Reverse Remodeling With Left Ventricular Assist Devices

Abstract

HomeCirculation: Heart FailureVol. 4, No. 2Reverse Remodeling With Left Ventricular Assist Devices Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBReverse Remodeling With Left Ventricular Assist DevicesA Review of Clinical, Cellular, and Molecular Effects Amrut V. Ambardekar, MD and Peter M. Buttrick, MD Amrut V. AmbardekarAmrut V. Ambardekar From the Division of Cardiology, University of Colorado Denver, Aurora, CO. Search for more papers by this author and Peter M. ButtrickPeter M. Buttrick From the Division of Cardiology, University of Colorado Denver, Aurora, CO. Search for more papers by this author Originally published1 Mar 2011https://doi.org/10.1161/CIRCHEARTFAILURE.110.959684Circulation: Heart Failure. 2011;4:224–233IntroductionOver 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.Table. Summary of Research of LVAD Support on Clinical Effects and the Cellular and Molecular Changes That May Contribute to Reverse RemodelingSummary of FindingsReferencesClinical effects MortalityMajority survive to transplant1Improved survival compared with medical therapy in nontransplant candidates2 Functional statusLower New York Heart Association HF class3Improved 6-minute walk test1, 3 Quality of lifeMinnesota Living With Heart Failure questionnaire score improved1, 3Kansas City Cardiomyopathy questionnaire score improved1, 3SF-36 score improved2Beck Depression Score with less depression2 Organ perfusionSerum creatine lower1Blood urea nitrogen lower1Serum liver function tests improved1 Chamber sizeLeft atrial size decreased7LV size decreased6, 7LV mass decreased6 ContractilityEjection fraction higher5–7LVAD explantation in majority5LVAD explantation in minority6 HemodynamicsCardiac output/cardiac index increase1, 3Mean pulmonary pressure lower1Pulmonary capillary wedge pressure lower1, 3 NeurohormonesEpinephrine and norepinephrine decreased18Renin decreased18Angiotensin II decreased18Arginine vasopressin decreased18 Natriuretic peptidesAtrial natriuretic peptide decreased19Brain natriuretic peptide decreased (serum and tissue levels)19 CytokinesTumor necrosis factor-α decreased (serum and tissue levels)6, 20 ElectricalQRS duration decreased21QT interval increased21QTc interval increased in initial period after LVAD21QTc interval shortened with sustained LVAD21Action potential duration shortened21, 22Cellular and molecular changes Myocyte morphologyLV myocyte hypertrophy regresses23–30Right ventricular myocyte size unchanged25LV myocyte atrophy in animals35–37 Myocyte histologyOverall histology only partially improved7, 39Distortion of sarcomeric proteins only partially improved26Cardiomyocyte DNA content decreased40Polyploid myocytes decreased and diploid myocytes increased40 ContractilityBasal myocyte contractility increased41, 42Improved contractile response to β-adrenergic stimuli41, 43, 44Abnormal force-frequency relationship either reversed or attenuated25, 27, 41, 45 β-Adrenergic systemβ-Receptor density increased43, 44, 46–49Normalization in location of β-receptors29, 47Adenyl cyclase activity higher49 Calcium handlingSarcolemmal Ca2+ entry faster22, 45, 50Sarcoplasmic reticulum Ca2+ content higher22, 45, 50SERCA abundance may increase to nonfailing levels25, 27, 45, 52Na+/Ca2+ exchanger abundance decreases to nonfailing levels27Phospholamban abundance unchanged (ratio of SERCA/phospholamban may improve)27, 53 Sarcomere proteinsAbundance of some sarcomeric proteins may increase57Posttranslational modifications of sarcomeric proteins may change48 Extracellular matrix and cytoskeletonCollagen content may increase or decrease6, 59–61Myocardial stiffness may decrease with angiotensin-converting enzyme inhibitors64Dystrophin improved67, 68 MetabolismImproved mitochondrial function69, 70 Cellular response to stressMetallothionein reduced24Heme oxygenase-1 decreased71Apoptosis and cell breakdown reduced72, 73 Gene expressionGene expression patterns may differentiate pre- from post-LVAD state74Many genes altered in HF, very few have complete reversal with LVAD84 MicroRNAsMany upregulated or downregulated in HF with normalization after LVAD85, 86May be more sensitive than gene expression for reverse remodeling86Clinical Effects of LVADsClinical Efficacy as Bridge to Transplantation and Destination TherapyLVADs were first introduced to support and stabilize patients with end-stage HF until a donor heart was available for cardiac transplantation. A multicenter, prospective study has shown that these devices restore cardiac output, improve hemodynamics, and are successful in bridging the majority