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Background: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed "responders"). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown.Methods: To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders.Results: These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions.Conclusions: This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Left ventricular assist device (LVAD) unloading and hemodynamic support in patients with advanced chronic heart failure can result in significant improvement in cardiac function allowing LVAD removal; however, the rate of this is generally considered to be low. This prospective multicenter nonrandomized study (RESTAGE-HF [Remission from Stage D Heart Failure]) investigated whether a protocol of optimized LVAD mechanical unloading, combined with standardized specific pharmacological therapy to induce reverse remodeling and regular testing of underlying myocardial function, could produce a higher incidence of LVAD explantation.Methods: Forty patients with chronic advanced heart failure from nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled from 6 centers. LVAD speed was optimized with an aggressive pharmacological regimen, and regular echocardiograms were performed at reduced LVAD speed (6000 rpm, no net flow) to test underlying myocardial function. The primary end point was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with sustained remission from heart failure (freedom from transplant/ventricular assist device/death) at 12 months.Results: Before LVAD, age was 35.1±10.8 years, 67.5% were men, heart failure mean duration was 20.8±20.6 months, 95% required inotropic and 20% temporary mechanical support, left ventricular ejection fraction was 14.5±5.3%, end-diastolic diameter was 7.33±0.89 cm, end-systolic diameter was 6.74±0.88 cm, pulmonary artery saturations were 46.7±9.2%, and pulmonary capillary wedge pressure was 26.2±7.6 mm Hg. Four enrolled patients did not undergo the protocol because of medical complications unrelated to the study procedures. Overall, 40% of all enrolled (16/40) patients achieved the primary end point, P<0.0001, with 50% (18/36) of patients receiving the protocol being explanted within 18 months (pre-explant left ventricular ejection fraction, 57±8%; end-diastolic diameter, 4.81±0.58 cm; end-systolic diameter, 3.53±0.51 cm; pulmonary capillary wedge pressure, 8.1±3.1 mm Hg; pulmonary artery saturations 63.6±6.8% at 6000 rpm). Overall, 19 patients were explanted (19/36, 52.3% of those receiving the protocol). The 15 ongoing explanted patients are now 2.26±0.97 years after explant. After explantation survival free from LVAD or transplantation was 90% at 1-year and 77% at 2 and 3 years.Conclusions: In this multicenter prospective study, this strategy of LVAD support combined with a standardized pharmacological and cardiac function monitoring protocol resulted in a high rate of LVAD explantation and was feasible and reproducible with explants occurring in all 6 participating sites. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01774656. [ABSTRACT FROM AUTHOR]

The article offers information on the role of the lymphatic system in the modulation of cardiac disease, leading to an enhanced interest in the potential therapeutic manipulation of cardiac lymphangiogenesis. Information on chronic rejection and cardiac allograft vasculopathy as well as the modulation of the cardiac lymphatic response to injury to attenuate disease is presented.

Background: The number of centers with left ventricular assist device (LVAD) research programs focused on cardiac recovery is very small. Therefore, this phenomenon has been reported in real-world multi-center registries as a rare event.Objectives: This study evaluated the incidence of cardiac recovery with an a priori LVAD implantation strategy of bridge-to-recovery (BTR) and constructed a recovery predictive model.Methods: The study included LVAD recipients registered in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Cardiac recovery was evaluated in BTR and non-BTR patients. A weighted score was derived and externally validated in patients of the Utah Cardiac Recovery (UCAR) program.Results: Of 15,138 INTERMACS patients, cardiac recovery occurred in 192 (1.3%). The incidence of recovery was 11.2% (n = 14) in BTR compared with 1.2% (n = 178) in non-BTR patients (p < 0.0001). Independent predictors of recovery included: age <50 years, non-ischemic cardiomyopathy, time from cardiac diagnosis <2 years, absence of ICD, creatinine ≤1.2 mg/dl, and LVEDD <6.5 cm (c-index: 0.85; p < 0.0001). A weighted score termed I-CARS, effectively stratified patients based on their probability of recovery. I-CARS was validated in the UCAR cohort (n = 190) with good performance (AUC: 0.94; 95% CI: 0.91 to 0.98). One-year survival after LVAD explantation, available in INTERMACS for 21 (11%) patients, was 86%.Conclusions: The incidence of cardiac recovery is higher in patients implanted with an a priori BTR strategy. We developed a simple tool to help identify patients in whom recovery is feasible. In BTR patients with favorable characteristics, I-CARS suggests a 24% probability of successful LVAD explantation. Large-scale studies to better address post-explantation outcomes are warranted. [ABSTRACT FROM AUTHOR]

