Financial impact of donation after circulatory death heart transplantation: A single-center analysis.

INTRODUCTION: Clinical success of donation after circulatory death (DCD) heart transplantation is leading to growing adoption of this technique. In comparison to procurement from a brain-dead donor, DCD requires additional resources. The economic impact of DCD heart transplantation from the hospital perspective is not well known. METHODS: We compared the financial data of patients who received DCD allografts to those who received a DBD organ at our institution from January 1, 2021 to December 31, 2022. We also compared the cost of ex-situ machine perfusion to in-situ organ perfusion employed during DCD recovery. RESULTS: We performed 58 DBD and 22 DCD heart-alone transplantations during the study period. Out of 22 DCD grafts, 16 were recovered with thoracoabdominal normothermic regional perfusion (TA-NRP) and six with direct procurement followed by normothermic machine perfusion (DP-NMP). The contribution margin per case for DBD versus DCD was $234,362 and $235,440 (P = .72). The direct costs did not significantly differ between the two groups ($171,949 and 186,250; P = .49). In comparing the two methods of procuring hearts from DCD donors, the direct cost of TA-NRP was $155,955 in comparison to $223,399 for DP-NMP (P = .21). This difference translated into a clinically meaningful but not statistically significant greater contribution margin for TA-NRP ($242, 657 vs. $175,768; P = .34). CONCLUSIONS: Our data showed that the adoption of DCD procurement did not have a negative financial impact on the contribution margin in our institution. Programs considering starting DCD heart transplantation, and those who are currently performing DCD procurement should evaluate their own financial situation.

Utilization of Paragonix Sherpapak Cardiac Transport System for the Preservation of Donor Hearts After Circulatory Death.

BACKGROUND: Donation after circulatory death (DCD) heart transplantation is being increasingly adopted by transplant centers. The optimal method of DCD heart preservation during transport after in situ thoracoabdominal normothermic regional perfusion (TA-NRP) is not known. METHODS: We evaluated our experience with the Paragonix SherpaPak Cardiac Transport System (SCTS) for the transport of DCD cardiac allografts after TA-NRP recovery between January 2021 and December 2022. We collected and evaluated donor characteristics, allograft ischemic intervals, and recipient baseline demographic and clinical variables, and short-term outcomes. RESULTS: Twelve recipients received DCD grafts recovered with TA-NRP and transported in SCTS during the study period. The median age of 10 male and 2 female donors was 32 years (min 15, max 38). The median duration of functional warm ischemia was 12 minutes (min 8, max 22). Hearts were preserved in SCTS for a median of 158 minutes (min 37, max 224). Median recipient age was 61 years (min 28, max 70). Ten recipients (83%) survived to hospital discharge, with one death attributable to graft dysfunction (8%). The median vasoactive-inotropic (VIS) score at 72 hours post-transplantation of the entire cohort was 6 (min 0, max 15). The median length of intensive care unit stay in hospital survivors was 5 days (min 3, max 17) days and hospital stay 17 days (min 9, max 37). CONCLUSIONS: The Paragonix SCTS provides efficacious preservation of DCD grafts for ≥3.5 hours. Organs transported with this device showed satisfactory post-transplantation function.

An extensive ß1-adrenergic receptor gene signaling network regulates molecular remodeling in dilated cardiomyopathies.

We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a ß1-adrenergic receptor-linked (ß1-AR-linked) gene signaling network (ß1-GSN) involved in left ventricular (LV) eccentric pathologic remodeling. A 430-member ß1-GSN was identified by mRNA expression in transgenic mice overexpressing human ß1-ARs or from literature curation, which exhibited opposite directional behavior in interventricular septum endomyocardial biopsies taken from patients with beta-blocker-treated, reverse remodeled dilated cardiomyopathies. With reverse remodeling, the major biologic categories and percentage of the dominant directional change were as follows: metabolic (19.3%, 81% upregulated); gene regulation (14.9%, 78% upregulated); extracellular matrix/fibrosis (9.1%, 92% downregulated); and cell homeostasis (13.3%, 60% upregulated). Regarding the comparison of ß1-GSN categories with expression from 19,243 nonnetwork genes, phenotypic selection for major ß1-GSN categories was exhibited for LV end systolic volume (contractility measure), ejection fraction (remodeling index), and pulmonary wedge pressure (wall tension surrogate), beginning at 3 months and persisting to study completion at 12 months. In addition, 121 lncRNAs were identified as possibly involved in cis-acting regulation of ß1-GSN members. We conclude that an extensive 430-member gene network downstream from the ß1-AR is involved in pathologic ventricular remodeling, with metabolic genes as the most prevalent category.