of LVAD-supported patients to cardiac transplantation.1 The landmark REMATCH study further expanded the use of LVADs to patients with end-stage HF who were not transplant candidates, termed destination therapy.2 As confirmed in these trials as well as other trials and case series, patients who received LVADs demonstrated improved hemodynamics, functional status, and quality of life.Despite the significantly improved survival among LVAD patients in the REMATCH study compared with medical therapy,2 widespread use of LVADs for destination therapy was somewhat limited, even in transplant centers, because the 2-year survival was still quite low. This mortality was largely related to problems with bleeding, infection, and pump failure that were probably compounded by the first-generation, pulsatile flow LVADs. The second-generation, continuous axial flow LVADs are advantageous in that they are smaller and are less susceptible to mechanical wear and tear. In a randomized trial comparing these 2 types of LVADs, patients supported by the continuous flow devices had superior survival with less adverse events related to LVAD device failure compared with the pulsatile flow devices.3 As a result, the continuous flow LVAD is now the mechanical therapy of choice for both bridge to transplant and destination therapy.Clinical Efficacy as Bridge to RecoveryEarly in the use of LVADs as a bridge to transplant, isolated reports and case series noted some patients having sufficient recovery of native LV function to allow for LVAD explantation—leading to the idea of using LVADs as a bridge to recovery. The largest of these early reports was from Germany, where investigators noted successful weaning and LVAD explantation in 32 of 131 patients with chronic idiopathic dilated cardiomyopathy (mean duration of HF before LVAD implantation, 4.3 years).4 All of these patients received medical therapy with β-blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists while being supported with a LVAD for a mean duration of 4.6 months. The 5-year survival among patients who had LVAD explantation was 78.3%, with an HF recurrence rate of 31.3% in the first 3 years after LVAD removal.4Further enthusiasm for LVAD-induced reverse remodeling and use of LVADs as a bridge and facilitator for LV recovery was bolstered by a report from the United Kingdom of successful LVAD explantation in 11 of 15 patients with nonischemic cardiomyopathy.5 While receiving LVAD support for a mean duration of 320 days, patients in this series were initially treated with a combination of traditional HF medications including angiotensin enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists. With echocardiographic evidence of regression of LV enlargement, the β2-agonist clenbuterol was added to the pharmacological regimen to counteract atrophy. The authors reported that of the 11 patients who underwent successful LVAD explantation, only 2 patients died in the 4-year follow-up period (1 of arrhythmias 24 hours after explantation and 1 of lung carcinoma 27 months after explantation). Survival free of HF in this subpopulation was 100% at 1 year and 88.9% at 4 years.5Unfortunately, these initial optimistic single-center reports have yet to be replicated in larger multicenter studies. In the Multi-Institutional LVAD Working Group Study from the United States, only 6 of 67 patients (9%) underwent successful LVAD explantation for recovery.6 Thus, investigations into the mechanical, biochemical, cellular, and molecular effects of LVADs have become increasingly important in advancing our ability to optimize this therapy.Chamber SizeIt is clear that mechanical unloading with an LVAD successfully unloads the LV and results in reduction in the LV dilation seen in end-stage HF. Imaging evidence of decreased LV size is evident immediately after LVAD implantation on transesophageal echocardiography in the operating room7 and reductions in LV dilation and LV mass have been noted to persist for extended periods of time after LVAD placement,6 as illustrated in the Figure. In addition, LV pressure-volume recordings confirm lower LV volumes for equivalent pressure loads with LVAD support; however, these physiological changes may not be evident until more than 40 days after LVAD placement.8Download figureDownload PowerPointFigure. A, Transthoracic apical echocardiographic image obtained in end-diastole from a patient with idiopathic dilated cardiomyopathy demonstrates severe LV dilation. B, Follow-up image obtained in end-diastole from the same patient after placement of a continuous axial flow LVAD demonstrates mechanical unloading