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Cardiac remodeling is an adaptive, compensatory biological process following an initial insult to the myocardium that gradually becomes maladaptive and causes clinical deterioration and chronic heart failure (HF). This biological process involves several pathophysiological adaptations at the genetic, molecular, cellular, and tissue levels. A growing body of clinical and translational investigations demonstrated that cardiac remodeling and chronic HF does not invariably result in a static, end-stage phenotype but can be at least partially reversed. One of the paradigms which shed some additional light on the breadth and limits of myocardial elasticity and plasticity is long term mechanical circulatory support (MCS) in advanced HF pediatric and adult patients. MCS by providing (a) ventricular mechanical unloading and (b) effective hemodynamic support to the periphery results in functional, structural, cellular and molecular changes, known as cardiac reverse remodeling. Herein, we analyze and synthesize the advances in our understanding of the biology of MCS-mediated reverse remodeling and myocardial recovery. The MCS investigational setting offers access to human tissue, providing an unparalleled opportunity in cardiovascular medicine to perform in-depth characterizations of myocardial biology and the associated molecular, cellular, and structural recovery signatures. These human tissue findings have triggered and effectively fueled a "bedside to bench and back" approach through a variety of knockout, inhibition or overexpression mechanistic investigations in vitro and in vivo using small animal models. These follow-up translational and basic science studies leveraging human tissue findings have unveiled mechanistic myocardial recovery pathways which are currently undergoing further testing for potential therapeutic drug development. Essentially, the field is advancing by extending the lessons learned from the MCS cardiac recovery investigational setting to develop therapies applicable to the greater, not end-stage, HF population. This review article focuses on the biological aspects of the MCS-mediated myocardial recovery and together with its companion review article, focused on the clinical aspects, they aim to provide a useful framework for clinicians and investigators., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) Bridge to Transplant (BTT) trial was a multicenter, prospective trial of the HeartWare Ventricular Assist Device (HVAD). The performance of the HVAD in various demographic sub-groups was evaluated., Methods: Baseline characteristics, adverse events, and survival were compared for men vs. women and whites vs. non-whites in the combined ADVANCE BTT and continued access protocol trial. Of 332 patients enrolled in these trials, 236 were men and 96 women, with 228 whites and 104 non-whites., Results: At baseline, women had a smaller body surface area (1.8 ± 0.2 vs. 2.1 ± 0.3 m2, p < 0.0001), less hypertension (50.0% vs. 61.9%, p = 0.05), and less ischemic cardiomyopathy (15.6% vs. 45.3%, p < 0.0001). Differences in Kaplan-Meier survival were not significant at 180 days (men, 91.8%; women, 91.7%) and 1 year (men, 85.3%; women, 85.1%) despite adjustment for baseline differences. Men had a lower incidence of early right heart failure and renal and respiratory dysfunction, and a shorter length of stay. In the analysis by race, non-whites were younger than whites and had less ischemic heart failure, more hypertension, and lower creatinine levels at baseline. Non-whites had lower rates of arrhythmia, bleeding requiring rehospitalization, and device malfunctions than whites. Survival was high in non-whites and whites, at 94.1% vs. 90.4% at 180 days and 89.2% vs. 82.8% at 1 year, respectively, despite adjustment for baseline differences., Conclusions: Although heart failure etiology differed between men and women and between whites and non-whites, sex and race were not factors that affected survival in patients receiving the HVAD as BTT, which was high in all sub-groups., (Copyright © 2015. Published by Elsevier Inc.)

