Characteristics and Outcomes of Prolonged Venoarterial Extracorporeal Membrane Oxygenation After Cardiac Surgery: The Post-Cardiotomy Extracorporeal Life Support (PELS-1) Cohort Study.

OBJECTIVES: Most post-cardiotomy (PC) extracorporeal membrane oxygenation (ECMO) runs last less than 7 days. Studies on the outcomes of longer runs have provided conflicting results. This study investigates patient characteristics and short- and long-term outcomes in relation to PC ECMO duration, with a focus on prolonged (> 7 d) ECMO. DESIGN: Retrospective observational cohort study. SETTING: Thirty-four centers from 16 countries between January 2000 and December 2020. PATIENTS: Adults requiring post PC ECMO between 2000 and 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Characteristics, in-hospital, and post-discharge outcomes were compared among patients categorized by ECMO duration. Survivors and nonsurvivors were compared in the subgroup of patients with ECMO duration greater than 7 days. The primary outcome was in-hospital mortality. Two thousand twenty-one patients were included who required PC ECMO for 0-3 days (n = 649 [32.1%]), 4-7 days (n = 776 [38.3%]), 8-10 days (n = 263 [13.0%]), and greater than 10 days (n = 333 [16.5%]). There were no major differences in the investigated preoperative and procedural characteristics among ECMO duration groups. However, the longer ECMO duration category was associated with multiple complications including bleeding, acute kidney injury, arrhythmias, and sepsis. Hospital mortality followed a U-shape curve, with lowest mortality in patients with ECMO duration of 4-7 days (n = 394, 50.8%) and highest in patients with greater than 10 days ECMO support (n = 242, 72.7%). There was no significant difference in post-discharge survival between ECMO duration groups. In patients with ECMO duration greater than 7 days, age, comorbidities, valvular diseases, and complex procedures were associated with nonsurvival. CONCLUSIONS: Nearly 30% of PC ECMO patients were supported for greater than 7 days. In-hospital mortality increased after 7 days of support, especially in patients undergoing valvular and complex surgery, or who had complications, although the long-term post-discharge prognosis was comparable to PC ECMO patients with shorter support duration.

Heterogeneity in Clinical Practices for Post-Cardiotomy Extracorporeal Life Support: a Pilot Survey from the PELS-1 Multicenter Study.

BACKGROUND: High-quality evidence for post-cardiotomy extracorporeal life support (PC-ECLS) management is lacking. This study investigated the real-world PC-ECLS clinical practices. METHODS: This cross-sectional, multi-institutional, international pilot survey explored center organization, anticoagulation management, left ventricular unloading, distal limb perfusion, PC-ECLS monitoring and transfusions practices. Twenty-nine questions were distributed among 34 hospitals participating in the Post-cardiotomy Extra-Corporeal Life Support Study. RESULTS: Of the 32 centers [16 low-volume (50%); 16 high-volume (50%)] that responded, 16 (50%) had dedicated ECLS specialists. Twenty-six centers (81.3%) reported using additional mechanical circulatory supports. Anticoagulation practices were highly heterogeneous: 24 hospitals (75%) reported using patient's bleeding status as a guide, without a specific threshold in 54.2% of cases. Transfusion targets ranged 7-10 g/dL. Most centers used cardiac venting on a case-by-case basis (78.1%) and regular distal limb perfusion (84.4%). Nineteen (54.9%) centers reported dedicated monitoring protocols including daily echocardiography (87.5%), Swan-Ganz catheterization (40.6%), cerebral near-infrared spectroscopy (53.1%) and multimodal assessment of limb ischemia. Inspection of the circuit (71.9%), oxygenator pressure drop (68.8%), plasma free hemoglobin (75%), d-dimer (59.4%), lactate dehydrogenase (56.3%) and fibrinogen (46.9%) are used to diagnose hemolysis and thrombosis. CONCLUSIONS: This study shows remarkable heterogeneity in clinical practices for PC-ECLS management. More standardized protocols and better implementation of available evidence are recommended.

Bone marrow- or adipose-mesenchymal stromal cell secretome preserves myocardial transcriptome profile and ameliorates cardiac damage following ex vivo cold storage.