with normalization of LV dimensions. LVAD inflow cannula (asterisk) is visible in the LV apex. LV indicates left ventricle; LA, left atrium; RV, right ventricle; and Ao, aorta.The degree of unloading may vary, based on the type of LVAD used. Some have suggested that using pulsatile flow support may unload the heart to a greater degree than the newer continuous flow LVADs. In one study, echocardiographic LV dimensions as well as LV mass were more improved in patients supported with pulsatile LVADs compared with continuous flow LVADs.9 However, their larger size, poorer durability, and greater complication rate have limited the use of pulsatile flow LVADs. Whether there is an optimal ventricular geometry that might result in sustained ventricular recovery is an open question.Furthermore, most studies examining the effects of LVAD on chamber size have been done with full unloading of the LV. Some studies have examined the role of echocardiographic assessment of LV size after temporarily decreasing or turning off LVAD flow support as a predictor of recovery and successful LVAD explantation—in which persistently small LV dimensions or a limited increase in LV dimensions both correlate with better outcomes.6,10–13 Similarly, small LV dimensions with administration of dobutamine or during exercise may also be predictors for recovery during LVAD support.10,13Contractility and HemodynamicsIn addition to improving LV dimensions, LVAD support can greatly improve blood flow, thus increasing cardiac output and lowering filling pressure.1,3 Moreover, patients also demonstrate recovery of LV contractile function as evidenced by improved ejection fraction (EF). In a large recent cohort study, nearly a third of patients showed an EF of >40% with partial LVAD support.6 Interestingly, though the EF appeared to improve by 30 days, further support up to 120 days resulted in declining EF which approached pre-LVAD values.6 It has been postulated that LV atrophy may occur with prolonged LVAD support. Animal studies in which normal hearts were subjected to sustained mechanical unloading have shown cardiac atrophy, a decline in contractile function,14 an increase in activation of the fetal gene program,15 and activation of protein degradation pathways.16 However, there may be differential effects on unloading normal versus failing hearts. One study reported improvements in calcium handling properties and myocardial contractility from unloaded failing hearts only—unloading of normal hearts did not demonstrate such effects.17 Understanding clinical predictors of improved EF after LVAD placement and how to clinically balance the presumed beneficial impact of reverse remodeling with the potentially deleterious impact of muscle atrophy is an important area of clinical investigation.In addition, it is unclear how to predict whether the improvements in contractility and hemodynamics during LVAD support will persist after LVAD explantation. Higher EF values as assessed by echocardiography during full and partial LVAD support may be predictive of LV recovery and successful LVAD explantation.6,11–13 Furthermore, inotropic reserve as assessed by echocardiographic EF and dP/dt during administration of dobutamine may also have a role.6,10 The role of exercise echocardiographic and hemodynamic testing with partial and full LVAD support has also been studied in small numbers of patients—with lower filling pressure and greater exercise tolerance being more predictive than oxygen consumption or cardiac output.11,13 The optimal modalities and protocols that should be used to predict LV recovery during LVAD support and successful LVAD explantation remain largely unknown and are areas of active clinical investigation.Neurohormone, Natriuretic Peptide, and Cytokine LevelsThe initial compensatory neurohormonal activation of the failing heart chronically creates a vicious cycle that can exacerbate the failing phenotype. Many current evidence-based HF therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and β-blockers are meant to counteract this chronically maladaptive neurohormonal activation. There is clear evidence that by normalizing hemodynamics, LVADs result in great improvements in the neurohormonal milieu that is deranged in HF. Plasma epinephrine, norepinephrine, renin, angiotensin II, and arginine vasopressin levels all significantly decrease after LVAD implantation.18 Circulating as well as LV tissue levels of natriuretic peptides decrease after LVAD placement.19 Systemic cytokines such as tumor necrosis factor-α also decrease in the periphery as well as the LV tissue.6,20 These improvements