates to clinical benefits warrants further investigation. Other potential advantages of continuous-flow devices include increased pump durability,1 which allows longer recovery time if needed, and the greater ability to modify the degree of unloading over time.Download figureDownload PowerPointFigure 2. Cardiovascular functional effects of pulsatile- vs continuous-flow left ventricular (LV) assist devices (LVADs) in advanced heart failure (HF) patients.1,21,27–30,32,36,38 E indicates pulsed-wave Doppler early mitral peak inflow velocity; E′, tissue Doppler early diastolic mitral annular velocity; dP/dtmax, first derivative of LV pressure with respect to time; LVEF, LV ejection fraction; PHT, fixed pulmonary hypertension; and RVF, acute right ventricular failure after LVAD implantation requiring right ventricular assist device support. *Absence of studies directly addressing the issues mentioned under this heading.LVAD Bridge to Recovery: Biological OutcomesParameters of cardiac remodeling that have been shown to be favorably altered—improved or normalized—during LVAD unloading are summarized in Table 2. These effects are described briefly in this section.Table 2. Cardiac Remodeling Parameters Favorably Altered With Left Ventricular Assist Device UnloadingMyocyte biology changes Hypertrophy Contractile dysfunction Calcium cycling Cytoskeletal proteins (sarcomeric, nonsarcomeric, membrane) β-Adrenergic signaling Metabolism and bioenergeticsMyocardial changes Myocyte death (apoptosis, autophagy, stress) Endothelium and microvasculature Sympathetic innervationCirculating systemic markers Neurohormones Natriuretic peptides CytokinesCardiac Hypertrophy- AtrophyPulsatile LVAD unloading has repeatedly been shown to induce the regression of cardiac myocyte hypertrophy: cell length, width, and thickness.22,39 In terms of the exact mechanisms governing hypertrophy regression during pulsatile-flow LVAD support, reviewed in detail elsewhere,26 ongoing investigations have been examining the roles of several complex pathways, including cyclooxygenase-2–induced Akt phosphorylation, mitogen-activated protein kinase/Erk, and Akt kinase/glycogen synthase kinase 3β. Whether the primary stimulus for the regression of hypertrophy is related directly to mechanical unloading/stretch or to circulating systemic factors needs to be investigated further.Animal models of prolonged unloading of nonfailing, nonhypertrophic myocardium by means of heterotopic transplantation,40 LVAD,41 or severing of the chordae tendinae of the mitral papillary muscle42 suggested that mechanical unloading could lead to cardiac myocyte atrophy. Whether this phenomenon applies exclusively to unloaded nonfailing and nonhypertrophic myocardium or also to hypertrophic and failing myocardium is controversial.43,44 In 2 human HF studies, unloading by means of pulsatile-flow LVAD support decreased cardiac myocyte size but not to levels below the respective of normal donor cardiac myocytes.45,46 In the latter study, light microscopy findings complemented by ultrastructural and metabolic data did not identify any evidence suggesting cardiac myocyte atrophy or degeneration during pulsatile-flow LVAD support.46 These data are in agreement with echocardiographic data in pulsatile-flow LVAD patients.8 However, whether prolonged mechanical unloading with the currently used continuous-flow LVADs affects the basic protein degradation pathways and/or fetal gene program overexpression implicated in cardiac hypertrophy and atrophic remodeling43,47,48 remains to be investigated.Contractile Dysfunction, Calcium Handling, and Cytoskeletal ProteinsThe myocyte contractile defects observed in failing hearts were shown to be reversed after pulsatile-flow LVAD unloading, showing improved shortening and relaxation in isolated myocytes and isolated strips of ventricular tissue.6,49 These interesting effects on contractile dysfunction can be partially explained by pulsatile-flow LVAD studies demonstrating significant improvements in Ca2+ handling such as faster sarcolemmal Ca2+ entry and shorter action potential durations, higher sarcoplasmic reticulum Ca2+ content, improved abundance of sarcoplasmic/endoplasmic reticulum calcium ATPase, decreased abundance of Na+/Ca2+ exchanger, and beneficial changes in L-type calcium channel and ryanodine receptor function.6,7,50,51 The aforementioned LVAD-induced benefits in myocardial contractility have been associated with favorable changes in cytoskeletal proteins: sarcomeric and nonsarcomeric proteins and the membrane-associated integrin pathway known to play an important role in mechanotransduction by mediating stretch signals from the extracellular matrix.52–56β-Adrenergic Signaling and Sympathetic InnervationPulsatile LVAD unloading has been shown to induce improvements in β-adrenergic receptor density, location and distribution pattern, contractile response to β-adrenergic stimuli, and adenyl cyclase activity.6,7,49 In a recent investigation using iodine 123-meta iodobenzylguanidine scintigraphy, it was shown that pulsatile-flow LVAD unloading resulted in improvements in sympathetic innervation in the failing heart accompanied by clinical, functional, and hemodynamic improvements.57Metabolism and BioenergeticsPulsatile LVAD support has been shown to be associated with improved respiratory capacity and augmented nitric oxide–dependent control of mitochondria respiration.58,59 Furthermore, cardiolipin, a lipid component of the mitochondrial membrane important for ATP formation and substrate transport, has been shown to normalize after pulsatile-flow LVAD