BACKGROUND: Heart transplantation, a life-saving approach for patients with end-stage heart disease, is limited by shortage of donor organs. While prolonged storage provides more organs, it increases the extent of ischemia. Therefore, we seek to understand molecular mechanisms underlying pathophysiological changes of donor hearts during prolonged storage. Additionally, considering mesenchymal stromal cell (MSC)-derived paracrine protection, we aim to test if MSC secretome preserves myocardial transcriptome profile and whether MSC secretome from a certain source provides the optimal protection in donor hearts during cold storage. METHODS AND RESULTS: Isolated mouse hearts were divided into: no cold storage (control), 6 h cold storage (6 h-I), 6 h-I + conditioned media from bone marrow MSCs (BM-MSC CM), and 6 h-I + adipose-MSC CM (Ad-MSC CM). Deep RNA sequencing analysis revealed that compared to control, 6 h-I led to 266 differentially expressed genes, many of which were implicated in modulating mitochondrial performance, oxidative stress response, myocardial function, and apoptosis. BM-MSC CM and Ad-MSC CM restored these gene expression towards control. They also improved 6 h-I-induced myocardial functional depression, reduced inflammatory cytokine production, decreased apoptosis, and reduced myocardial H2O2. However, neither MSC-exosomes nor exosome-depleted CM recapitulated MSC CM-ameliorated apoptosis and CM-improved mitochondrial preservation during cold ischemia. Knockdown of Per2 by specific siRNA abolished MSC CM-mediated these protective effects in cardiomyocytes following 6 h cold storage. CONCLUSIONS: Our results demonstrated that using MSC secretome (BM-MSCs and Ad-MSCs) during prolonged cold storage confers preservation of the normal transcriptional "fingerprint", and reduces donor heart damage. MSC-released soluble factors and exosomes may synergistically act for donor heart protection.

Long term survival after lung transplantation: A single center experience.

BACKGROUND: There are approximately 2000 lung transplants performed across the United States annually. There is limited data to identify factors predictive of long-term survival. OBJECTIVE: We evaluated 10-year survivors after lung transplant to determine predictors of long-term survival. METHODS: Data were collected from the United Network for Organ Sharing registry database from a single institution. Inclusion criteria were: patients who received a lung transplant between 1989 and 2005. Descriptive statistics were calculated, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: Three hundred sixty-one patients received a lung transplant between 1989 and 2005, and 77 patients survived at least 10 years (21%). Diagnoses at the time of transplant included: chronic obstructive pulmonary disease/emphysema 45 (58.4%), idiopathic pulmonary fibrosis 12 (15.6%), alpha 1 anti-trypsin deficiency 6 (7.8%), cystic fibrosis 4 (5.2%), primary pulmonary hypertension 2 (2.6%), and Eisenmenger's syndrome 1 (1.3%). Seventy-four recipients (96.10%) were Caucasian; 46 (59.74%) were female. Age at the time of transplant ranged from 19 to 67 years (mean 50.8; median 52). Forty-two patients (54.5%) were double lung recipients. Survival ranged from 10.0 to 21.9 years (mean 15.5y; median 15.48y). Forty-two (54.5%) subjects are currently alive; the most common causes of death included: chronic rejection (20%), and infection (17.14%). CONCLUSIONS: Ten-year survivors were significantly younger, weighed less, and had significantly shorter lengths of hospitalization after transplantation. Bilateral lung transplantation was a significant factor in prolonged survival. Survival also improved with institutional experience.

Postischemic application of estrogen ameliorates myocardial damage in an in vivo mouse model.