in systemic circulating and paracrine factors suggest that the failing heart may have a more favorable environment to recover in after LVAD placement.Electric RemodelingIn addition to the structural and contractile effects of LVAD support, LVAD placement appears to have an effect on the heart's electric system. In ECG analysis of patients before and after LVAD placement, the QRS duration decreased, the QT interval increased, and the QTc increased.21 With sustained unloading, however, the QTc decreased. This finding was confirmed in isolated myocytes as demonstrated by a shortened duration of the action potential,21,22 suggesting an electric contribution to the improved contractile performance seen after LVAD therapy.Cellular and Molecular ChangesMyocyte MorphologyPathological hypertrophy is a hallmark feature of the failing myocyte. Numerous studies have suggested that LVAD support helps myocytes regress toward the dimensions of nonfailing myocytes.23–30 Although there does appear to be improvement in length, width, and thickness (thus decreasing myocyte volume and cross-sectional area), cell length appears to decrease the most with LVAD support.23 The relation of myocyte hypertrophy with LV recovery during LVAD support remains unclear. One study examining myocytes from LVAD supported hearts with improved EF compared with those without improved EF suggested that patients with smaller myocytes and less fibrosis at baseline (the time of LVAD implantation) would be more likely to recover contractile function as assessed by EF with LVAD support.28 Another study examining myocytes from LVAD patients with clinical recovery compared with LVAD patients without clinical recovery found that myocytes from both groups showed similar reductions in cell size, suggesting that reduction in myocyte hypertrophy is not associated with LV recovery.22The stimulus for the regression of hypertrophy appears to be related to mechanical unloading rather than changes in circulating systemic factors. It has been suggested that hypertrophy regression is more prominent with longer duration of support and that the greatest regression of hypertrophy occurs in the subendocardium.24 This theory is further supported by the fact that regression of hypertrophy appears to be more prominent in myocytes from the LV as opposed to the right ventricle.25 The biochemical mechanisms of myocyte hypertrophy regression with LVAD therapy are not well understood. Alterations in a number of signaling pathways have been examined. Specifically, a number of studies have noted that regulation of mitogen-activated protein kinases may lead to reduced myocyte hypertrophy and less myocyte apoptosis.31,32 In addition, paradoxical enhancement of transcription regulation of ribosomal biogenesis33 and activation of insulin-like growth factor-I34—both of which may serve to limit and/or counterbalance the parallel engagement of protein degradation pathways—have been described both in human and animal models. Interestingly, the elevated insulin-like growth factor-I expression found in patients with clinical recovery during LVAD placement correlated with stem cell recruitment factor SDF-1 expression.34 Insulin-like growth-factor-I and SDF-1 have been shown to be involved in stem cell recruitment and in limiting apoptosis, both of which may have beneficial roles in the myocardial response to damage and the process of reverse remodeling with mechanical unloading.Although there is reduction in myocyte hypertrophy with LVAD support, it is not clear to what extent atrophy occurs in human myocyte. Several animal models of unloading do suggest that myocyte atrophy can occur with prolonged mechanical unloading.35–38 One these studies used a rat heterotopic transplant model and found that LV unloading initially led to normalization of myocyte size with improvement in papillary muscle contractile function, but prolonged LV unloading resulted in myocyte atrophy, fibrosis, and worsening of papillary muscle function.38 If atrophy does in fact occur in human myocytes supported with LVADs, consideration may need to be given to partial LVAD unloading or pharmacological therapy with β2-adrenergic agonists such as clenbuterol to avoid atrophy and to enhance cellular mechanisms that might better allow for LV recovery.Myocyte HistologyAlthough the literature suggests that there is a clear reduction in myocyte size with LVAD support, whether there are improvements in other histological features is unclear. An autopsy study of myocardial tissue from patients before and after LVAD found that LVAD support reduced the amount of coagulative