unloading.60 These changes, along with post-LVAD alterations in the expression of several metabolism-related genes and proteins,49,51,61 require further investigation to elucidate their role within the broader metabolic changes occurring during cardiac remodeling.62Cell Death and StressMarkers of autophagy have been shown to be downregulated after LVAD unloading of failing hearts.63 Several studies demonstrating changes compatible with reduced apoptosis during LVAD unloading were recently reviewed in detail by Soppa et al.49 These favorable changes in myocyte attrition are complemented by data suggesting that pulsatile-flow LVAD unloading reduces myocardial stress, as indicated by the reductions of the stress proteins metallothionein and heme oxygenase-1.64,65Endothelium and MicrovasculaturePulsatile-flow LVAD support was associated with changes in the expression of genes involved in the regulation of vascular organization and migration.66 In addition, animal data showed that mechanical unloading by means of heterotopic transplantation increased microvascular density.67 In agreement with these experimental findings, a recent human study showed that microvascular density was decreased in the failing human hearts compared with normal donors and that pulsatile-flow LVAD unloading induced a significant increase in the microvascular density toward normalization.46 The same study provided immunohistochemical and ultrastructural evidence of endothelial cell activation that is consistent with the observed increase in microvascular density.46Natriuretic Peptides, Cytokines, and NeurohormonesPulsatile LVAD unloading has been associated with decreased levels of atrial and brain natriuretic peptides and tumor necrosis factor-α both in serum and in myocardial tissue.8,68,69 The changes in the levels of other key neurohormones implicated in the progression of HF syndrome appear to be more complex. Specifically, the circulating levels of epinephrine, norepinephrine, renin, angiotensin II, and arginine vasopressin have been shown to decrease during LVAD unloading.70 However, as discussed below, the effects on the myocardial tissue levels of these neurohormones are not uniform.Extracellular MatrixInvestigations of the effect of LVAD unloading on extracellular matrix have shown conflicting results; a few studies reported decreased fibrosis, whereas most other investigations found a significant increase in fibrosis.26,34,49 The explanation for the contradictory observations is not clear, with some attributing the inconsistent results to differences in the background medications or the applied methodology.26,49 This controversial issue was recently addressed with the use of advanced image analysis techniques in whole-field digital microscopy, an approach that reduces observer bias, markedly increases the amount of myocardial tissue analyzed, and permits comprehensive endocardium-to-epicardium evaluation.46 It was found that myocardial tissue from HF patients undergoing LVAD implantation, compared with normal myocardium, had increased interstitial and total fibrosis.46 The interstitial and total collagen content further increased after pulsatile-flow LVAD unloading in these patients.46 Recent findings on the effects of pulsatile-flow LVAD unloading on the myocardial tissue levels of neurohormones of the renin-angiotensin-aldosterone axis and matrix metalloproteinases support the above results.71,72 However, whether the observed increase in fibrosis is a manifestation of further progression of this aspect of cardiac remodeling that pulsatile-flow LVAD unloading failed to reverse or is a direct result of pulsatile-flow LVAD unloading actively inducing an increase in fibrosis warrants further investigation.Gene Expression, MicroRNAs, and Proteomic ProfilingStudies in LVAD patients investigated mRNA, microRNA, and protein expression profiling.73–77 We hope that future investigations using these technologies will consistently include in their study design the collection of functional myocardial recovery data77 and thus increase their potential to provide mechanistic insights.Why Do We Observe a Disconnect Between Clinical and Biological Outcomes?Any attempt to associate in a systematic and logical way the key LVAD-induced biological effects with their expected corresponding clinical outcomes would be challenging. It could be argued that the reported beneficial LVAD-induced biological outcomes (Table 2) should have more consistently led to better clinical outcomes in terms of functional myocardial recovery (Table 1). The anticipated "sequential pattern" of biology findings defining clinical functional response does not appear to always be clear or consistent (Tables 1 and 2). Therefore, we wonder why we observe these discrepancies:Structure Function Correlation: A Critical Starting Point That Has Yet to be Defined (see p 234)Major Limitations in Study Design (see p 235)Biological Signature of Myocardial Recovery: Still in Search (see p 236)Structure-Function Correlation: A Critical Starting Point That Has Yet to be DefinedOne possible reason for the observed disconnect between the clinical and biological outcomes is the attempt to correlate findings across separate clinical and biological studies rather than focusing this effort on investigations using the same structured and well-controlled approach. Specifically, as we have previously reviewed in detail,13 in most of the reported LVAD tissue/biological outcomes studies, no functional myocardial recovery data were collected; vice versa, most of the clinical outcomes/bridge-to-recovery studies (Table 