Background: The HeartWare Ventricular Assist System (HeartWare Inc, Framingmam, MA) is a miniaturized implantable, centrifugal design, continuous-flow blood pump. The pivotal bridge to transplant and continued access protocols trials have enrolled patients with advanced heart failure in a bridge-to-transplant indication., Methods: The primary outcome, success, was defined as survival on the originally implanted device, transplant, or explant for ventricular recovery at 180 days. Secondary outcomes included an evaluation of survival, functional and quality of life outcomes, and adverse events., Results: A total of 332 patients in the pivotal bridge to transplant and continued access protocols trial have completed their 180-day primary end-point assessment. Survival in patients receiving the HeartWare pump was 91% at 180 days and 84% at 360 days. Quality of life scores improved significantly, and adverse event rates remain low., Conclusions: The use of the HeartWare pump as a bridge to transplant continues to demonstrate a high 180-day survival rate despite a low rate of transplant. Adverse event rates are similar or better than those observed in historical bridge-to-transplant trials, despite longer exposure times due to longer survival and lower transplant rates., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Testing of native myocardial function in patients with continuous-flow pumps is challenging as reduction/cessation of the pump could result in regurgitation, although the amount and significance of this regurgitation remains unknown. The aim of this study was to determine the optimal speed at which to assess the native left ventricular (LV) function and the physiologic response to speed reduction., Methods: Fifteen male patients with a HeartMate II (HMII) device were studied prospectively on 46 occasions. Measurements were performed serially at three device speed settings: baseline speed; 6,000 rpm; and either 5,000 rpm (Group A) or 4,000 rpm (Group B). The device's forward and reverse velocity (Vmax(f), Vmax(r)), forward and reverse velocity time integral (VTI(f), VTI(r)) and blood volume (BV) were also measured using Doppler with LV echocardiographic parameters and peripheral hemodynamics., Results: No adverse incidents were reported. Speed reduction to 6,000 rpm resulted in a significant decrease in Vmax(f), VTI(f) and BV. There was no significant difference in either forward or reverse flow with further speed reduction in either group. Speed reduction to <6,000 rpm did not have a significant effect on LV loading., Conclusions: Speed reduction in patients with the HMII device is safe. There was no difference between 6,000 rpm and lower speeds, suggesting that 6,000 rpm is sufficient to assess native myocardial function. The absence of significant retrograde filling suggests that LV loading is a physiologic response to speed reduction at 6,000 rpm., (Copyright © 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Abnormalities in the extracellular matrix (ECM) can occur in heart failure. In this study we analyzed ECM gene expression in patients with advanced dilated cardiomyopathy who did and did not develop sustained myocardial recovery after left ventricular assist device (LVAD) unloading combined with pharmacologic therapy., Methods: Myocardial gene expression of collagens (COL1A1 and COL3A1), fibronectin (FN), matrix metalloproteinases (MMPs 1 to 14), tissue inhibitors of metalloproteinases (TIMPs 1 to 4), connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-beta1) and THY1 was measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) at LVAD implantation and again at explantation (recovery, n = 11) or transplantation (non-recovery, n = 5)., Results: The non-recovery group had higher levels of pro-fibrotic markers (COL1A1, TGF-beta1 and THY1) at implantation compared with the recovery group (1.82 +/- 0.74-, 1.81 +/- 0.69- and 3.01 +/- 1.70-fold, respectively; p

Background: Ventricular assist devices are effective in severe end-stage cardiac failure but outcomes remain poor in critically ill patients. Cheaper and less invasive short-term devices have been used in this setting. We report our experience with the Levitronix CentriMag short-term ventricular assist device as a potential bridge prior to deciding whether a more expensive device should be used or whether transplantation should be undertaken., Methods: Since August 2003, 16 moribund patients (14 males; age 32.7 +/- 14.9 [range 16 to 62] years) have been supported with the CentriMag device as a "bridge to decision." Twelve patients had an intra-aortic balloon pump pre-operatively, 13 had multi-organ failure, 11 had septic shock, and in 5 patients the neurologic status was uncertain at the time of insertion of the device., Results: Operative mortality was 18.7% (3 patients). Seven patients (43.7%) were reoperated for bleeding. The mean support duration was 46.9 +/- 32.3 (range 6 to 111) days. There were 2 late deaths during Levitronix utilization. Follow-up was 12.8 +/- 12.5 (range 0.6 to 43) months. Eleven patients (68.7%) are currently alive and well: 2 patients recovered and had the Levitronix device explanted; 6 patients were upgraded to a long-term device; and 3 patients were bridged directly to transplantation. The actuarial survival at 1, 6 and 12 months was 85.7%, 64.9% and 64.9%, respectively. There were no instances of device failure., Conclusions: The Levitronix device is effective in rescuing critically ill "moribund" patients and can provide an opportunity for low-cost support and optimization of their condition prior to deciding whether a more expensive device should be placed or if transplantation should be undertaken. Better candidate selection for further procedures can then be allowed.