BACKGROUND: Cardioprotection provided by estrogen has been recognized for many years. It is noteworthy that most of these studies employ a means of preinjury application in experimental research and the preventive usage in clinical studies. Compared to pretreatment, postischemic administration of estrogen will be more practical in treating myocardial ischemia. On the other hand, defect in circadian clock gene period2 (Per2) has been shown to aggravate ischemia-induced heart damage. Given that Per2 expression decreases as a consequence of menopause, in this study, we aim to determine (1) potential improvement of myocardial function by postischemic administration of 17ß-estradiol (E2) using an in vivo mouse myocardial ischemia/reperfusion (I/R) model and (2) the role of E2 in regulating myocardial Per2 expression following I/R. METHODS: Thirty-minute occlusion of left anterior descending artery followed by 24-h reperfusion was performed on adult C57BL ovariectomized female mice. Groups (n = 3-6/group) were as follows: (1) Sham, (2) I/R + vehicle, and (3) I/R + E2. Vehicle or 0.5 mg/kg of E2 was subcutaneously injected right after 30-min ischemia. Following 24-h reperfusion, myocardial function was determined. Heart tissue was collected for analysis of cleaved caspase-3 and Per2 expression by Western blotting, as well as proinflammatory cytokine production (IL-1ß, IL-6, and TNF-α) by enzyme-linked immunosorbent assay. RESULTS: I/R significantly impaired left ventricular function and increased myocardial levels of active caspase-3, IL-1ß, and IL-6. Importantly, postischemic treatment of E2 markedly restored I/R-depressed myocardial function, reduced caspase-3 activation, and decreased proinflammatory cytokine production (IL-1ß, IL-6, and TNF-α). Intriguingly, a trend of the decreased Per2 level was observed in ovariectomized female hearts subjected to I/R, whereas E2 treatment upregulated myocardial Per2 expression. CONCLUSIONS: Our study represents the initial evidence that postischemic administration of E2 effectively preserves the myocardium against I/R injury and this protective effect of E2 may involve upregulation of Per2 in ischemic heart.

Regulation of myocardial stromal cell-derived factor 1α/CXCL12 by tumor necrosis factor signaling.

BACKGROUND: Global myocardial ischemia-reperfusion (I/R) occurs during cardiac operations. This I/R injury leads to increased production of tumor necrosis factor α (TNF) instantly and upregulated expression of stromal cell-derived factor 1 α (SDF-1). On the basis of the published data from our laboratory and other groups, locally produced TNF contributes to cardiac dysfunction mainly via binding to its receptor (tumor necrosis factor receptor 1 [TNFR1]), whereas ischemia-induced myocardial SDF-1 mediates cardioprotection. Although TNF has been shown to work as an upstream initiator for induction of other cytokines and chemokines, there is no information regarding the interaction among TNF, TNFRs, and myocardial SDF-1 expression. In this study, given that TNF downregulated SDF-1 in vascular endothelial cells, we therefore hypothesized that TNF would have a negative effect on myocardial SDF-1 production, which is attributable to TNFR-initiated actions. METHODS: Using a Langendorff model, isolated male mouse hearts were infused with TNF for 45 min. Male adult mouse hearts from wild type, TNFR1 knockout (TNFR1KO), TNFR2KO, and TNFR1/2KO were subjected to global I/R. H9c2 cells with small interfering RNA transfection were used as an in vitro model. The levels of SDF-1 (protein and messenger RNA) were detected by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction . Protein kinases of IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α) and c-jun N-terminal kinase were also determined using Western blot assay. RESULTS: TNF infusion downregulated myocardial SDF-1 production in a dose-dependent manner in the hearts. In addition, using TNF significantly decreased SDF-1 expression in cardiomyoblasts (H9c2 cells), which was associated with reduced IκB level. Knockdown of TNFR1 or TNFR2 by small interfering RNAs neutralized TNF-suppressed SDF-1 in H9c2 cells. Furthermore, deletion of TNFR1/2 or TNFR2 increased SDF-1 production in the hearts after I/R. CONCLUSIONS: Our study represents the initial evidence showing that TNF plays an inhibitory role in modulating myocardial SDF-1 production and blockade of TNF signaling by ablation of TNFR1 and TNFR2 genes increased SDF-1 expression in the heart. These data expand on TNF signaling-initiated mechanisms in myocardium, which may lend a more complete understanding of SDF-1 and TNFR-derived actions in hopes of advancing ischemic heart injury treatments.

Pulse Oximeter Derived Blood Pressure Measurement in Patients With a Continuous Flow Left Ventricular Assist Device.

Currently, blood pressure (BP) measurement is obtained noninvasively in patients with continuous flow left ventricular assist device (LVAD) by placing a Doppler probe over the brachial or radial artery with inflation and deflation of a manual BP cuff. We hypothesized that replacing the Doppler probe with a finger-based pulse oximeter can yield BP measurements similar to the Doppler derived mean arterial pressure (MAP). We conducted a prospective study consisting of patients with contemporary continuous flow LVADs. In a small pilot phase I inpatient study, we compared direct arterial line measurements with an automated blood pressure (ABP) cuff, Doppler and pulse oximeter derived MAP. Our main phase II study included LVAD outpatients with a comparison between Doppler, ABP, and pulse oximeter derived MAP. A total of five phase I and 36 phase II patients were recruited during February-June 2014. In phase I, the average MAP measured by pulse oximeter was closer to arterial line MAP rather than Doppler (P = 0.06) or ABP (P < 0.01). In phase II, pulse oximeter MAP (96.6 mm Hg) was significantly closer to Doppler MAP (96.5 mm Hg) when compared to ABP (82.1 mm Hg) (P = 0.0001). Pulse oximeter derived blood pressure measurement may be as reliable as Doppler in patients with continuous flow LVADs.