Impact of donation after circulatory death heart transplantation on waitlist outcomes and transplantation activity.

INTRODUCTION: Donation after circulatory death (DCD) heart transplantation has been shown to have comparable outcomes to transplantation using brain death donors (DBDs). This study evaluates the impact of this alternative source of allografts on waitlist mortality and transplant volume. METHODS: We compared waitlist mortality and transplant rates in patients who were registered before (2019 period) and after we adopted DCD heart transplantation (2021 period). RESULTS: We identified 111 patients who were on the waiting list in 2019 and 77 patients who were registered during 2021. Total number of donor organ offers received in 2019 was 385 (178 unique donors) versus 3450 (1145 unique donors) in 2021. More than 40% of all donors in 2021 were DCDs. Waitlist mortality was comparable for patients in 2019 and 2021 (18/100 person-years in 2019 vs. 26/100 person-years in 2021, p = .49). The transplant rate was 67/100 person-years in 2019 versus 207/100 person-years in 2021 (p < .001). After adjusting for acuity status, gender, blood type, and weight, patients listed in 2021 had 2.08 times greater chance of transplantation compared to patients listed in 2019 (HR 2.08, 95% confidence interval [CI] 1.26-3.45, p = .004). CONCLUSIONS: Use of DCD donor hearts significantly increased heart transplant rate in our institution.

Cardiac function unchanged following reanimation with normothermic regional perfusion in donation after circulatory death.

Objectives: To determine whether hearts reanimated with normothermic regional perfusion (NRP) have clinically detectable changes in function using echocardiography comparing the prearrest and post-NRP imaging. As heart transplantation from donation after circulatory death (DCD) continues to increase, preliminary results suggest outcomes comparable with donation after brain death. It is unknown whether the obligatory period of warm ischemia experienced during DCD withdrawal process causes immediate changes in cardiac allograft function following in situ reanimation. Methods: We retrospectively reviewed and compared predonation with postreanimation echocardiographic findings in all DCD donors at our institution from January to October 2021. All DCD donor organs were reanimated with in situ thoracoabdominal NRP after circulatory death. Echocardiographic assessment included (1) 2-dimensional and speckle-tracking measures of chamber size and function; (2) ejection fraction; (3) fractional area change; and (4) global longitudinal strain. Results: Altogether, 4 DCD heart donations were performed during the study period. Basic demographics and withdrawal ischemic time periods are reported. There were no changes in left ventricular ejection fraction and right ventricular fractional area change when comparing the predonation and the postreanimation echocardiogram. There was a minimal, nonstatistically significant decrease in left ventricular global longitudinal strain and right ventricular free-wall systolic strain in 3 of the 4 donors following reanimation. Conclusions: DCD cardiac allografts reanimated with NRP demonstrated no change in echocardiographic parameters used for a standard predonation donor heart evaluation. Findings suggest cardiac function of DCD allografts reanimated with thoracoabdominal NRP is not adversely impacted by limited period of warm ischemia following circulatory arrest.

Impact of digoxin utilization on clinical outcomes following left ventricular assist device implantation.