Myocardial remodeling induced by pressure and volume overload drives the vicious cycle of progressive myocardial dysfunction in chronic heart failure (HF). Mechanical volume and pressure unloading induced by implantable cardiac assist devices allows a reversal of stress-related compensatory responses of the overloaded myocardium so that selected patients requiring long-term mechanical circulatory support for advanced HF can achieve clinically meaningful degrees of improvement in the structure and function of their native heart. Insights from clinical and translational studies on myocardial recovery with mechanical circulatory support may enhance the understanding of how the pathophysiologic mechanisms of HF progression might be reversed. The end points of ongoing and future translational and clinical studies are discussed to identify specific investigational strategies that may advance the field of myocardial recovery driven by hemodynamic unloading of the heart. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to prospectively investigate the longitudinal effects of continuous-flow left ventricular assist device (LVAD) unloading on myocardial structure and systolic and diastolic function. Background: The magnitude, timeline, and sustainability of changes induced by continuous-flow LVAD on the structure and function of the failing human heart are unknown. Methods: Eighty consecutive patients with clinical characteristics consistent with chronic heart failure requiring implantation of a continuous-flow LVAD were prospectively enrolled. Serial echocardiograms (at 1, 2, 3, 4, 6, 9, and 12 months) and right heart catheterizations were performed after LVAD implant. Cardiac recovery was assessed on the basis of improvement in systolic and diastolic function indices on echocardiography that were sustained during LVAD turn-down studies. Results: After 6 months of LVAD unloading, 34% of patients had a relative LV ejection fraction increase above 50% and 19% of patients, both ischemic and nonischemic, achieved an LV ejection fraction ≥40%. LV systolic function improved as early as 30 days, the greatest degree of improvement was achieved by 6 months of mechanical unloading and persisted over the 1-year follow up. LV diastolic function parameters also improved as early as 30 days after LVAD unloading, and this improvement persisted over time. LV end-diastolic and end-systolic volumes decreased as early as 30 days after LVAD unloading (113 vs. 77 ml/m2, p < 0.01, and 92 vs. 60 ml/m2, p < 0.01, respectively). LV mass decreased as early as 30 days after LVAD unloading (114 vs. 95 g/m2, p < 0.05) and continued to do so over the 1-year follow-up but did not reach values below the normal reference range, suggesting no atrophic remodeling after prolonged LVAD unloading. Conclusions: Continuous-flow LVAD unloading induced in a subset of patients, both ischemic and nonischemic, early improvement in myocardial structure and systolic and diastolic function that was largely completed within 6 months, with no evidence of subsequent regression. [Copyright &y& Elsevier]

Background:--Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list. Methods and Results:--We analyzed mortality and morbidity in 33073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, IB, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P<0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P<0.0001) and similar to that in status IB patients (HR, 1.04; P=0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P=0.12) and lower mortality compared with status lAand IB patients (HR, 0.24 and 0.47; P<0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P=0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P<0.0001) and temporary VADs (HR, 7.72; P<0.0001). Conclusions:--Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts. [ABSTRACT FROM AUTHOR]

The article discusses a study on the use of Left ventricular (LV) assist devices (LVADs) as a tool for end-stage heart failure (HF) patients to heart transplantation or as a permanent therapy. It mentions that increase in clinical use of LVADs presents a key opportunity for in-depth investigations of the biology of the failing human heart. It also informs that trough biological and clinical outcomes it is possible to identify new therapeutic strategies of myocardial recovery and regeneration.

Background: Patients bridged to heart transplantation with left ventricular assist devices (LVADs) have been reported to have higher post-transplant mortality compared with those without LVADs. Our aim was to determine the impact of the type of LVAD and implant era on post-transplant survival. Methods: In this study we included 8,557 patients from the registry of the International Society for Heart and Lung Transplantation. We examined post-transplant outcomes in 1,100 patients bridged to transplant with pulsatile-flow LVADs between January 2000 and June 2004 (first era), 880 patients bridged with pulsatile-flow LVADs between July 2004 and May 2008 (second era), and 417 patients bridged with continuous-flow LVADs in the second era. Patients who required intravenous inotropes but not LVAD support (n = 2,728) and patients who did not require either LVAD or inotropes (n = 3,432) served as controls. Results: Post-transplant survival of patients bridged with pulsatile LVADs improved significantly between the first and the second era (p = 0.03). In the second era, there was no significant difference in post-transplant survival of patients bridged with pulsatile- vs continuous-flow LVADs (p = 0.26), and survival rates in the 2 groups were not statistically different from that of the non-LVAD group. Graft rejection was similar in patients bridged with LVADs compared to those without LVADs. Conclusions: In the most recent era, the use of either pulsatile- or continuous-flow LVADs did not result in increased post-transplant mortality. This finding is important as the proportion of patients with LVADs at the time of transplant has been rising. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krev1 interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Krit1. PDCD10 bound to germinal center kinase III (GCKIII) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcd10 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity. [ABSTRACT FROM AUTHOR]

Objectives: This study investigates alterations in myocardial microvasculature, fibrosis, and hypertrophy before and after mechanical unloading of the failing human heart. Background: Recent studies demonstrated the pathophysiologic importance and significant mechanistic links among microvasculature, fibrosis, and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown, and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial. Methods: Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n = 15) and from normal donors (n = 8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size, and glycogen content. Ultrastructural assessment was done with electron microscopy. Results: Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p = 0.001) and a 36% decrease in microvascular lumen area (p = 0.028). We also identified, in agreement with these findings, ultrastructural and immunohistochemical evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural, or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration. Conclusions: The LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features might guide future studies of unloading-induced reverse remodeling of the failing human heart. [Copyright &y& Elsevier]

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for ≥48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the β coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation. [Copyright &y& Elsevier]

Left ventricular assist device (LVAD) implantation before heart transplantation has been associated with formation of antibodies directed against human leukocyte antigens (HLA), often referred to as sensitization. This study investigated whether prior sensitization or LVAD type affected the degree of post-implantation sensitization. The records of consecutive HeartMate (HM) I and HM II LVAD patients were reviewed. Panel reactive antibody (PRA) was assessed before LVAD implantation and biweekly thereafter. Sensitization was defined as PRA > 10%, and high-degree sensitization was defined as PRA > 90%. An HM LVAD was implanted in 64 patients, and 11 received a HM II LVAD as a bridge to transplant. Ten HM I patients (16%) were sensitized before LVAD implantation (HM I-S), and 54 (84%) were not (HM I-Non-S). Nine HM I-S patients (90%) became highly sensitized (PRA > 90%) compared with 9 HM I-Non-S patients (16.7%; p < 0.001). The PRA remained elevated (> 90%) in 8 of the 9 (88.9%) highly sensitized HM I-S patients vs 5 of the 9 (55.6%) HM I-Non-S highly sensitized patients. The PRA levels in the rest of the HM I-S highly sensitized patients declined from 93% ± 4% to 55% ± 15% (p = 0.01). Among the 11 HM II patients, 1 (9%) was sensitized before LVAD implantation (PRA, 40%) and the PRA moderately increased to 80%. No other HM II patient became sensitized after implantation. Thus, 1 of 11 (9%) HM II patients became sensitized compared with 29 of 64 (45%) HM I patients (p = 0.04). Pre-sensitized patients are at higher risk for becoming and remaining highly HLA-allosensitized after LVAD implantation. The HeartMate II LVAD appears to cause less sensitization than HeartMate I. [Copyright &y& Elsevier]