necrosis, myocytolysis, and myocyte waviness but did not change fibrosis, eosinophilia, or contraction bands.39 Another study showed reductions in wavy fibers and contraction band necrosis, but myocardial fibrosis increased.7Further evidence that myocyte hypertrophy reduction may not correlate to biochemical improvement came from histological staining and immunohistochemistry from a number of contractile proteins within the myocyte. Despite improvement in myocyte size, the widespread evidence of sarcomeric disarray including distortion of actin, tropomyosin, troponin C, troponin T, and titan before LVAD only partially recovered after LVAD.26 One protein, myosin, actually had a worse histological appearance after LVAD.26Cellular-level changes appear to be accompanied by changes within the myocyte nucleus as well, including possible reactivation of the cell cycle. The median cardiomyocyte DNA content and number of polyploid myocytes declined after LVAD, whereas diploid cardiomyocytes and binucleated cardiomyocytes increased after LVAD.40 This evidence suggests that an increase in diploid myocytes either through cell cycle progression with completion of mitosis or by an increase in differentiation of pluripotent stem cells may allow for cardiac regeneration.40ContractilityIn vitro assessments of contractility have suggested that there is an improvement in myocyte force with LVAD support. In a study of myocytes obtained from patients with HF at transplant compared with patients with HF supported with a LVAD at the time of transplant, the myocytes from LVAD supported patients had greater magnitude of shortening, faster time to peak contraction, and faster time to shortening.41 In paired samples from the same patient before and after LVAD, in vitro motility and force assays demonstrated a near normalization of maximal calcium activated force with LVAD42 and our laboratory has demonstrated similar improvements in isometric force generation in skinned cell fragments after LVAD support.There also appears to be improvement in the myocardial contractile response to β-adrenergic stimulation with LVAD support in patients with HF. Force measured from LV trabeculae from HF patients showed a blunted response to isoproterenol. By contrast, the response to isoproterenol in LV trabeculae from HF patients supported with a LVAD was similar to that of nonfailing myocardial tissue.43,44 Similar improvements were noted in myocyte sample preparations from HF patients with and without LVAD support at the time of transplant.41Finally, the failing heart is characterized by a negative force frequency relationship, and it is unclear whether LVAD support can reverse this abnormal finding. Two in vitro studies using LV trabeculae from nonfailing hearts, failing hearts, and failing hearts supported with a LVAD suggest that there is reversal of the force frequency relationship.25,45 Two other similar studies using trabeculae and myocyte preparations found an attenuated decline in the force-frequency relationship in samples from failing hearts supported with a LVAD but not restoration to the normal positive force-frequency relationship.27,41β-Adrenergic Systemβ-Adrenergic receptors are downregulated in patients with chronic HF. The improvement in contractile response to β-adrenergic stimulation probably involves reversal of this β-receptor downregulation and restoration of normal receptor density. The downregulation of β-receptors in HF requires targeting of phosphoinositide 3-kinase (PI3K)-γ and redistribution of β-receptors into endosomal compartments. One study of myocardial tissue from patients before LVAD implantation compared with tissue from nonfailing hearts found that increased β-receptor associated PI3K activity was associated with downregulation of β-receptors from the plasma membrane and sequestration into endosomes compared with tissue obtained after LVAD support.46 In short, LVAD support reversed PI3K-γ activation, normalized levels of β-receptors in the plasma membranes, and depleted β-receptors from endosomes. Multiple other studies have also noted increased β-adrenergic receptor density after LVAD placement.43,44,47–49 In addition to greater β-receptor density, 2 studies have suggested that β-receptors relocalize from an abnormal punctate/clumped pattern to the normal homogenous pattern after LVAD support.29,47Improvements in the adrenergic response after LVAD may also be related to changes in adenyl cyclase. Basal adenyl cyclase activity is lower in myocardium from failing hearts compared with nonfailing hearts, and isoproterenol-stimulated adenyl cyclase activity is blunted in