INTRODUCTION: We aimed to assess the impact of digoxin use following left ventricular assist device (LVAD) implantation on clinical outcomes. METHODS: Patients implanted with continuous flow LVADs at a single academic medical center and survived to initial hospital discharge were included in the analysis (n = 346). Clinical events were captured at a maximum of 2 years of follow up. Digoxin use was defined as 30-day continuous use post-LVAD. Negative binomial regression and Kaplan-Meier method were used to assess the association between digoxin use and clinical outcomes. RESULTS: Mean age of the cohort was 56 years (±13) and 23% (79/346) were female sex. Digoxin was used in 144 patients (41.6%) for a median of 268 days (IQR 154, 616). Digoxin use was associated with a significant reduction in cumulative incidence of gastrointestinal bleeding (GIB) (15% vs 26%, p = 0.004). After adjusting for age, hypertension, post-operative hemoglobin, RDW, potassium, and GFR, and use of angiotensin receptor/neprilysin inhibitor, there remained a significant 47% reduction in GIB incidence in patients treated with digoxin. There was no significant difference in cumulative incidence in right ventricular failure (RVF) between the two groups. There was no difference in overall 2-year survival between groups. CONCLUSIONS: Digoxin use was associated with reduction in GIB events, but not in RVF or mortality. Further studies are needed to confirm these findings and to investigate optimal timing and patient population.

Pulmonary Function Testing Pre-heart Transplant Predicts Posttransplant Survival.

Although pulmonary function testing (PFT) is typically performed for heart transplant evaluation, the prognostic utility of PFTs after transplantation is unknown. We evaluated whether PFT parameters were correlated with outcomes following heart transplantation. METHODS: International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry data were utilized. Survival was assessed using Kaplan-Meier method and compared via log-rank test. Cox proportional hazard modeling was used to evaluate univariate and multivariate predictors of survival. RESULTS: Eight hundred two patients pretransplant PFT data were available for evaluation. Forced expiratory volume in 1 s (FEV1) < 50% predicted (P < 0.0001), and forced vital capacity (FVC) < 50% predicted each had significantly higher mortality (P = 0.001) compared with patients with FEV1 or FVC 50%-80% or >80%. FEV1/FVC < 0.7 was not associated with increased mortality. FEV1 and FVC below 50% both predicted longer lengths of stay (P = 0.028 for FEV1 and P = 0.0075 for FVC). After adjusting for male gender, age, body mass index, smoking history, chronic obstructive pulmonary disease, creatinine, albumin, and total bilirubin, FEV1 < 50% (hazard ratio, 4.91; P < 0.0001; 95% confidence interval, 2.69-8.94) and FVC < 50% (hazard ratio, 2.75; P = 0.003; 95% confidence interval, 1.4-5.4) both remained independent predictors of mortality. CONCLUSIONS: Abnormal pulmonary function (FEV1 or FVC below 50% of predicted) pre-heart transplantation is associated with increased mortality and longer lengths of stay posttransplant.

Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Devices (RESTAGE-HF [Remission from Stage D Heart Failure]): Medium-Term and Primary End Point Results.

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.

PROVIDE-HF primary results: Patient-Reported Outcomes inVestigation following Initiation of Drug therapy with Entresto (sacubitril/valsartan) in heart failure.

BACKGROUND: In PARADIGM-HF, sacubitril/valsartan improved quality of life (QOL) versus enalapril in heart failure with reduced ejection fraction (HFrEF), yet limited data are available regarding QOL changes after sacubitril/valsartan initiation in routine practice. METHODS: PROVIDE-HF was a prospective study within a national research network (Patient-Centered Outcomes Research Network) of HFrEF outpatients recently initiated on sacubitril/valsartan versus controls with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change. The primary end point was mean Kansas City Cardiomyopathy Questionnaire (KCCQ) change through 12 weeks. Other end points included responder analyses: ≥5-point and ≥20-point KCCQ increase. Adjusted QOL change was estimated after propensity score weighting. RESULTS: Overall, 270 patients had both baseline and 12-week KCCQ data (151 sacubitril/valsartan; 119 control). The groups had similar demographics and HF details: median EF 28% and N-terminal pro-brain natriuretic peptide 1083 pg/mL. Sacubitril/valsartan patients had larger improvements in KCCQ (mean difference +4.76; P = .027) and were more likely to have a ≥5-point and ≥20-point response (all P < .05). Adjusted comparisons demonstrated similar numerical improvements in the change in KCCQ (+4.55; 95% CI -0.89 to 9.99; P = .101) and likelihood of ≥5-point increase (odds ratio 1.55; 95% CI: 0.84-2.86; P = .16); ≥20-point increase remained statistically significant (odds ratio 3.79; 95% CI 1.47-9.73; P = .006). CONCLUSIONS: In this prospective HFrEF study of sacubitril/valsartan initiation compared with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change, the between-group difference in the primary end point, mean KCCQ change at 12 weeks was not statistically significant following adjustment, but sacubitril/valsartan initiation was associated with early improvements in QOL and a higher likelihood of ≥20-point improvement in KCCQ at 12 weeks. These data add additional real-world evidence related to patient-reported outcomes following the initiation of sacubitril/valsartan in routine clinical practice.

Impact of temporary mechanical circulatory support for early graft failure on post-heart transplantation outcomes.

Although temporary mechanical circulatory support (tMCS) for hemodynamic failure following heart transplantation is associated with increased early morbidity and mortality, the impact of etiology of graft dysfunction and long-term clinical implications are less well known. The objective of our study was to evaluate outcomes in patients who required venoarterial extracorporeal membrane oxygenation (VA ECMO) or temporary right ventricular assist device (RVAD) support for either primary or secondary early graft dysfunction. Hospital mortality in 27 patients who required tMCS following heart transplantation at our institution between 2007 and 2017 was 56%, 30% in patients with right ventricular dysfunction secondary to increased afterload, 60% in patients with primary graft dysfunction, and 100% in patients with graft failure secondary to coagulopathy with intraoperative bleeding or overwhelming sepsis. Conditional 1-year and 5-year survival was comparable between patients with, and without, the need for post-transplantation support with tMCS (98% and 89%; 92% and 65% at 1 and 5 years, P = .21). Etiology of early graft failure plays an important part in determining the short-term post-heart transplantation outcome. Although complications associated with tMCS use, such as renal dysfunction and infection, extend beyond index transplant hospitalization, long-term conditional survival is not compromised.

Electronic cigarette extract induced toxic effect in iPS-derived cardiomyocytes.

BACKGROUND: Cigarette smoking is an important risk factor for cardiac diseases. In the current study, we sought to assess the effect of electronic cigarette extract (ECE) and conventional cigarette smoke extract (CSE) on cardiomyocytes. METHODS: iPSCs-derived cardiomyocytes were used in the study to evaluate cellular toxicities. Cells were exposed to either ECE or CSE for two consecutive days as an acute exposure or every other day for 14 days. Concentration of nicotine in both ECE and CSE were measured by Mass-Spectrometry and Q-Exactive-HF was used to identify other ingredients in both extracts. Fluorescent microscopy was used to measure the oxidative stress after ECE and CSE exposure. Motility and beat frequency of cardiomyocytes were determined using the Sisson-Ammons Video Analysis system. Heart failure target panel genes of exposed cardiomyocytes were compared to control unexposed cells. RESULTS: Despite nicotine concentration in CSE being six-fold higher than ECE (50 µg in CSE and 8 µg in ECE), ECE had similar toxic effect on cardiomyocytes. Both CSE and ECE generate significant cellular reactive oxygen species. The Sisson-Ammons Video Analysis (SAVA) analysis showed significant changes in myocyte function with both CSE and ECE slowing beating and increasing cell death. Chronic exposure of both ECE and CSE significantly decreased cardiomyocytes viability long term at all doses. Target panel gene expression profiles of both ECE and CSE exposed cardiomyocytes were different from controls with distinct pattern of genes that involved cell proliferation, inflammation, and apoptosis. CONCLUSION: ECE and CSE produce similar cardiomyocyte toxicities which include generating oxidative stress, negative chronotropic effects, adverse changes in myocardial gene expression and ultimately cell death.

Dynamic Regulation of SARS-Cov-2 Binding and Cell Entry Mechanisms in Remodeled Human Ventricular Myocardium.

Using serial analysis of myocardial gene expression employing endomyocardial biopsy starting material in a dilated cardiomyopathy cohort, we show that mRNA expression of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) cardiac myocyte receptor ACE2 is up-regulated with remodeling and with reverse remodeling down-regulates into the normal range. The proteases responsible for virus-cell membrane fusion were expressed but not regulated with remodeling. In addition, a new candidate for SARS-CoV-2 cell binding and entry was identified, the integrin encoded by ITGA5. Up-regulation in ACE2 in remodeled left ventricles may explain worse outcomes in patients with coronavirus disease 2019 who have underlying myocardial disorders, and counteracting ACE2 up-regulation is a possible therapeutic approach to minimizing cardiac damage.

Association of Clinical Outcomes With Left Ventricular Assist Device Use by Bridge to Transplant or Destination Therapy Intent: The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) Randomized Clinical Trial.

Importance: Left ventricular assist devices (LVADs) are well established in the treatment of advanced heart failure, but it is unclear whether outcomes are different based on the intended goal of therapy in patients who are eligible vs ineligible for heart transplant. Objective: To determine whether clinical outcomes in the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) trial differed by preoperative categories of bridge to transplant (BTT) or bridge to transplant candidacy (BTC) vs destination therapy (DT). Design, Setting, and Participants: This study was a prespecified secondary analysis of the MOMENTUM 3 trial, a multicenter randomized clinical trial comparing the magnetically levitated centrifugal-flow HeartMate 3 (HM3) LVAD to the axial-flow HeartMate II (HMII) pump. It was conducted in 69 centers with expertise in managing patients with advanced heart failure in the United States. Patients with advanced heart failure were randomized to an LVAD, irrespective of the intended goal of therapy (BTT/BTC or DT). Main Outcomes and Measures: The primary end point was survival free of disabling stroke or reoperation to remove or replace a malfunctioning device at 2 years. Secondary end points included adverse events, functional status, and quality of life. Results: Of the 1020 patients with implants (515 with HM3 devices [50.5%] and 505 with HMII devices [49.5%]), 396 (38.8%) were in the BTT/BTC group (mean [SD] age, 55 [12] years; 310 men [78.3%]) and 624 (61.2%) in the DT group (mean [SD] age, 63 [12] years; 513 men [82.2%]). Of the patients initially deemed as transplant ineligible, 84 of 624 patients (13.5%) underwent heart transplant within 2 years of LVAD implant. In the primary end point analysis, HM3 use was superior to HMII use in patients in the BTT/BTC group (76.8% vs 67.3% for survival free of disabling stroke and reoperation; hazard ratio, 0.62 [95% CI, 0.40-0.94]; log-rank P = .02) and patients in the DT group (73.2% vs 58.7%; hazard ratio, 0.61 [95% CI, 0.46-0.81]; log-rank P < .001). For patients in both BTT/BTC and DT groups, there were not significantly different reductions in rates of pump thrombosis, stroke, and gastrointestinal bleeding with HM3 use relative to HMII use. Improvements in quality of life and functional capacity for either pump were not significantly different regardless of preimplant strategy. Conclusions and Relevance: In this trial, the superior treatment effect of HM3 over HMII was similar for patients in the BTT/BTC or DT groups. It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure. Trial Registration: ClinicalTrials.gov identifier: NCT02224755.

Impaired Exercise Tolerance Early After Heart Transplantation Is Associated With Development of Cardiac Allograft Vasculopathy.

BACKGROUND: Exercise performance remains limited in some patients after heart transplantation (HTx). The goal of this study was to assess for association between cardiopulmonary exercise test performance at 1 year after HTx and future development of cardiac allograft vasculopathy (CAV). METHODS: Overall 243 HTx recipients performed cardiopulmonary exercise testing at 1 year after HTx. During the median follow-up period of 31 (interquartile range 19;61) months, 76 (32%) patients were diagnosed with CAV (CAV group). RESULTS: The CAV group patients had lower exercise capacity (5.2 ± 1.9 versus 6.5 ± 2.2 metabolic equivalents; P = 0.001) and duration (9.6 ± 3.5 versus 11.4 ± 4.8 min; P = 0.008), lower peak oxygen consumption (VO2) (18.4 ± 5.4 versus 21.4 ± 6.1 mL/kg/min; P = 0.0005), lower normalized peak VO2 (63% ± 18% versus 71% ± 19%; P = 0.007), and higher minute ventilation (VE)/carbon dioxide production (VCO2) (34 ± 5 versus 32 ± 5, P = 0.04). On Cox proportional hazards regression analysis, normalized peak VO2 ≤60%, and VE/VCO2 ≥34 were associated with a high hazard for CAV (HR = 1.8 [95% CI 1.10-4.53, P = 0.03] and 2.5 [95% CI 1.01-8.81, P = 0.04], respectively). The subgroup of patients with both normalized peak VO2 ≤60% and VE/VCO2 ≥34 was at highest risk for development of CAV (HR = 5.2, 95% CI 2.27-15.17, P = 0.001). CONCLUSIONS: Normalized peak VO2 ≤60% and VE/VCO2 ≥34 at 1 year after HTx are associated with the development of CAV.

TGF-ß induces a heart failure phenotype via fibroblasts exosome signaling.

PURPOSE: The mechanisms for persistent and progressive loss of myocardial function in advanced heart failure (HF) remain incompletely characterized. In the current study, we sought to determine the impact of TGF-ß on fibroblasts transcriptional profiles and assess if exosomes from TGF-ß treated fibroblasts could induce a heart failure phenotype in co-cultured cardiomyocytes. METHOD: Normal heart fibroblasts were treated with TGF-ß with a final conc. of 2.5 ng/ml in serum free media. HF fibroblasts were also obtained from patients undergoing implantation of left ventricular assist devices. Exosomes were collected using three-step ultracentrifugation. Cardiomyocytes were co-cultured with exosomes from TGF-ß-treated, HF and control fibroblasts. RNA was extracted from the fibroblasts, exosomes, and the cardiomyocytes for a targeted panel of genes using Ion AmpliSeq. Fibroblast function was evaluated by collagen gel contraction. RESULTS: Fibroblasts treated with TGF-ß differentially express 21 of the 140 genes in our targeted panel. These fibroblasts exhibit enhanced collagen gel contraction similar to HF fibroblasts. Fifty of these targeted genes were also differentially expressed in fibroblast exosomes. Pathway analysis of these transcriptional changes suggest hypertrophic signaling to cardiac muscle. Cardiomyocytes, co-cultured with exosomes from TGF- ß treated fibroblasts or heart failure patients, differentially expressed 40 genes compared to controls. Cardiomyocytes co-cultured with exosomes of TGF-ß treated fibroblasts induced a molecular phenotype similar to cardiomyocytes co-cultured with exosomes from HF fibroblasts. These changes involve contractile proteins, adrenergic receptors, calcium signaling, metabolism and cell renewal. CONCLUSION: TGF-ß induces broad transcriptional changes in fibroblasts as well as their exosomes. These exosomes induce a heart failure phenotype in cardiomyocytes. Exosome signaling from fibroblasts likely contributes to disease progression in heart failure.

Correction: Sequential analysis of myocardial gene expression with phenotypic change: Use of cross-platform concordance to strengthen biologic relevance.

[This corrects the article DOI: 10.1371/journal.pone.0221519.].

Sequential analysis of myocardial gene expression with phenotypic change: Use of cross-platform concordance to strengthen biologic relevance.

OBJECTIVES: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling. BACKGROUND: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices. METHODS: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3-12 months of ß-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF). Cross-platform gene expression change concordance was investigated in reverse remodeling Responders (R) and Nonresponders (NR) using 3 platforms (RT-qPCR, microarray, and RNA-Seq) and two cohorts (All 47 subjects (A-S) and a 12 patient "Super-Responder" (S-R) subset of A-S). RESULTS: For 50 prespecified candidate genes, in A-S mRNA expression 2 platform concordance (CcpT), but not single platform change, was directly related to reverse remodeling, indicating CcpT has biologic significance. Candidate genes yielded a CcpT (PCR/microarray) of 62% for Responder vs. Nonresponder (R/NR) change from baseline analysis in A-S, and ranged from 38% to 100% in S-R for PCR/microarray/RNA-Seq 2 platform comparisons. Global gene CcpT measured by microarray/RNA-Seq was less than for candidate genes, in S-R R/NR 17.5% vs. 38% (P = 0.036). For S-R global gene expression changes, both cross-cohort concordance (CccT) and CcpT yielded markedly greater values for an R/NR vs. an R-only analysis (by 22 fold for CccT and 7 fold for CcpT). Pathway analysis of concordant global changes for R/NR in S-R revealed signals for downregulation of multiple phosphoinositide canonical pathways, plus expected evidence of a ß1-adrenergic receptor gene network including enhanced Ca2+ signaling. CONCLUSIONS: Two-platform concordant change in candidate gene expression is associated with LV biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information.

A Fully Magnetically Levitated Left Ventricular Assist Device - Final Report.

BACKGROUND: In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device. METHODS: We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years. RESULTS: This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P<0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group. CONCLUSIONS: Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).

Elevated Heart Rate Following Heart Transplantation Is Associated With Increased Graft Vasculopathy and Mortality.

BACKGROUND: The effect of elevated heart rate (HR) on outcomes after heart transplantation (HT) has not been well established. The aim of this study was to assess predictors of elevated HR following HT and its impact on outcomes. METHODS AND RESULTS: We retrospectively evaluated 394 patients who underwent HT at 2 academic medical centers from 2005 to 2016. Patients were divided into 2 groups based on HR 1 year after HT: HR ≥95 beats/min (n = 162; 41%) and HR <95 beats/min (n = 232; 59%). Median follow-up time was 6.6 (interquartile range [IQR] 2.2-7.5) years. HR ≥95 beats/min 1 year after HT was associated with younger donor age, whereas HR <95 beats/min was associated with heavy donor alcohol use and African-American recipient race. Left ventricular (LV) end-diastolic dimension, mass, and ejection fraction were lower and E/E' higher in the HR ≥95 group at the time of the last follow up. HR ≥95 beats/min at 1 year after HT was independently associated with the development of cardiac allograft vasculopathy and increased mortality. CONCLUSIONS: HR ≥95 beats/min 1 year after HT is associated with a reduction in LV size and function, increased incidence of cardiac allograft vasculopathy, and reduced survival. Studies investigating the effect of medical HR reduction on post-HT outcomes are warranted.

The effect of donor alcohol abuse on outcomes following heart transplantation.

BACKGROUND: Current guidelines recommend against the use of hearts from donors that abuse alcohol. We explored the effect of donor alcohol abuse (AA) on cardiac allograft function and outcomes in heart transplant (HTx) recipients. METHODS: Overall, 370 HTx recipients were divided into two groups: (a) the alcoholic donor group (AD, n = 58) and (b) the non-alcoholic donor group (NAD, n = 312). RESULTS: Recipients in the AD group had a slower heart rate (86 ± 13 vs 93 ± 13, P = 0.004) and an increased incidence of early atrial fibrillation (AF) (30% vs 11%, P = 0.003). Echocardiographic left ventricular mass was higher among alcoholic donors (171.7 ± 66.7 vs 151.6 ± 54.7, P = 0.02). This difference remained present 1 year following HTx (185 ± 43 vs 166 ± 42, P = 0.007). E/E' was higher in the AD group (9.5 ± 3.9 vs 8.4 ± 2.9, P = 0.04) and a larger number of AD recipients had a ventilatory equivalent for VCO2  > 34 (50% vs 31%, P = 0.04) on cardiopulmonary exercise test. There was no significant difference in rejection, cardiac allograft vasculopathy (CAV), or survival between the groups. CONCLUSIONS: Our data suggest that donor AA does not impact rejection, CAV, or intermediate-term survival, but may cause increased incidence of post-HTx AF and impaired cardiac allograft diastolic function.