Abstract: A significant proportion of patients placed on long-term mechanical circulatory support for end-stage heart failure can be weaned from mechanical assistance after functional recovery of their native heart (“bridge to recovery”). The pathophysiological mechanisms implicated in reverse remodeling that cause a sustained functional myocardial recovery have recently become the subject of intensive research, expected to provide information with a view to accurately identify reliable prognostic indicators of recovery. In addition, this kind of information will enable changes in the strategy of myocardial recovery by modifying the duration and scale of the unloading regimen or by combining it with other treatments that promote reverse remodeling. [Copyright &y& Elsevier]

Abstract: Background: Heart failure (HF) patients may require cardiac assist device implantation prior to transplantation (Tx) because of either acute cardiogenic shock (ACS), with no prior history of HF, or for progression of pump failure in the setting of chronic HF. Aims: To investigate whether patients implanted with a cardiac assist device for ACS, have similar post-Tx outcomes as those who underwent cardiac assist device implantation because of progressive chronic HF. Methods and results: We compared post-Tx outcomes of consecutive patients bridged due to ACS (Acute Group) with the outcomes of patients bridged due to deterioration of chronic HF (Chronic Group). Seventy-three patients had a cardiac assist device implanted and underwent subsequent cardiac Tx. Thirty-five patients (48%) had a cardiac assist device implanted due to ACS, most often caused by massive acute myocardial infarction, and 38 patients (52%) because of progressive chronic HF. Despite greater compromise at the time of implantation, the Acute Group recovered satisfactorily and underwent Tx with similar post-Tx survival rates as the Chronic Group patients [1-year survival: 88.6% vs 86.8%, p =0.80, actuarial survival (mean follow-up 4.2 years): 80.0% vs 81.6%, p =0.86)]. Furthermore, no significant differences were observed between the 2 groups in various post-Tx events. Conclusion: Patients with ACS who underwent emergency cardiac assist device implantation as bridge to Tx had similar post-Tx outcomes as their more chronically ill counterparts who underwent device implantation on a non-urgent basis. [Copyright &y& Elsevier]

Background: Conflicting data exist regarding the impact of reversible pulmonary hypertension (PHTN) on post-transplant (Tx) outcomes. In this study we sought to determine the influence of reversible PHTN on outcomes after Tx. Methods: We retrospectively reviewed the records of adult patients who underwent heart Tx from 1993 to 2002. Patients were grouped depending on their measured pulmonary vascular resistance (PVR). Group 1 patients had a pre-Tx pulmonary vascular resistance (PVR) of <3 Wood units (WU). Patients with reversible PHTN, defined as pre-Tx PVR ≥3 WU and reversing to <3 WU either with sub-lingual or intravenous vasodilatory agents, were divided into two groups based on their PVR before the reversibility test (PVR: Group 2, 3 to 4.5 WU; Group 3, >4.5 WU). Results: Records for 222 adult heart recipients were reviewed (Group 1, n = 171; Group 2, n = 35; Group 3, n = 16). Baseline clinical characteristics (age, gender, heart failure etiology, history of diabetes, ischemic time, donor age and gender) were similar in the three groups and the average follow-up was 58 months. One-month and 1-year mortality (Groups 1, 2 and 3: 2%, 0% and 13%; and 8%, 0% and 13%, respectively) did not differ significantly between groups. Actuarial mortality was assessed using Cox regression analysis, adjusted for age and gender, and no increased risk of death was demonstrated for patients with reversible PHTN (for Group 2: multivariate hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.17 to 1.32, p = 0.15; for Group 3: HR 0.98, CI 0.34 to 2.84, p = 0.97). No differences were observed between the three groups for various post-Tx events, such as hospital stay, ICU stay, extubation time, transfusions, acute allograft dysfunction, acute hepatic dysfunction, acute and chronic renal dysfunction, infections, neurologic complications, gastrointestinal complications and coronary allograft vasculopathy. Conclusions: Reversible pulmonary hypertension is associated with similarly good post-transplant survival outcomes and morbidity, regardless of severity. [Copyright &y& Elsevier]

Background: Mechanical circulatory support (MCS) before heart transplantation was previously associated with worse post-transplant outcomes than when MCS was not required. Given the changes in technology, expertise, patient selection, and timing of subsequent transplantation, we hypothesized that patients who require MCS before heart transplantation have similar outcomes after transplantation as those not requiring pre-transplant MCS. Methods: We retrospectively reviewed 278 patients who underwent cardiac transplantation from 1993 to 2002. MCS was required in 72 patients (HeartMate LVAS in 66, CardioWest Total Artificial Heart in 6) and was not required in 206 patients. The influence of pre-transplant MCS on post-transplant outcomes was assessed in the 2 groups. Results: Baseline clinical characteristics (age, gender, etiology of heart failure, history of diabetes mellitus, and donor age and gender) were similar in the 2 groups. One-month and 1-year survival after transplantation did not differ between the groups (MCS, 92% and 85%, respectively vs no MCS, 97% and 92%, respectively). Similar proportions of patients were free from rejection (International Society for Heart and Lung Transplantation score ≥3A) at 1 year of follow-up (MCS, 56% vs no MCS, 52%, p = 0.60). No difference was observed between MCS and no MCS patients in other post-transplant events such as hospital stay, intensive care unit stay, extubation time, acute allograft dysfunction, reoperation rates, acute renal dysfunction, acute hepatic dysfunction, infections, arrhythmias, thromboembolic complications, neurologic complications, gastrointestinal complications and the development of cardiac allograft vasculopathy. The incidence of chronic renal insufficiency was actually lower in the MCS Group (15.3% vs 37.9%, p = .001). Conclusion: Post-transplant outcomes after pre-transplant use of MCS are similar to those when MCS is not required. [Copyright &y& Elsevier]