1) were lacking a comprehensive structural or molecular investigational arm.13 As a consequence, we cannot distinguish between structural, cellular, and molecular changes that occur in all LVAD patients regardless of possible induced myocardial recovery and changes that occur exclusively in patients in whom LVAD unloading induced myocardial functional recovery (target 1 in Figure 3). These biological changes unique to LVAD patients who achieved functional recovery might help us identify mechanisms of reverse remodeling that lead to myocardial recovery. Examination of tissue from both patients with evidence of various degrees of LVAD-induced myocardial functional recovery (ie, responders) and LVAD patients without functional myocardial improvement (ie, nonresponders) is critical.34 This type of study8,50,51,53,54,56,57,61,77,79–81 becomes the springboard for further in-depth investigational steps through future animal and human studies that will determine causality and provide mechanistic insights.Download figureDownload PowerPointFigure 3. Left ventricular (LV) assist device (LVAD) unloading and cardiac reverse remodeling: unresolved issues and future directions. The figure includes a typical depiction of the progression of LV remodeling (maladaptive changes in structure and function)78 and emphasizes the central role of increased load in the vicious cycle of heart failure (HF) progression.4 LVAD therapy intervenes in this vicious cycle by inducing a profound degree of pressure and volume unloading (white rectangles). Ongoing research targets (identified with circled numbers) have been placed in specific locations corresponding to their potential relationship in the continuum of the cardiac remodeling and myocardial recovery processes (see Roadmap to Connect and Improve LVAD-Induced Clinical and Biological Outcomes: Future Directions for details).In fact, the ability offered by LVAD studies to correlate human tissue to functional data is something rare in clinical medicine. This type of tight association between structure and function is achievable in animal models; however, it is very unusual to achieve this level of understanding in human investigational models. From that perspective, the LVAD patient population offers an important opportunity for performing in-depth structure-function investigations that will, we hope, lead to clarification of some of the observed discrepancies between LVAD clinical and biological outcomes. The current absence of such in-depth structure-function investigations makes any attempt to connect the biological and clinical outcomes very difficult. In essence, at least a degree of the observed disconnect between clinical and biological outcomes is a result of these missing data.Major Limitations in Study DesignThe aforementioned disconnect between clinical and biological outcomes may also be a consequence of a series of major limitations that are confounding many of the reported studies. As analyzed in the following sections, these specific limitations may have led to an inaccurate description, and thus poor understanding of both the clinical and biological effects of LVAD unloading. Thus, attempts to understand the potential associations or connections between the reported clinical and biological outcomes might be hampered by several problems in the design of these studies. In essence, we may be trying to connect 2 locations on the map (ie, biological and clinical outcomes), but the coordinates of these 2 locations have not been well defined.Issues Limiting the Reported LVAD Biological OutcomesConfounding Effects of Concurrent Drug TherapyVarious medications known to affect the function and structure of the failing human heart (β-blockers, renin-angiotensin axis inhibitors, aldosterone antagonists) have been routinely used in previous studies in patients with LVADs, but no standardization or randomization of their use was attempted. In most LVAD tissue studies, no information on concurrent antiremodeling drug therapy was reported.34 In fact, systemic blood pressure increases in many LVAD patients, and consequently, these patients are often treated with high doses of these medications. This is an important confounder because, in the studies reported so far, the drug-induced effects on cardiac remodeling cannot be separated from the effects of mechanical unloading alone.Propensity for Reversal of Cardiac RemodelingThe patient populations studied so far differ in their potential for reversal of cardiac remodeling; factors such as specific HF cause and duration of HF symptoms have been reported to play significant role in this propensity for recovery.10,12,24 Both of these factors varied significantly among the reported clinical and biological studies, making comparisons or associations between their findings problematic.Variable Duration of LVAD SupportClinical and experimental studies demonstrated that the duration of mechanical unloading significantly affects the changes in the remodeling of the failing heart.8,25,44,53,82,83 Therefore, it might be misleading to either claim or negate associations between biological and clinical outcomes studies that had different durations of LVAD unloading. Even within a single study, more often than not, LVAD support duration varied considerably between patients.LVAD Era ChangeThe great majority of biological outcomes reported in the literature were derived from studies involving pulsatile-flow LVADs. However, because of mainly engineering reasons, newer second-generation, nonpulsatile, continuous-flow LV
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