failing hearts. LVAD support has been shown to increase basal and isoproterenol-stimulated adenyl cyclase activity to levels closer to that seen in nonfailing hearts.49Calcium HandlingCalcium is required for muscle contraction, and alterations in calcium handling of the cell may contribute to the decreased contractility and negative force-frequency relationship seen in HF. LVAD support does appear to be associated with changes in the calcium handling properties of the myocyte. Two studies have assessed calcium transients of myocytes from patients with HF and from those with HF supported with a LVAD. The LVAD-supported myocytes had calcium transients more similar to nonfailing myocytes, with a greater peak systolic ratio and a faster rate of decay than myocytes from failing hearts.27,41 Such changes in calcium transients are associated with faster calcium entry via sarcolemmal calcium channels, higher sarcoplasmic reticulum calcium content, and shorter action potential durations.22,45,50Changes in calcium cycling related to changes in the balance of the calcium regulatory proteins, sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA), the sarcolemmal Na/Ca exchanger, and phospholamban, have also been seen. LVAD support appears to increase Na/Ca exchanger and SERCA gene expression,8,51 but the effect of LVAD support on SERCA protein abundance is unclear. Some studies suggest no change in SERCA content with LVAD support, and others show an increase in SERCA content closer to nonfailing levels.25,27,45,52 Na/Ca exchanger abundance and activity decreased with LVAD support to levels closer to nonfailing hearts.27 There appears to be no change in phospholamban abundance, but the ratio of SERCA to phospholamban, an indicator of calcium uptake by the sarcoplasmic reticulum and of diastolic relaxation, appears to normalize early after LVAD.27,53 Further alterations in calcium cycling may be the result of changes in L-type calcium channel function and ryanodine receptor function because LVADs have been shown to affect the function of these channels via posttranslational modifications.44,54–56Although the impact of LVAD support on these calcium handling proteins seems evident, the effects of LVADs on calcium handling are incompletely understood. Likewise, the stimulus that drives these changes in calcium regulatory proteins is unclear. Systemic neurohormones seem unlikely to significantly contribute to such changes because variation in SERCA content appears to be localized to the LV and not the right ventricle.25 These changes may also vary with the duration of LVAD support because one study described normalization of SERCA and SERCA/phospholamban ratios early after LVAD implantation with reversion back to failing levels with prolonged LVAD support53—again raising the question of optimal timing.Sarcomeric ProteinsThe sarcomeric contractile proteins of actin, myosin, tropomyosin, and the troponin complex are responsible for cross-bridge cycling of actin thin filaments and myosin thick filaments—ultimately generating the force in striated muscle. As noted above, immunohistochemical analysis confirms widespread distortion of several of these sarcomeric proteins in failing hearts, and these are only partially improved with LVAD placement.26 Furthermore, alterations in the abundance of these sarcomeric proteins with LVAD support may contribute to the reverse remodeling process. In patients with evidence of LV recovery with LVAD placement, there were statistically significant increases in the sarcomeric proteins myosin heavy chain, troponin C, troponin T, and actin,57 although whether this translates into an increase in functional contractile elements is not clear.In addition, there may be changes in some of the posttranslational modifications of sarcomeric proteins after LVAD placement. For example, protein kinase A–dependent phosphorylation of troponin I in LVAD-supported hearts was lower compared with measurements before LVAD implantation.48 Animal models of unloading with heterotropic heart transplantation suggest that there are alterations in the protein kinase–phosphatase balance. These alterations may affect the phosphorylation state of sarcomeric proteins, which play a key role in the regulation of contractility and relaxation of the heart.58 There is still a gap in the knowledge of the effects of these proteins after LVAD support, and this remains an area for potential research and therapeutics.Extracellular Matrix and CytoskeletonNumerous studies have assessed changes in the extracellular matrix with LVAD support. Results have been inconsistent with regard to LVA