The 12th annual Utah Cardiac Recovery Symposium (U-CARS) in 2024 continued its mission to advance cardiac recovery by uniting experts across various fields. The symposium featured key presentations on cutting-edge topics such as CRISPR gene editing for heart failure, guideline-directed medical therapy for heart failure (HF) with improved/recovered ejection fraction (HFimpEF), the role of extracorporeal cardiopulmonary resuscitation (ECPR) in treating cardiac arrest, and others. Discussions explored genetic and metabolic contributions to HF, emphasized the importance of maintaining pharmacotherapy in HFimpEF to prevent relapse, and identified future research directions including refining ECPR protocols, optimizing patient selection, and leveraging genetic insights to enhance therapeutic strategies. [ABSTRACT FROM AUTHOR]

Despite impressive improvements in the care of patients with ST-segment elevation myocardial infarction, mortality remains high. Reperfusion is necessary for myocardial salvage, but the abrupt return of flow sets off a cascade of injurious processes that can lead to further necrosis. This has been termed myocardial ischemia-reperfusion injury and is the subject of this review. The pathologic and molecular bases for myocardial ischemia-reperfusion injury are increasingly understood and include injury from reactive oxygen species, inflammation, calcium overload, endothelial dysfunction, and impaired microvascular flow. A variety of pharmacologic strategies have been developed that have worked well in preclinical models and some have shown promise in the clinical setting. In addition, there are newer mechanical approaches including mechanical unloading of the heart prior to reperfusion that are in current clinical trials. [Display omitted] • MIRI exacerbates myocardial necrosis in patients with STEMI, contributing to mortality. • MIRI is mediated by varying combinations of ROS, inflammation, endothelial dysfunction, impaired microvascular flow, and other factors. • A variety of pharmacologic and mechanical strategies that mitigate MIRI in preclinical models have shown promise in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Centrifugal-flow left ventricular assist devices (CF-LVADs) have improved morbidity and mortality for their recipients. Hospital readmissions remain common, negatively impacting quality of life and survival. We sought to identify risk factors associated with hospital readmissions among patients with CF-LVADs. Methods: Consecutive patients receiving a CF-LVAD between February 2011 and March 2021 were retrospectively evaluated using prospectively maintained institutional databases. Hospital readmissions within three years post-LVAD implantation were dichotomized into heart failure (HF)/LVAD-related or non-HF/LVAD-related readmissions. Multivariable Cox regression models augmented using a machine learning algorithm, the least absolute shrinkage and selection operator (LASSO) method, for variable selection were used to estimate associations between HF/LVAD-related readmissions and pre-, intra- and post-operative clinical variables. Results: A total of 204 CF-LVAD recipients were included, of which 138 (67.7%) had at least one HF/LVAD-related readmission. HF/LVAD-related readmissions accounted for 74.4% (436/586) of total readmissions. The main reasons for HF/LVAD-related readmissions were major bleeding, major infection, HF exacerbation, and neurological dysfunction. Using pre-LVAD variables, HF/LVAD-related readmissions were associated with substance use, previous cardiac surgery, HF duration, pre-LVAD inotrope dependence, percutaneous LVAD/VA-ECMO support, LVAD type, and the left ventricular ejection fraction in multivariable analysis (Harrell's concordance c-statistic; 0.629). After adding intra- and post-operative variables in the multivariable model, LVAD implant hospitalization length of stay was an additional predictor of readmission. Conclusions: Using machine learning-based techniques, we generated models identifying pre-, intra-, and post-operative variables associated with a higher likelihood of rehospitalizations among patients on CF-LVAD support. These models could provide guidance in identifying patients with increased readmission risk for whom clinical strategies to mitigate this risk may further improve LVAD recipient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Since the 2018 change in the US adult heart allocation policy, more patients are bridged‐to‐transplant on temporary mechanical circulatory support (tMCS). Previous studies indicate that durable left ventricular assist devices (LVAD) may lead to allosensitization. The goal of this study was to assess whether tMCS implantation is associated with changes in sensitization. Methods: We included patients evaluated for heart transplants between 2015 and 2022 who had alloantibody measured before and after MCS implantation. Allosensitization was defined as development of new alloantibodies after tMCS implant. Results: A total of 41 patients received tMCS before transplant. Nine (22.0%) patients developed alloantibodies following tMCS implantation: 3 (12.0%) in the intra‐aortic balloon pump group (n = 25), 2 (28.6%) in the microaxial percutaneous LVAD group (n = 7), and 4 (44.4%) in the veno‐arterial extra‐corporeal membrane oxygenation group (n = 9)—p =.039. Sensitized patients were younger (44.7 ± 11.6 years vs. 54.3 ± 12.5 years, p =.044), were more likely to be sensitized at baseline ‐ 4 of 9 (44.4%) compared to 1 out of 32 (3.1%) (p =.001) and received more transfusions with red blood cells (6 (66.7%) vs. 8 (25%), p =.02) and platelets (6 (66.7%) vs. 5 (15.6%), p =.002). There was no significant difference in tMCS median duration of support (4 [3,15] days vs. 8.5 [5,14.5] days, p =.57). Importantly, out of the 11 patients who received a durable LVAD after tMCS, 5 (45.5%) became sensitized, compared to 4 out of 30 patients (13.3%) who only had tMCS—p =.028. Conclusions: Our findings suggest that patients bridged‐to‐transplant with tMCS, without significant blood product transfusions and a subsequent durable LVAD implant, have a low risk of allosensitization. Further studies are needed to confirm our findings and determine whether risk of sensitization varies by type of tMCS and duration of support. [ABSTRACT FROM AUTHOR]