B-Type Natriuretic Peptide Levels Predict Ventricular Arrhythmia Post Left Ventricular Assist Device Implantation.

B-type natriuretic peptide (BNP) levels have been shown to predict ventricular arrhythmia (VA) and sudden death in patients with heart failure. We sought to determine whether BNP levels before left ventricular assist device (LVAD) implantation can predict VA post LVAD implantation in advanced heart failure patients. We conducted a retrospective study consisting of patients who underwent LVAD implantation in our institution during the period of May 2009-March 2013. The study was limited to patients receiving a HeartMate II or HeartWare LVAD. Acute myocardial infarction patients were excluded. We compared between the patients who developed VA within 15 days post LVAD implantation to the patients without VA. A total of 85 patients underwent LVAD implantation during the study period. Eleven patients were excluded (five acute MI, four without BNP measurements, and two discharged earlier than 13 days post LVAD implantation). The incidence of VA was 31%, with 91% ventricular tachycardia (VT) and 9% ventricular fibrillation. BNP remained the single most powerful predictor of VA even after adjustment for other borderline significant factors in a multivariate logistic regression model (P < 0.05). BNP levels are a strong predictor of VA post LVAD implantation, surpassing previously described risk factors such as age and VT in the past.

Recipient body mass index and age interact to impact survival after heart transplantation.

Although recipient body mass index (BMI) and age are known risk factors for mortality after heart transplantation, how they interact to influence survival is unknown. Our study utilized the UNOS registry from 1997 to 2012 to define the interaction between BMI and age and its impact on survival after heart transplantation. Recipients were stratified by BMI: underweight (<18.5), normal weight (18.5-24.99), overweight (25-29.99), and either moderate (30-34.99), severe (35-39.99), or very severe (≥40) obesity. Recipients were secondarily stratified based on age: 18-40 (younger recipients), 40-65 (reference group), and ≥65 (advanced age recipients). Among younger recipients, being underweight was associated with improved adjusted survival (HR 0.902; p = 0.010) while higher mortality was seen in younger overweight recipients (HR 1.260; p = 0.005). However, no differences in adjusted survival were appreciated in underweight and overweight advanced age recipients. Obesity (BMI ≥ 30) was associated with increased adjusted mortality in normal age recipients (HR 1.152; p = 0.021) and even more so with young (HR 1.576; p < 0.001) and advanced age recipients (HR 1.292; p = 0.001). These results demonstrate that BMI and age interact to impact survival as age modifies BMI-mortality curves, particularly with younger and advanced age recipients.

Impact of donor age on survival after heart transplantation: an analysis of the United Network for Organ Sharing (UNOS) registry.

BACKGROUND: Data are limited regarding the influence of donor age on outcomes after heart transplantation. We sought to determine if advanced donor age is associated with differences in survival after heart transplantation and how this compares to waitlist survival. METHODS: All adult heart transplants from 2000 to 2012 were identified using the United Network for Organ Sharing database. Donors were stratified into four age groups: 18-39 (reference group), 40-49, 50-54, and 55 and above. Propensity scoring was used to compare status IA waitlist patients who did not undergo transplantation with IA recipients who received hearts from advanced age donors. The primary outcome of interest was recipient survival and this was analyzed with multivariate Cox regression analysis and the Kaplan-Meier method. RESULTS: A total of 22,960 adult heart transplant recipients were identified. Recipients of hearts from all three older donor groups had significantly increased risk of mortality (HR, 1.187-1.426, all p < 0.001) compared to recipients from donors age 18 to 39. Additionally, propensity-matched status IA patients managed medically without transplantation had significantly worse adjusted survival than status IA recipients who received hearts from older donors age ≥55 (HR, 1.362, p < 0.001). CONCLUSIONS: Compared to donors aged 18-39, age 40 and above is associated with worse adjusted recipient survival in heart transplantation. This survival difference becomes more pronounced as age increases to above 55. However, the survival rate among status IA patients who receive hearts from advanced age donors (≥55) is significantly better compared to similar status IA patients who are managed without transplantation.