Background: Longer term quality of life (QOL) outcome in patients who have had a left ventricular assist device (LVAD) explanted due to myocardial recovery (bridge to recovery, BTR) remains uncertain. This study evaluates the QOL of those patients and compares them to bridge-to-transplant (BTT) and transplanted (Tx) patients., Methods: Anonymized QOL Short Form (SF)-36 questionnaires were sent to a total of 72 patients, including: 14 BTR patients (3.6 +/- 1.9 years since LVAD removal); 29 BTT patients (3.3 +/- 2.3 years since transplantation); and 29 Tx patients (3.8 +/- 0.6 years since transplantation)., Results: Questionnaires were returned by 78.6%, 79.3% and 56.7% of patients from the BTR, BTT and Tx groups, respectively. In all but two of the domains of the SF-36 questionnaire, scores were significantly better in the BTR group compared with the BTT and Tx groups. Analysis of the two main dimensions and the total SF-36 score between the three groups showed that: (i) physical health dimension tended to be better in BTR (71.9 +/- 21) vs BTT (64.5 +/- 23.2) and Tx (41.4 +/- 48) groups (p = not statistically significant [NS]); (ii) mental health dimension was better in both BTR (78 +/- 16.1) and BTT (71.4 +/- 21.1) groups compared with the Tx group (39.4 +/- 44, p < 0.05); and (iii) total SF-36 score was significantly higher in the BTR and BTT groups compared with the Tx group (76.8 +/- 17.6 and 69 +/- 21.1 vs 41.4 +/- 48, p = NS)., Conclusions: BTR patients appear to have better QOL than both BTT and Tx patients. In addition, BTT patients seem to have a better QOL compared with Tx patients, suggesting that placement of ventricular assist devices could improve the physiologic outcome for transplanted patients.

Background: Assessment of myocardial recovery during left ventricular assist device (LVAD) support is difficult to perform both safely and effectively. We developed a test involving short-term interruption of LVAD support with measurements of several hemodynamic and echocardiographic parameters at rest and, whenever possible, after exercise, to investigate inotropic reserve., Methods: After full heparinization, the HeartMate I XVE device was switched off. MAP, heart rate (HR), ejection fraction (EF) and left ventricular dimensions were measured on switching off, after 5, 10 and 15 minutes, and after 6-minute walk (6MW)., Results: In total, 207 serial tests were performed on 22 patients. A total of 97.6% of the patients tolerated the tests. Of the 202 tolerated tests, 130 were performed on 16 patients who had their device explanted due to myocardial recovery (recovered group), and 72 on 6 patients who did not recover and were transplanted (non-recovered group). After device discontinuation there was an immediate drop in mean arterial blood pressure (MAP), a rise in HR, a reduction in EF and increases in ventricular dimensions. These changes tended to be more marked in the non-recovered group. After 6MW, the recovered group had a significant rise in HR and EF and a non-significant increase in MAP, whereas, the non-recovered group there was a significant drop in MAP compensated by a rise in HR. The distance walked in the recovered group was significantly higher (544 +/- 102 vs 418 +/- 109 meters, p < 0.05). MAP, pulse pressure and EF were strong predictive factors for recovery., Conclusions: Acute discontinuation of the device to assess recovery is safe and well tolerated and is followed by specific changes in hemodynamic and echocardiographic parameters. This helps in the assessment of recovery, particularly with regard to findings taken after exercise.

Background: Reverse remodeling can occur after left ventricular assist device (LVAD) support, which is sufficient in some cases to allow explantation of the device without cardiac transplantation. The molecular mechanisms involved remain unknown. A specific pattern of expression of sarcomeric and non-sarcomeric proteins in the myocardium is thought to be essential for normal myocardial function. However, a detailed protein analysis of their role in recovery has not been performed previously., Methods: Myocardial samples were collected at implantation and explantation in 7 patients with dilated cardiomyopathy who had sufficient recovery for device explantation. Western blotting and immunoprobing were used to quantitate changes in the expression of sarcomeric and cytoskeletal proteins., Results: At implantation, all patients (6 men and 1 woman, age [mean +/- SD] 36.1 +/- 10.4 years) were inotrope-dependent; ejection fraction (EF) was 12.6 +/- 4.6%, cardiac index (CI) was 1.66 +/- 0.5 liters/min/m2 and pulmonary capillary wedge pressure (PCWP) was 26 +/- 6 mm Hg. Mean duration of LVAD support was 333 +/- 235 days. Prior to explantation, EF (pump off for 15 minutes) was 62.7 +/- 11.4%, CI was 2.7 +/- 0.7 liters/min/m2 and PCWP was 10.9 +/- 3.5 mm Hg. At explantation, the following statistically significant increases were noted: myosin heavy chain, 1.90-fold (p < 0.05); sarcomeric actin, 1.80-fold (p < 0.05); alphaII spectrin, 1.40-fold (p = 0.05); troponin C, 1.34-fold (p < 0.05); troponin T, 2.10-fold (p < 0.05); cytoskeletal actinin, 5.16-fold (p < 0.05); and smooth muscle alpha-actin, 4.10-fold (p = 0.05). Although not significant (NS), increases were also seen for: troponin I, 1.27-fold; myosin light chain 1, 1.28-fold; tropomyosin, 1.28-fold; and sarcomeric actinin at 3.24-fold. There was a decrease in talin of 2.01-fold (p = NS) between implant and explant. Vimentin was unchanged., Conclusions: Our data suggest that reverse remodeling of the myocardium parallels improvements in hemodynamic function in LVAD patients showing clinical myocardial recovery.