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo‐responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B‐type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank‐sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo‐responsiveness to NPs. [ABSTRACT FROM AUTHOR]

Despite advances in medical therapy for patients with stage C heart failure (HF), survival for patients with advanced HF is <20% at 5 years. Durable left ventricular assist device (dLVAD) support is an important treatment option for patients with advanced HF. Innovations in dLVAD technology have reduced the risk of several adverse events, including pump thrombosis, stroke, and bleeding. Average patient survival is now similar to that of heart transplantation at 2 years, with 5-year dLVAD survival now approaching 60%. Unfortunately, greater adoption of dLVAD therapy has not been realized due to delayed referral of patients to advanced HF centers, insufficient clinician knowledge of contemporary dLVAD outcomes (including gains in quality of life), and deprioritization of patients with dLVAD support waiting for heart transplantation. Despite these challenges, novel devices are on the horizon of clinical investigation, offering smaller size, permitting less invasive surgical implantation, and eliminating the percutaneous lead for power supply. [Display omitted] • The prognosis for patients with advanced HF refractory to guideline-directed medical therapy is poor. • Durable, implantable LVAD therapy can improve survival and quality of life for these patients. • Although contemporary LVAD technology has reduced the incidence of adverse events, durable mechanical circulatory support is underutilized. [ABSTRACT FROM AUTHOR]

In terms of preserving multicellularity and myocardial function in vitro, the cultivation of beating myocardial slices is an emerging technique in basic and translational cardiac research. It can be used, for example, for drug screening or to study pathomechanisms. Here, we describe staining for viable cardiomyocytes based on the immunofluorescence of ryanodine receptors (RyRs) in human and rabbit myocardial slices. Biomimetic chambers were used for culture and measurements of contractile force. Fixable fluorophore-conjugated dextran, entering cells with a permeable membrane, was used for death staining. RyRs, nuclei and the extracellular matrix, including the t-system, were additionally stained and analyzed by confocal microscopy and image processing. We found the mutual exclusion of the RyR and dextran signals in cultivated slices. T-System density and nucleus size were reduced in RyR-negative/dextran-positive myocytes. The fraction of RyR-positive myocytes and pixels correlated with the contractile force. In RyR-positive/dextran-positive myocytes, we found irregular RyR clusters and SERCA distribution patterns, confirmed by an altered power spectrum. We conclude that RyR immunofluorescence indicates viable cardiomyocytes in vibratome-cut myocardial slices, facilitating the detection and differential structural analysis of living vs. dead or dying myocytes. We suggest the loss of sarcoplasmic reticulum integrity as an early event during cardiomyocyte death. [ABSTRACT FROM AUTHOR]

By unloading the failing heart, left ventricular (LV) assist devices (LVADs) provide a favorable environment for reversing adverse structural and functional cardiac changes. Prior reports have suggested that an improved native LV function might contribute to the development of LVAD thrombosis. We used the Interagency Registry for Mechanically Assisted Circulatory Support and found that LV functional improvement is associated with a lower risk for device thrombosis. The risk for cerebrovascular accident and transient ischemic attack was comparable across post-LVAD LV function subgroups, while the risk of hemolysis was lower in subgroups of patients with better LV function on LVAD support. [ABSTRACT FROM AUTHOR]

SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury. [ABSTRACT FROM AUTHOR]

In this paper, the feasibility of myocardial recovery is analyzed through a literature review. First, the phenomena of remodeling and reverse remodeling are analyzed, approached through the physics of elastic bodies, and the terms myocardial depression and myocardial recovery are defined. Continuing, potential biochemical, molecular, and imaging markers of myocardial recovery are reviewed. Then, the work focuses on therapeutic techniques that can facilitate the reverse remodeling of the myocardium. Left ventricular assist device (LVAD) systems are one of the main ways to promote cardiac recovery. The changes that take place in cardiac hypertrophy, extracellular matrix, cell populations and their structural elements, β-receptors, energetics, and several biological processes, are reviewed. The attempt to wean the patients who experienced cardiac recovery from cardiac assist device systems is also discussed. The characteristics of the patients who will benefit from LVAD are presented and the heterogeneity of the studies performed in terms of patient populations included, diagnostic tests performed, and their results are addressed. The experience with cardiac resynchronization therapy (CRT) as another way to promote reverse remodeling is also reviewed. Myocardial recovery is a phenomenon that presents with a continuous spectrum of phenotypes. There is a need for algorithms to screen suitable patients who may benefit and identify specific ways to enhance this phenomenon in order to help combat the heart failure epidemic. [ABSTRACT FROM AUTHOR]