Human immunodeficiency virus infection is associated with greater risk of pneumonia and readmission after cardiac surgery.

Objective: Human immunodeficiency virus infection (HIV+) is associated with a 2-fold increased risk of cardiovascular disease. Increasingly, patients who are HIV + are being evaluated to undergo cardiac surgery. Current risk-adjusted scoring systems, including the Society of Thoracic Surgeons Predicted Risk of Mortality score, fail to stratify HIV + risk. Unfortunately, there exists a paucity of cardiac surgery outcomes data in modern patients who are HIV+. Methods: We conducted a retrospective review of PearlDiver, an all-payer claims administrative database. In total, 14,714,743 patients were captured between 2010 and 2020. Of these, 59,695 (0.4%) of patients had a history of HIV+, and 1759 (2.95%) of these patients underwent cardiac surgery. Patients who were HIV+ were younger, more often male, and had greater comorbidity, history of hypertension, chronic obstructive pulmonary disease, chronic liver disease, chronic kidney disease, chronic lung disease, and heart failure. Results: Postoperatively, patients who were HIV + had significantly greater rates of pneumonia (relative risk, 1.70; P = .0003) and 30-day all-cause readmission (relative risk, 1.28, P < .0001). After linear regression analysis, these results remained significant. Data also show that a lesser proportion of patients with HIV + underwent coronary artery bypass grafting, aortic valve replacement, and any cardiac surgery compared with controls. Conclusions: Patients who are HIV + undergoing cardiac surgery are at greater risk of pneumonia and readmission. Moreover, we discovered lower rates of cardiac surgery in patients who are HIV+, which may reflect limited access to surgery when indicated. Today's risk-adjusted scoring systems in cardiac surgery need to better account for the modern patient who is HIV+.

Increasing Utilization of Extended Criteria Donor Hearts for Transplantation: The OCS Heart EXPAND Trial.

BACKGROUND: Extended criteria donor (ECD) hearts available with donation after brain death (DBD) are underutilized for transplantation due to limitations of cold storage. OBJECTIVES: This study evaluated use of an extracorporeal perfusion system on donor heart utilization and post-transplant outcomes in ECD DBD hearts. METHODS: In this prospective, single-arm, multicenter study, adult heart transplant recipients received ECD hearts using an extracorporeal perfusion system if hearts met study criteria. The primary outcome was a composite of 30-day survival and absence of severe primary graft dysfunction (PGD). Secondary outcomes were donor heart utilization rate, 30-day survival, and incidence of severe PGD. The safety outcome was the mean number of heart graft-related serious adverse events within 30 days. Additional outcomes included survival through 2 years benchmarked to concurrent nonrandomized control subjects. RESULTS: A total of 173 ECD DBD hearts were perfused; 150 (87%) were successfully transplanted; 23 (13%) did not meet study transplantation criteria. At 30 days, 92% of patients had survived and had no severe PGD. The 30-day survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of heart graft-related serious adverse events within 30 days was 0.17 (95% CI: 0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months, respectively, and was comparable with concurrent nonrandomized control subjects. CONCLUSIONS: Use of an extracorporeal perfusion system resulted in successfully transplanting 87% of donor hearts with excellent patient survival to 2 years post-transplant and low rates of severe PGD. The ability to safely use ECD DBD hearts could substantially increase the number of heart transplants and expand access to patients in need. (International EXPAND Heart Pivotal Trial [EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol; NCT03835754).

Features and outcomes of female and male patients requiring postcardiotomy extracorporeal life support.