Background: The UK Government funds ventricular assist device (VAD) implantation as bridge to transplantation (BTT) at three centers. Results from this program have not been published., Methods: All 70 VAD implants for BTT, 71 inotrope-dependent and 179 non-VAD transplant candidates, accepted for transplantation between April 2002 and December 2004, were prospectively monitored for survival to transplantation, survival overall and quality of life., Results: Of the 70 VAD patients, 31 (44%) survived to heart transplantation, 4 (6%) were bridged to recovery and 5 remained on support at the end of the study. Thirty patients (43%) died while on support. Overall survival from VAD implant was 52% at 1 year. Ten percent of non-VAD inotrope-dependent patients and 9% of routine transplant candidates died while on the waiting list. For transplant recipients, 12-month post-operative survival was 84%, 85% and 84%, respectively, for VAD, inotrope-dependent and routine transplant candidates. VAD and non-VAD patients had similar post-transplant adverse event rates., Conclusions: There was a role for VAD bridge to transplant for selected patients in the UK, despite the availability of an effective urgent transplant list. VAD patients who underwent transplantation had survival rates similar to other transplant candidates.

Background: Mechanisms underlying the rapid deterioration of heart failure patients who subsequently require left ventricular assist device (LVAD) support are poorly understood. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a key role in myocardial remodelling and heart failure. We hypothesized that MMP and TIMP expression would be altered in these patients., Methods: Quantitative polymerase chain reaction was used to measure myocardial messenger RNA levels of MMP1 to MMP14, TIMP1 to TIMP4, collagen I and collagen III in 24 dilated cardiomyopathy (DCM) patients with deteriorating clinical status who required LVAD support (LVAD Group) and in 7 stable DCM patients undergoing transplantation without need for LVAD support (Tx Group)., Results: Levels of MMP1, MMP8 and TIMP4 were higher in the LVAD Group compared with the Tx Group (188% +/- 141%, 646% +/- 432%, and 66% +/- 33% higher, respectively, p < 0.05) whereas MMP2, MMP9, MMP10, MMP11, and MMP14 levels were similar. MMP3, MMP7, MMP12, and MMP13 were undetectable. All TIMPs were generally higher in the LVAD group, but only TIMP4 reached significance. Collagen I and III were not altered. We tested for correlations between MMP and TIMP expression with myocardial cytokine levels. MMP8 correlated positively with interleukin-6 and interleukin-1beta, suggesting a link between cytokines and MMPs in these patients., Conclusions: The data show that high myocardial collagenase (MMP1 and MMP8) expression without compensatory changes in collagen or TIMP expression is a feature of patients requiring LVAD support. This may be linked in part to elevated cytokine expression and suggests collagenase activity may be an important therapeutic target in deteriorating heart failure.

Background: Primary graft failure after heart transplantation is a well-recognized catastrophic complication with a high mortality rate. It is becoming more frequent due to the increasing use of marginal donors. In these difficult cases a ventricular assist device (VAD) as a bridge to recovery or as a bridge to re-transplantation can be used. The recently introduced Levitronix Centrimag centrifugal pump might be an ideal device for this purpose., Methods: In this study we describe 2 patients with primary graft failure who received a Levitronix in the last 2 years, immediately after failure to wean from cardiopulmonary bypass. Biventricular support was necessary in both patients., Results: One patient was successfully re-transplanted after 2 days of support, and subsequently discharged. After 16 months she has good ventricular function with no symptoms of cardiac failure. The second patient showed signs of ventricular recovery after a few days and was weaned from the device after 7 days, with good graft function. No device-related complications were recorded. After 14 days he was discharged from the intensive care unit (ICU), and a post-operative echocardiogram showed normal dimensions, good ejection fraction and no valvular regurgitation. He was discharged home 26 days after the transplant., Conclusions: In our experience, the Levitronix Centrimag seems to be safe and effective in the treatment of primary graft failure, achieving effective circulatory support and ventricular off-loading. We propose its use in isolated or biventricular graft failure either as bridge to re-transplant or as a bridge to recovery.