Intra-aortic balloon pump (IABP) utilization has significantly outpaced other Status 2 eligibility criteria for heart transplant. The risk of waitlist mortality of IABP-supported patients relative to other Status 2 listed patients has not been described. We performed a retrospective analysis of all adult patients listed Status 2 for heart transplantation under the current U.S. allocation policy, using data from the United Network for Organ Sharing. Patients listed status 1 and status 3 for high-dose inotropes were included for reference. Mortality and waitlist decompensation were modeled as a function of time-varying status in cause-specific Cox survival models. We identified 3638 Status 2 listings, of whom 1676 (46%) were Status 2 due to IABP. Relative to patients supported with IABP, status 2 patients with ventricular tachycardia/fibrillation [VT/VF] (HR 4.0, p <.001), right-or-biventricular assist device configurations (HR 2.3, p =.002), or temporary surgical left ventricular assist devices [LVAD] (HR 2.6, p =.003) had greater risk of waitlist mortality and decompensation. Other Status 2 subgroups had mortality comparable to IABP Status 2. Risk of waitlist mortality and decompensation for IABP Status 2 was similar to Status 3 patients listed for high-dose inotropes (HR 1.2, p =.27) and lower than Status 1 patients (HR 0.7, p =.002). Waitlist mortality varies significantly by Status 2 eligibility criteria and is highest among patients listed for VT/VF, right-or-biVAD configurations, or temporary surgical LVADs. IABP-supported patients were among those with the lowest Status 2 waitlist mortality risk and comparable to Status 3 inotrope-supported patients. [ABSTRACT FROM AUTHOR]

The time between onset of cardiogenic shock and initiation of mechanical circulatory support is inversely related to patient survival as delays in transporting patients to the operating room (OR) for venoarterial extracorporeal membrane oxygenation (VA ECMO) could prove fatal. A primed and portable VA ECMO system may allow faster initiation of ECMO in various hospital locations and subsequently improve outcomes for patients in cardiogenic shock. We reviewed our institutional experience with VA ECMO based on two time periods: beginning of our VA ECMO program and from initiation of our primed and portable in-hospital ECMO system. The primary endpoint was patient survival to discharge. A total of 137 patients were placed on VA ECMO during the study period; n = 66 (48%) before and n = 71 (52%) after program initiation. In the second era, the proportion of OR ECMO initiation decreased significantly (from 92% to 49%, p < 0.01) as more patients received ECMO in other hospital units, including the emergency department (p < 0.01) and during cardiac arrest (12% vs. 38%, p < 0.01). Survival to hospital discharge was equivalent between the two groups (30% vs. 42%, p = 0.1) despite more patients being placed on ECMO during ongoing cardiac arrest. Finally, we observed increased clinical volume since initiation of the in-hospital, portable ECMO system. Developing an in-hospital, primed and portable VA ECMO program resulted in increased clinical volume with equivalent patient survival despite a sicker cohort of patients. We conclude that more rapid deployment of VA ECMO may extend the treatment eligibility to more patients and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background Within the past 10 years, continuous-flow left ventricular assist devices (LVADs) have replaced pulsatile-flow LVADs as the standard of care for both destination therapy and bridging patients to heart transplantation. Despite the rapid clinical adoption of continuous-flow LVADs, an understanding of the effects of continuous-flow physiology, as opposed to more natural pulsatile-flow physiology, is still evolving. Materials and methods A thorough review of the relevant scientific literature regarding the physiological and clinical effects of continuous-flow physiology was performed. These effects were analyzed on an organ system basis and include an evaluation of the cardiovascular, respiratory, hematologic, gastrointestinal, renal, hepatic, neurologic, immunologic, and endocrine systems. Results Continuous-flow physiology is, generally speaking, well tolerated over the long term. However, several changes are manifest at the organ system level. Although many of these changes are without appreciable clinical significance, other changes, such as an increased rate of gastrointestinal bleeding, appear to be associated with continuous-flow physiology. Conclusions Continuous-flow LVADs confer a significant advantage over their pulsatile-flow counterparts with regard to size and durability. From a physiological standpoint, continuous-flow physiology has limited clinical effects at the organ system level. Although improved over previous generations, challenges with this technology remain. Approaching these problems with a combination of clinical and engineering solutions may be needed to achieve continued progression in the field of durable mechanical circulatory support. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Arrhythmogenic right ventricular cardiomyopathy is a rare but significant cause of advanced heart failure with biventricular compromise. • Biventricular mechanical circulatory support is often necessary in low organ donation environments but with suboptimal outcomes. • Heart transplant is the advanced heart failure therapy of choice in this population. Arrhythmogenic right ventricular cardiomyopathy (ARVC) may be complicated by heart failure. Management of advanced heart failure in this context is challenging. We reviewed our center's experience with advanced heart failure therapies in patients with ARVC. Three rapidly deteriorating patients with ARVC with biventricular heart failure were found. Their management and outcomes are presented. Data on ventricular fibrosis were available in 2 of them and are also included. The first patient underwent initially successful paracorporeal pulsatile biventricular assist device (BiVAD) implantation. However, a large ischemic stroke occurred 2 weeks later, and the patient died after 2 months. The second patient underwent urgent BiVAD implantation after extracorporeal membrane oxygenation support because of cardiogenic shock, but his course was complicated by multiorgan failure due to systemic infection and the patient died. The last patient, being at Interagency Registry for Mechanically Assisted Circulatory Support 3-4 profile, underwent heart transplant with uneventful recovery. Extensive fibrosis was present in both ventricles of 2 patients undergoing pathology examination. Patients with ARVC and advanced biventricular heart failure are characterized by extensive ventricular fibrosis and considerable risk, but data on their management are limited. Biventricular circulatory support is associated with suboptimal outcomes, and prioritization for heart transplant seems preferable. [ABSTRACT FROM AUTHOR]