OBJECTIVES: Although cardiogenic shock requiring extracorporeal life support after cardiac surgery is associated with high mortality, the impact of sex on outcomes of postcardiotomy extracorporeal life support remains unclear with conflicting results in the literature. We compare patient characteristics, in-hospital outcomes, and overall survival between females and males requiring postcardiotomy extracorporeal life support. METHODS: This retrospective, multicenter (34 centers), observational study included adults requiring postcardiotomy extracorporeal life support between 2000 and 2020. Preoperative, procedural, and extracorporeal life support characteristics, complications, and survival were compared between females and males. Association between sex and in-hospital survival was investigated through mixed Cox proportional hazard models. RESULTS: This analysis included 1823 patients (female: 40.8%; median age: 66.0 years [interquartile range, 56.2-73.0 years]). Females underwent more mitral valve surgery (females: 38.4%, males: 33.1%, P = .019) and tricuspid valve surgery (feamales: 18%, males: 12.4%, P < .001), whereas males underwent more coronary artery surgery (females: 45.9%, males: 52.4%, P = .007). Extracorporeal life support implantation was more common intraoperatively in feamales (females: 64.1%, females: 59.1%) and postoperatively in males (females: 35.9%, males: 40.9%, P = .036). Ventricular unloading (females: 25.1%, males: 36.2%, P < .001) and intra-aortic balloon pumps (females: 25.8%, males: 36.8%, P < .001) were most frequently used in males. Females had more postoperative right ventricular failure (females: 24.1%, males: 19.1%, P = .016) and limb ischemia (females: 12.3%, males: 8.8%, P = .23). In-hospital mortality was 64.9% in females and 61.9% in males (P = .199) with no differences in 5-year survival (females: 20%, 95% CI, 17-23; males: 24%, 95% CI, 21-28; P = .069). Crude hazard ratio for in-hospital mortality in females was 1.12 (95% CI, 0.99-1.27; P = .069) and did not change after adjustments. CONCLUSIONS: This study demonstrates that female and male patients requiring postcardiotomy extracorporeal life support have different preoperative and extracorporeal life support characteristics, as well as complications, without a statistical difference in in-hospital and 5-year survivals.

Rice GA3ox1 modulates pollen starch granule accumulation and pollen wall development.

The rice GA biosynthetic gene OsGA3ox1 has been proposed to regulate pollen development through the gametophytic manner, but cellular characterization of its mutant pollen is lacking. In this study, three heterozygotic biallelic variants, "-3/-19", "-3/-2" and "-3/-10", each containing one null and one 3bp-deletion allele, were obtained by the CRISPR/Cas9 technique for the functional study of OsGA3ox1. The three homozygotes, "-19/-19", "-2/-2" and "-10/-10", derived from heterozygotic variants, did not affect the development of most vegetative and floral organs but showed a significant reduction in seed-setting rate and in pollen viability. Anatomic characterizations of these mutated osga3ox1 pollens revealed defects in starch granule accumulation and pollen wall development. Additional molecular characterization suggests that abnormal pollen development in the osga3ox1 mutants might be linked to the regulation of transcription factors OsGAMYB, OsTDR and OsbHLH142 during late pollen development. In brief, the rice GA3ox1 is a crucial gene that modulates pollen starch granule accumulation and pollen wall development at the gametophytic phase.

Patient and Management Variables Associated With Survival After Postcardiotomy Extracorporeal Membrane Oxygenation in Adults: The PELS-1 Multicenter Cohort Study.

Background Extracorporeal membrane oxygenation (ECMO) has been increasingly used for postcardiotomy cardiogenic shock, but without a concomitant reduction in observed in-hospital mortality. Long-term outcomes are unknown. This study describes patients' characteristics, in-hospital outcome, and 10-year survival after postcardiotomy ECMO. Variables associated with in-hospital and postdischarge mortality are investigated and reported. Methods and Results The retrospective international multicenter observational PELS-1 (Postcardiotomy Extracorporeal Life Support) study includes data on adults requiring ECMO for postcardiotomy cardiogenic shock between 2000 and 2020 from 34 centers. Variables associated with mortality were estimated preoperatively, intraoperatively, during ECMO, and after the occurrence of any complications, and then analyzed at different time points during a patient's clinical course, through mixed Cox proportional hazards models containing fixed and random effects. Follow-up was established by institutional chart review or contacting patients. This analysis included 2058 patients (59% were men; median [interquartile range] age, 65.0 [55.0-72.0] years). In-hospital mortality was 60.5%. Independent variables associated with in-hospital mortality were age (hazard ratio [HR], 1.02 [95% CI, 1.01-1.02]) and preoperative cardiac arrest (HR, 1.41 [95% CI, 1.15-1.73]). In the subgroup of hospital survivors, the overall 1-, 2-, 5-, and 10-year survival rates were 89.5% (95% CI, 87.0%-92.0%), 85.4% (95% CI, 82.5%-88.3%), 76.4% (95% CI, 72.5%-80.5%), and 65.9% (95% CI, 60.3%-72.0%), respectively. Variables associated with postdischarge mortality included older age, atrial fibrillation, emergency surgery, type of surgery, postoperative acute kidney injury, and postoperative septic shock. Conclusions In adults, in-hospital mortality after postcardiotomy ECMO remains high; however, two-thirds of those who are discharged from hospital survive up to 10 years. Patient selection, intraoperative decisions, and ECMO management remain key variables associated with survival in this cohort. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03857217.