Background: Transplantation for patients with a high pulmonary vascular resistance (PVR) carries an increased risk of mortality and right heart failure following heart transplantation and continues to be a major problem. We evaluated the use of hearts from patients who underwent heart and lung transplantation for primary pulmonary hypertension (PPH) as part of a domino procedure because these hearts have hypertrophied right ventricles used to increased pulmonary pressures, but could have a compromised left ventricle or irreversible damage of the right ventricle., Methods: We reviewed 12 patients with PVR >4 Wood units who underwent orthotopic heart transplantation between 1989 and 1998 using hearts from donors with PPH as part of a domino procedure., Results: We studied 10 men and 2 women, mean age 42.9 years. Mean PVR was 5.3 (range, 4-9) Wood units. Mean ischemia time was 85.3 minutes, and mean donor age was 32 years. Actuarial survival was 75% at 1 year and 75% at 5 years. In the early post-operative period, 3 patients had temporary arrhythmias, 2 required permanent pacemaker implantation, 1 had atrial fibrillation, and 1 had ventricular tachycardia that required defibrillator implantation. At a mean follow-up of 7.8 years, 2 patients had developed asymptomatic transplant coronary disease (both at 8.5 years after transplantation), 1 moderate and 1 very mild; the rest had none. Mean left ventricular ejection fraction at latest follow-up was 70.1% (range, 63%-78%). Right ventricular function assessed clinically and by echocardiography was adequate in the short and long term., Conclusions: Our results suggest that heart and lung recipients with PPH can provide useful donor hearts to patients with increased PVR and that these hearts function well in the intermediate and long term.

Background: Cytokine activation in the myocardium of deteriorating patients with heart failure who undergo left ventricular assist-device (LVAD) implantation has been documented, but the underlying mechanisms remain poorly understood. We hypothesized the innate immune system is activated with expression of Toll-like receptor 4 (TLR4), leading to cytokine activation in these patients., Methods: We used quantitative real-time reverse-transcriptase polymerase chain reaction to measure TLR4, interleukin-1 (IL-1) receptor, IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) mRNA expression in myocardial samples from 36 patients. We compared 18 patients who underwent LVAD implantation with 18 patients with less severe heart failure who underwent elective heart transplantation., Results: Toll-like receptor 4 expression was 1.69-fold greater (p < 0.05) and IL-1 receptor expression was 3.64-fold greater (p < 0.0001) in the deteriorating patients who required LVADs. Myocardial TNF-alpha (1.71-fold, p < 0.05), IL-6 (2.57-fold, p < 0.005), and IL-1 beta (9.78-fold, p < 0.001) also were increased in the LVAD candidates. Toll-like receptor 4 expression correlated strongly with IL-1 receptor expression (r= 0.75, p < 0.0001) and with IL-1 beta expression in individual patients (r = 0.7, p < 0.0001). Interleukin-1 receptor expression also correlated with IL-1 beta expression (r = 0.78, p < 0.0001) within patients. We found no correlation between TLR4 and either TNF-alpha or IL-6 expression., Conclusions: Patients who required LVAD support showed evidence of innate immune system activation, indicated by an increase in the key effector molecule TLR4 associated with a specific pattern of cytokine expression in the myocardium.

Background: The authors previously identified and compared alterations in gene expression in the myocardia of patients with deteriorating heart failure who underwent left ventricular assist device (LVAD) implantation with those of patients with stable end-stage failure (ESF). We hypothesized that matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), would be implicated in the mechanisms that underlie deteriorating heart failure., Methods: Gridded macro-array filters were used to provide a broad overview of MMP and TIMP mRNA expression in heart failure. Precise mRNA levels of TIMP1, MMP1, and beta-spectrin were determined using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) of myocardial samples from 27 patients with deteriorating heart failure who underwent LVAD implantation, from 17 patients with stable ESF who underwent elective heart transplantation, and from 28 donor organs with good hemodynamic function., Results: Gridded macro-arrays analysis of pooled failing heart samples determined that TIMP1 mRNA was the most readily detectable TIMP in failing myocardium. Quantitative RT-PCR showed that expression levels in individual patients were similar in patients with stable ESF (1.00 +/- 0.24, n = 17) and in donor organ samples (1.49 +/- 0.22, n = 28) but were significantly increased in the deteriorating heart failure group (5.38 +/- 0.32, n = 26, p < 0.0001 compared with patients with ESF). Similarly, MMP1 levels did not differ between donor and ESF groups but increased in the deteriorating failure group (6.04 +/- 0.50, n = 27, p < 0.001 compared with the ESF group). Levels of beta-II spectrin were the same in all 3 groups. Both TIMP1 and MMP1 showed positive correlation with each other and with previously determined levels of mRNA for both interleukin-1beta (IL-1beta) and IL-6 in this patient series when considering all patients individually, but neither correlated with tumor necrosis factor alpha., Conclusions: Patients with deteriorating heart failure have increased expression of TIMP1 and MMP1 mRNA. Correlation with pro-inflammatory cytokines suggests common pathways of regulation and potential activation by IL-6 and IL1-beta.