Septic shock is a common deadly disease often associated with cardiovascular dysfunction. Left ventricular longitudinal strain (LV LS) has been proposed as a sensitive marker to measure cardiovascular function; however, it is not available universally in standard clinical echocardiograms. We sought to derive a predictive model for LV LS, using machine learning techniques with the hope that we may uncover surrogates for LV LS. We found that left ventricular ejection fraction, tricuspid annular plane systolic excursion, sepsis source, height, mitral valve Tei index, LV systolic dimension, aortic valve ejection time, and peak acceleration rate were all predictive of LV LS in this initial exploratory model. Future modeling work may uncover combinations of these variables which may be powerful surrogates for LV LS and cardiovascular function. [ABSTRACT FROM AUTHOR]

Left ventricular assist devices (LVADs) are an established treatment modality for advanced heart failure (HF). It has been shown that through volume and pressure unloading they can lead to significant functional and structural cardiac improvement, allowing LVAD support withdrawal in a subset of patients. In the first part of this review, we discuss the historical background, current evidence on the incidence and assessment of LVAD-mediated cardiac recovery, and out-comes including quality of life after LVAD support withdrawal. In the second part, we discuss current and future opportunities to promote LVAD-mediated reverse remodeling and improve our pathophysiological understanding of HF and recovery for the benefit of the greater HF population. [ABSTRACT FROM AUTHOR]

Altered biological and environmental factors have been linked to the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) pathogenesis. We determined the association between prognostic biomarkers and clinical parameters of pulmonary arterial hypertension (PAH) in adult Atrial Septal Defect (ASD) patients with right heart failure who were treated with sildenafil and beraprost combination therapy. We conducted an observational study using a cross-sectional design and examined the correlation between prognostic biomarkers (superoxide dismutase (SOD) and Platelet-derived growth factor-BB (PDGF-BB)) and clinical parameters (6 minute walking distance (6MWD) and echocardiography parameters (tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP)) in 41 adult patients with ASD diagnosed as pre-capillary pulmonary hypertension (WHO group 1) who were treated at the congenital outpatient clinic at Dr. Soetomo General Hospital Surabaya, Indonesia from October 1st to November 30th 2022. A Pearson correlation test was used to determine the correlation between normal distribution variables. Statistical analyses were done using SPSS software. The results indicated a moderately negative relationship between PDGF-BB and 6MWD (Pearson, r = −0.320, p = 0.041) and a medium significantly negative relationship between PDGF-BB and TAPSE/PASP (Pearson, r = −0.347, p = 0.026). Lower circulating PDGF-BB is associated with better functional capacity and echocardiographic parameters in adult ASD-PAH patients receiving sildenafil and beraprost combination therapy. PDGF-BB may strongly be used as a treatment progress monitoring and prognostic biomarker. • Lower circulating PDGF-BB is associated with better functional capacity as clinical outcome • Lower circulating PDGF-BB is associated with better echocardiographic parameters in adult PAH-ASD patients receiving sildenafil and beraprost combination therapy. • PDGF-BB may strongly be used as a treatment progress monitoring and prognostic biomarker, [ABSTRACT FROM AUTHOR]

Background: The 2018 U.S. heart allocation system offers an accelerated pathway for heart transplantation to the most urgent patients.Objectives: This study sought to determine whether the new allocation system resulted in lower likelihood of candidate recovery.Methods: Adult patients waitlisted for heart transplantation with temporary mechanical circulatory support at the time of initial listing between 2010 and 2020 in the United Network for Organ Sharing registry were included. Competing events of heart transplantation, waitlist death or delisting for deteriorating condition, and delisting for improved condition (candidate recovery) were analyzed in the new vs old heart allocation system.Results: A total of 688 patients were waitlisted with venoarterial extracorporeal membrane oxygenation or a surgical nondischargeable biventricular assist device (status 1 or old 1A). Overall, 2,237 patients were waitlisted with an intra-aortic balloon pump, a percutaneous left ventricular assist device (LVAD), or a surgical nondischargeable LVAD (status 2 or old 1A). Patients waitlisted with venoarterial extracorporeal membrane oxygenation or a nondischargeable biventricular assist device had significantly shorter median waitlist times (5 vs 31 days), higher incidence for cardiac transplantation (81.5% vs 43.0%), and lower incidence of candidate recovery (1.5% vs 7.9%) in the new vs old heart allocation system (all P < 0.05). Patients waitlisted with an intra-aortic balloon pump or percutaneous or a nondischargeable LVAD also had significantly shorter median waitlist times (8 vs 35 days), higher incidence of transplantation (88.9% vs 64.9%), and lower incidence of candidate recovery (0.2% vs 1.6%) in the new vs old heart allocation system (all P < 0.05).Conclusions: Current practice of the new allocation system may not offer select temporary mechanical circulatory support patients the opportunity and adequate time to recover to the point of waitlist removal. Further research will determine which patients would benefit from urgent transplantation vs recovery strategy. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Inotrope treatment is often necessary in refractory to optimal management end stage heart failure, when signs of end-organ hypoperfusion appear. The effect of specific inotropes on patient outcome remains controversial. The aim of the study was to compare the effect of levosimendan versus dobutamine, alone or in combination with levosimendan, on the outcome of end-stage heart failure patients, requiring inotropic therapy. Methods and results: We studied 63 patients in NYHA class IV, refractory to optimal medical therapy, recently hospitalized for cardiac decompensation and stabilized by an intravenous inotrope. They were randomly assigned to intermittent infusions of either a) dobutamine, 10mg/kg/min, versus b) levosimendan, 0.3mg/kg/min, versus c) dobutamine, 10mg/kg/min+levosimendan 0.2mg/kg/min, each administered weekly, for 6h, over a 6-month period. All patients received amiodarone, 400mg/day, to suppress the proarrhythmic effects of the inotropes. Baseline characteristics of the 3 groups were similar. At 6months, survival free from death or urgent left ventricular device implantation was 80% in the levosimendan, 48% in the dobutamine (P =0.037 versus levosimendan), and 43% in the levosimendan+dobutamine (P= 0.009 versus levosimendan) group. At 3months, NYHA class improved significantly in all 3 groups, whereas pulmonary capillary wedge pressure decreased (27±4 to 19±8mmHg, P= 0.008) and cardiac index increased (1.5±0.3 to 2.1±0.3l/min/m2, P= 0.002) significantly only in patients assigned to levosimendan. Conclusions: In patients with refractory end-stage heart failure, intermittent administration of levosimendan conferred survival and hemodynamic benefits in comparison to a regimen of intermittent infusions of dobutamine, alone or in combination with levosimendan. [Copyright &y& Elsevier]

The effects of the intra-aortic balloon pump (IABP) counterpulsation on the extent of myocardial infarction (MI), the no-reflow phenomenon (NRP), and coronary blood flow (CBF) during reperfusion in an ischemia-reperfusion experimental model have not been clarified. Eleven pigs underwent occlusion of the mid left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. CBF, distal to the occlusion site, was measured. In six experiments, IABP support began 10 min before, and continued throughout reperfusion (IABP Group). Five pigs without IABP support served as controls. At the end of each experiment, the myocardial area at risk (MAR) of infarction and the extent of MI and NRP were measured. Hemodynamic measurements at baseline and during coronary occlusion were similar in both groups. During reperfusion, systolic aortic blood pressure was significantly lower in the IABP Group than in controls. In the IABP Group, CBF reached a peak at 5 min of reperfusion, gradually decreased, but remained higher than at baseline, and significantly higher than in controls throughout the 2 h of reperfusion. In controls, CBF increased significantly above baseline immediately after the onset of reperfusion, then returned to baseline within 90 min. The extent of NRP (37 ± 25% vs. 68 ± 17%, P = 0.047) and MI (39 ± 23% vs. 67 ± 13%, P = 0.036), both expressed as percentage of MAR, was significantly less in the IABP group than in controls. After prolonged myocardial ischemia, IABP assistance started just 10 min before and throughout reperfusion increased CBF and limited infarct size and extent of NRP. [ABSTRACT FROM AUTHOR]

Specifically, we set out to determine whether long-term LVAD mechanical unloading results in metabolic activation of quiescent myocardial regions by prospectively and longitudinally examining myocardial SP 18 sp F-fluorodeoxyglucose (FDG) uptake in patients with end-stage heart failure after LVAD implantation. In patients 1 and 2, LVAD speed was 2660 rotations per minute, whereas LVAD speeds in patients 3 and 4 were 9200 and 5500 rotations per minute, respectively. Inversely, analysis of FDG uptake in myocardial areas that were metabolically active at baseline showed that 2 patients exhibited significant decreases in FDG uptake, 1 exhibited increased FDG uptake, and 1 exhibited little change. [Extracted from the article]

Implantable cardioverter-defibrillators (ICDs) remain the standard of care in advanced heart failure with reduced ejection fraction patients for the prevention of sudden cardiac death. However, current guidelines remain conflicting with respect to the use of ICDs in patients supported with a continuous flow left ventricular assist device (CF-LVAD). The current review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies comparing the use of ICD in patients with CF-LVADs were included. The 2 primary outcomes studied were all-cause mortality, and a successful bridge to heart transplantation. We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs). We also compared baseline characteristics between US and European studies, for CF-LVAD patients with an ICD. Among all studies, the use of an ICD was not associated with all-cause mortality in patients with CF-LVADs (OR: 0.85, 95% CIs: 0.64-1.12, p = 0.24). The presence of an ICD was associated with a trend towards increased likelihood of successful bridge to heart transplantation (OR: 1.12, 95% CI: 1.0-1.3, p = 0.06). A subgroup analysis of studies published by European centers revealed a significant decrease in pooled mortality (OR: 0.58, 95% CI: 0.4-0.83, p = 0.003) with the use of ICD, contrary to an increase in pooled mortality among studies published by US centers (OR: 1.2, 95% CI 1.02-1.33, p = 0.025). Moreover, we identified significant differences in baseline characteristics such as bridge to transplantation rate, Interagency Registry for Mechanically Assisted Circulatory Support profiles, and use of an intra-aortic balloon pump or extracorporeal membrane oxygenation preoperatively, between the US and European populations. While this meta-analysis did not show an overall survival benefit with the use of an ICD in CF-LVAD patients, it revealed significant differences in the derived benefit, in distinct patient populations. This might reflect differences in baseline patient characteristics and warrants further investigation. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: We sought to develop and validate machine learning (ML) models to increase the predictive accuracy of mortality after heart transplantation (HT). Methods and results: We included adult HT recipients from the United Network for Organ Sharing (UNOS) database between 2010 and 2018 using solely pre‐transplant variables. The study cohort comprised 18 625 patients (53 ± 13 years, 73% males) and was randomly split into a derivation and a validation cohort with a 3:1 ratio. At 1‐year after HT, there were 2334 (12.5%) deaths. Out of a total of 134 pre‐transplant variables, 39 were selected as highly predictive of 1‐year mortality via feature selection algorithm and were used to train five ML models. AUC for the prediction of 1‐year survival was.689,.642,.649,.637,.526 for the Adaboost, Logistic Regression, Decision Tree, Support Vector Machine, and K‐nearest neighbor models, respectively, whereas the Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score had an AUC of.569. Local interpretable model‐agnostic explanations (LIME) analysis was used in the best performing model to identify the relative impact of key predictors. ML models for 3‐ and 5‐year survival as well as acute rejection were also developed in a secondary analysis and yielded AUCs of.629,.609, and.610 using 27, 31, and 91 selected variables respectively. Conclusion: Machine learning models showed good predictive accuracy of outcomes after heart transplantation. [ABSTRACT FROM AUTHOR]