The importance of timing in postcardiotomy venoarterial extracorporeal membrane oxygenation: A descriptive multicenter observational study.

OBJECTIVES: Postcardiotomy extracorporeal membrane oxygenation (ECMO) can be initiated intraoperatively or postoperatively based on indications, settings, patient profile, and conditions. The topic of implantation timing only recently gained attention from the clinical community. We compare patient characteristics as well as in-hospital and long-term survival between intraoperative and postoperative ECMO. METHODS: The retrospective, multicenter, observational Postcardiotomy Extracorporeal Life Support (PELS-1) study includes adults who required ECMO due to postcardiotomy shock between 2000 and 2020. We compared patients who received ECMO in the operating theater (intraoperative) with those in the intensive care unit (postoperative) on in-hospital and postdischarge outcomes. RESULTS: We studied 2003 patients (women: 41.1%; median age: 65 years; interquartile range [IQR], 55.0-72.0). Intraoperative ECMO patients (n = 1287) compared with postoperative ECMO patients (n = 716) had worse preoperative risk profiles. Cardiogenic shock (45.3%), right ventricular failure (15.9%), and cardiac arrest (14.3%) were the main indications for postoperative ECMO initiation, with cannulation occurring after (median) 1 day (IQR, 1-3 days). Compared with intraoperative application, patients who received postoperative ECMO showed more complications, cardiac reoperations (intraoperative: 19.7%; postoperative: 24.8%, P = .011), percutaneous coronary interventions (intraoperative: 1.8%; postoperative: 3.6%, P = .026), and had greater in-hospital mortality (intraoperative: 57.5%; postoperative: 64.5%, P = .002). Among hospital survivors, ECMO duration was shorter after intraoperative ECMO (median, 104; IQR, 67.8-164.2 hours) compared with postoperative ECMO (median, 139.7; IQR, 95.8-192 hours, P < .001), whereas postdischarge long-term survival was similar between the 2 groups (P = .86). CONCLUSIONS: Intraoperative and postoperative ECMO implantations are associated with different patient characteristics and outcomes, with greater complications and in-hospital mortality after postoperative ECMO. Strategies to identify the optimal location and timing of postcardiotomy ECMO in relation to specific patient characteristics are warranted to optimize in-hospital outcomes.

The Relation Between Obesity and Mortality in Postcardiotomy Venoarterial Membrane Oxygenation.

BACKGROUND: Obesity is an important health problem in cardiac surgery and among patients requiring postcardiotomy venoarterial extracorporeal membrane oxygenation (V-A ECMO). Still, whether these patients are at risk for unfavorable outcomes after postcardiotomy V-A ECMO remains unclear. The current study evaluated the association between body mass index (BMI) and in-hospital outcomes in this setting. METHODS: The Post-cardiotomy Extracorporeal Life Support (PELS-1) study is an international, multicenter study. Patients requiring postcardiotomy V-A ECMO in 36 centers from 16 countries between 2000 and 2020 were included. Patients were divided in 6 BMI categories (underweight, normal weight, overweight, class I, class II, and class III obesity) according to international recommendations. Primary outcome was in-hospital mortality, and secondary outcomes included major adverse events. Mixed logistic regression models were applied to evaluate associations between BMI and mortality. RESULTS: The study cohort included 2046 patients (median age, 65 years; 838 women [41.0%]). In-hospital mortality was 60.3%, without statistically significant differences among BMI classes for in-hospital mortality (P = .225) or major adverse events (P = .126). The crude association between BMI and in-hospital mortality was not statistically significant after adjustment for comorbidities and intraoperative variables (class I: odds ratio [OR], 1.21; 95% CI, 0.88-1.65; class II: OR, 1.45; 95% CI, 0.86-2.45; class III: OR, 1.43; 95% CI, 0.62-3.33), which was confirmed in multiple sensitivity analyses. CONCLUSIONS: BMI is not associated to in-hospital outcomes after adjustment for confounders in patients undergoing postcardiotomy V-A ECMO. Therefore, BMI itself should not be incorporated in the risk stratification for postcardiotomy V-A ECMO.

On-Support and Postweaning Mortality in Postcardiotomy Extracorporeal Membrane Oxygenation.

BACKGROUND: Postcardiotomy venoarterial extracorporeal membrane oxygenation (VA ECMO) is characterized by discrepancies between weaning and survival-to-discharge rates. This study analyzes the differences between postcardiotomy VA ECMO patients who survived, died on ECMO, or died after ECMO weaning. Causes of death and variables associated with mortality at different time points are investigated. METHODS: The retrospective, multicenter, observational Postcardiotomy Extracorporeal Life Support Study (PELS) includes adults requiring postcardiotomy VA ECMO between 2000 and 2020. Variables associated with on-ECMO mortality and postweaning mortality were modeled using mixed Cox proportional hazards, including random effects for center and year. RESULTS: In 2058 patients (men, 59%; median age, 65 years; interquartile range [IQR], 55-72 years), weaning rate was 62.7%, and survival to discharge was 39.6%. Patients who died (n = 1244) included 754 on-ECMO deaths (36.6%; median support time, 79 hours; IQR, 24-192 hours), and 476 postweaning deaths (23.1%; median support time, 146 hours; IQR, 96-235.5 hours). Multiorgan (n = 431 of 1158 [37.2%]) and persistent heart failure (n = 423 of 1158 [36.5%]) were the main causes of death, followed by bleeding (n = 56 of 754 [7.4%]) for on-ECMO mortality and sepsis (n = 61 of 401 [15.4%]) for postweaning mortality. On-ECMO death was associated with emergency surgery, preoperative cardiac arrest, cardiogenic shock, right ventricular failure, cardiopulmonary bypass time, and ECMO implantation timing. Diabetes, postoperative bleeding, cardiac arrest, bowel ischemia, acute kidney injury, and septic shock were associated with postweaning mortality. CONCLUSIONS: A discrepancy exists between weaning and discharge rate in postcardiotomy ECMO. Deaths occurred during ECMO support in 36.6% of patients, mostly associated with unstable preoperative hemodynamics. Another 23.1% of patients died after weaning in association with severe complications. This underscores the importance of postweaning care for postcardiotomy VA ECMO patients.

Serotonin accumulation in transgenic rice by over-expressing tryptophan decarboxylase results in a dark brown phenotype and stunted growth.

A mutant M47286 with a stunted growth, low fertility and dark-brown phenotype was identified from a T-DNA-tagged rice mutant library. This mutant contained a copy of the T-DNA tag inserted at the location where the expression of two putative tryptophan decarboxylase genes, TDC-1 and TDC-3, were activated. Enzymatic assays of both recombinant proteins showed tryptophan decarboxylase activities that converted tryptophan to tryptamine, which could be converted to serotonin by a constitutively expressed tryptamine 5' hydroxylase (T5H) in rice plants. Over-expression of TDC-1 and TDC-3 in transgenic rice recapitulated the stunted growth, darkbrown phenotype and resulted in a low fertility similar to M47286. The degree of stunted growth and dark-brown color was proportional to the expression levels of TDC-1 and TDC-3. The levels of tryptamine and serotonin accumulation in these transgenic rice lines were also directly correlated with the expression levels of TDC-1 and TDC-3. A mass spectrometry assay demonstrated that the darkbrown leaves and hulls in the TDC-overexpressing transgenic rice were caused by the accumulation of serotonin dimer and that the stunted growth and low fertility were also caused by the accumulation of serotonin and serotonin dimer, but not tryptamine. These results represent the first evidence that over-expression of TDC results in stunted growth, low fertility and the accumulation of serotonin, which when converted to serotonin dimer, leads to a dark brown plant color.

Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling.

Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ∼6.3 × 6.3 cm(2) field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 ± 44 vs. 448 ± 39 ms, at BCL = 2,000 ms, P < 0.05). Dispersion of APD was increased in three failing hearts (161 ± 5 vs. 86 ± 19 ms, at BCL = 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 ± 11 vs. 98 ± 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF.