Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Predicting Incident Adenocarcinoma of the Esophagus or Gastric Cardia Using Machine Learning of Electronic Health Records.

BACKGROUND & AIMS: Tools that can automatically predict incident esophageal adenocarcinoma (EAC) and gastric cardia adenocarcinoma (GCA) using electronic health records to guide screening decisions are needed. METHODS: The Veterans Health Administration (VHA) Corporate Data Warehouse was accessed to identify Veterans with 1 or more encounters between 2005 and 2018. Patients diagnosed with EAC (n = 8430) or GCA (n = 2965) were identified in the VHA Central Cancer Registry and compared with 10,256,887 controls. Predictors included demographic characteristics, prescriptions, laboratory results, and diagnoses between 1 and 5 years before the index date. The Kettles Esophageal and Cardia Adenocarcinoma predictioN (K-ECAN) tool was developed and internally validated using simple random sampling imputation and extreme gradient boosting, a machine learning method. Training was performed in 50% of the data, preliminary validation in 25% of the data, and final testing in 25% of the data. RESULTS: K-ECAN was well-calibrated and had better discrimination (area under the receiver operating characteristic curve [AuROC], 0.77) than previously validated models, such as the Nord-Trøndelag Health Study (AuROC, 0.68) and Kunzmann model (AuROC, 0.64), or published guidelines. Using only data from between 3 and 5 years before index diminished its accuracy slightly (AuROC, 0.75). Undersampling men to simulate a non-VHA population, AUCs of the Nord-Trøndelag Health Study and Kunzmann model improved, but K-ECAN was still the most accurate (AuROC, 0.85). Although gastroesophageal reflux disease was strongly associated with EAC, it contributed only a small proportion of gain in information for prediction. CONCLUSIONS: K-ECAN is a novel, internally validated tool predicting incident EAC and GCA using electronic health records data. Further work is needed to validate K-ECAN outside VHA and to assess how best to implement it within electronic health records.

Dietary Sodium Intake and Outcomes: a Secondary Analysis From Sodium-HF.

OBJECTIVES: This post hoc analysis of SODIUM-HF (Study of Dietary Intervention under 100 mmol in Heart Failure) assessed the association between baseline dietary sodium intake and change at 6 months with a composite of cardiovascular (CV) hospitalizations, emergency department visits and all-cause death at 12 and 24 months. BACKGROUND: Dietary sodium restriction is common advice for patients with heart failure (HF). Randomized clinical trials have not shown a beneficial effect of dietary sodium restriction on clinical outcomes. METHODS: A multivariable Cox proportional hazard regression model was used to assess the association of dietary sodium intake measured at randomization with primary and secondary endpoints. RESULTS: The study included 792 participants. Baseline sodium intake was ≤ 1500 mg/day in 19.9% (n = 158), 1501-3000 mg/day in 56.5% (n = 448) and > 3000 mg/day in 23.4% (n = 186) of participants. The factors associated with higher baseline sodium intake were higher calorie consumption, higher body mass index and recruitment from Canada. Multivariable analyses showed no association between baseline sodium intake nor magnitude of 6-month change or 12- or 24-month outcomes. In a responder analysis, participants achieving a sodium intake < 1500 mg at 6 months showed an association with a decreased risk for the composite outcome (adjusted HR 0.52 [95% CI 0.25, 1.07] P = 0.08) and CV hospitalization (adjusted HR 0.51 [95% CI 0.24, 1.09] P = 0.08) at 12 months. CONCLUSION: There was no association between dietary sodium intake and clinical outcomes over 24 months in patients with HF. Responder analyses suggest the need for further investigation of the effects of sodium reduction in those who achieve the targeted dietary sodium-reduction level.

Using pulsatility responses to breath-hold maneuvers to predict readmission rates in continuous-flow left ventricular assist device patients.

BACKGROUND: Dynamic respiratory maneuvers induce heterogenous changes to flow-pulsatility in continuous-flow left ventricular assist device patients. We evaluated the association of these pulsatility responses with patient hemodynamics and outcomes. METHODS: Responses obtained from HVAD (Medtronic) outpatients during successive weekly clinics were categorized into three ordinal groups according to the percentage reduction in flow-waveform pulsatility (peak-trough flow) upon inspiratory-breath-hold, (%∆P): (1) minimal change (%∆P ≤ 50), (2) reduced pulsatility (%∆P > 50 but <100), (3) flatline (%∆P = 100). Same-day echocardiography and right-heart-catheterization were performed. Readmissions were compared between patients with ≥1 flatline response (F-group) and those without (NF-group). RESULTS: Overall, 712 responses were obtained from 55 patients (82% male, age 56.4 ± 11.5). When compared to minimal change, reduced pulsatility and flatline responses were associated with lower central venous pressure (14.2 vs. 11.4 vs. 9.0 mm Hg, p = 0.08) and pulmonary capillary wedge pressure (19.8 vs. 14.3 vs. 13.0 mm Hg, p = 0.03), lower rates of ≥moderate mitral regurgitation (48% vs. 13% vs. 10%, p = 0.01), lower rates of ≥moderate right ventricular impairment (62% vs. 25% vs. 27%, p = 0.03), and increased rates of aortic valve opening (32% vs. 50% vs. 75%, p = 0.03). The F-group (n = 28) experienced numerically lower all-cause readmissions (1.51 vs. 2.79 events-per-patient-year [EPPY], hazard-ratio [HR] = 0.67, p = 0.12), reduced heart failure readmissions (0.07 vs. 0.57 EPPY, HR = 0.15, p = 0.008), and superior readmission-free survival (HR = 0.47, log-rank p = 0.04). Syncopal readmissions occurred exclusively in the F-group (0.20 vs. 0 EPPY, p = 0.01). CONCLUSION: Responses to inspiratory-breath-hold predicted hemodynamics and readmission risk. The impact of inspiratory-breath-hold on pulsatility can non-invasively guide hemodynamic management decisions, patient optimization, and readmission risk stratification.

The Rapidly Evolving Landscape of DCD Heart Transplantation.

PURPOSE OF REVIEW: To summarise current international clinical outcomes from donation after circulatory death heart transplantation (DCD-HT); discuss procurement strategies, their impact on outcomes and overall organ procurement; and identify novel approaches and future areas for research in DCD-HT. RECENT FINDINGS: Globally, DCD-HT survival outcomes (regardless of procurement strategy) are comparable to heart transplantation from brain dead donors (BDD). Experience with normothermic machine perfusion sees improvement in rates of primary graft dysfunction. Techniques have evolved to reduce cold ischaemic exposure to directly procured DCD hearts, though controlled periods of cold ischaemia can likely be tolerated. There is interest in hypothermic machine perfusion (HMP) for directly procured DCD hearts, with promising early results. Survival outcomes are firmly established to be equivalent between BDD and DCD-HT. Procurement strategy (direct procurement vs. regional perfusion) remains a source of debate. Methods to improve allograft warm ischaemic tolerance are of interest and will be key to the uptake of HMP for directly procured DCD hearts.

Multiligament knee injury (MLKI): an expert consensus statement on nomenclature, diagnosis, treatment and rehabilitation.

Multiligament knee injuries (MLKIs) represent a broad spectrum of pathology with potentially devastating consequences. Currently, disagreement in the terminology, diagnosis and treatment of these injuries limits clinical care and research. This study aimed to develop consensus on the nomenclature, diagnosis, treatment and rehabilitation strategies for patients with MLKI, while identifying important research priorities for further study. An international consensus process was conducted using validated Delphi methodology in line with British Journal of Sports Medicine guidelines. A multidisciplinary panel of 39 members from 14 countries, completed 3 rounds of online surveys exploring aspects of nomenclature, diagnosis, treatment, rehabilitation and future research priorities. Levels of agreement (LoA) with each statement were rated anonymously on a 5-point Likert scale, with experts encouraged to suggest modifications or additional statements. LoA for consensus in the final round were defined 'a priori' if >75% of respondents agreed and fewer than 10% disagreed, and dissenting viewpoints were recorded and discussed. After three Delphi rounds, 50 items (92.6%) reached consensus. Key statements that reached consensus within nomenclature included a clear definition for MLKI (LoA 97.4%) and the need for an updated MLKI classification system that classifies injury mechanism, extent of non-ligamentous structures injured and the presence or absence of dislocation. Within diagnosis, consensus was reached that there should be a low threshold for assessment with CT angiography for MLKI within a high-energy context and for certain injury patterns including bicruciate and PLC injuries (LoA 89.7%). The value of stress radiography or intraoperative fluoroscopy also reached consensus (LoA 89.7%). Within treatment, it was generally agreed that existing literature generally favours operative management of MLKI, particularly for young patients (LoA 100%), and that single-stage surgery should be performed whenever possible (LoA 92.3%). This consensus statement will facilitate clinical communication in MLKI, the care of these patients and future research within MLKI.

Anterior Cruciate Ligament Reconstruction Plus Lateral Extra-articular Tenodesis Has a Similar Return-to-Sport Rate to Anterior Cruciate Ligament Reconstruction Alone but a Lower Failure Rate.

PURPOSE: To determine whether the addition of lateral extra-articular tenodesis (LET) to anterior cruciate ligament reconstruction (ACLR) would improve return-to-sport (RTS) rates in young, active patients who play high-risk sports. METHODS: This multicenter randomized controlled trial compared standard hamstring tendon ACLR with combined ACLR and LET using a strip of the iliotibial band (modified Lemaire technique). Patients aged 25 years or younger with an anterior cruciate ligament-deficient knee were included. Patients also had to meet 2 of the following criteria: (1) pivot-shift grade 2 or greater, (2) participation in a high-risk or pivoting sport, and (3) generalized ligamentous laxity. Time to return and level of RTS were determined via administration of a questionnaire at 24 months postoperatively. RESULTS: We randomized 618 patients in this study, 553 of whom played high-risk sports preoperatively. The proportion of patients who did not RTS was similar between the ACLR (11%) and ACLR-LET (14%) groups; however, the graft rupture rate was significantly different (11.2% in ACLR group vs 4.1% in ACLR-LET group, P = .004). The most cited reason for no RTS was lack of confidence and/or fear of reinjury. A stable knee was associated with nearly 2 times greater odds of returning to a high-level high-risk sport postoperatively (odds ratio, 1.92; 95% confidence interval, 1.11-3.35; P = .02). There were no significant differences in patient-reported functional outcomes or hop test results between groups (P > .05). Patients who returned to high-risk sports had better hamstring symmetry than those who did not RTS (P = .001). CONCLUSIONS: At 24 months postoperatively, patients who underwent ACLR plus LET had a similar RTS rate to those who underwent ACLR alone. Although the subgroup analysis did not show a statistically significant increase in RTS with the addition of LET, on returning, the addition of LET kept subjects playing longer by reducing graft failure rates. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Presence of Additional Pathology in Low-Grade Acromioclavicular Joint Injuries.

OBJECTIVE: To determine if additional pathology is present in low-grade acromioclavicular (AC) joint injuries. DESIGN: Prospective case series. SETTING: Patients were assessed by primary care sports medicine physicians at a single institution between 2019 and 2023. PATIENTS: Patients aged 18 to 65 years diagnosed with a type I to III AC injury based on clinical and radiographic evaluation. INTERVENTION: Consenting patients underwent magnetic resonance imaging (MRI) evaluation within 21 days of injury. All injuries were treated nonoperatively. MAIN OUTCOME MEASURES: Additional pathologies identified on MRI were reported in a standardized fashion by fellowship-trained musculoskeletal radiologists. RESULTS: Twenty-nine patients (26 men/3 women) were consented with a mean (±SD) age of 28.6 ± 9.5 years. The mean time from injury to MRI was 8.1 ± 5.9 days. Twenty-three injuries were sport related, and 6 were accidental traumas. Based on MRI, injury type was reclassified in 16 of 29 patients, and 13 remained unchanged. Additional pathologies identified included 14 muscle injuries, 5 rotator cuff tears, 5 labral tears, 1 nondisplaced fracture, and 1 intra-articular body. CONCLUSION: MRI evidence suggests that most AC joint injuries are more severe than clinically diagnosed. Identifying additional pathology may alter diagnostic and treatment guidelines for type I to III AC joint injuries.

The effect of intravenous tranexamic acid on visual clarity in arthroscopic shoulder surgery compared to epinephrine and a placebo: a double-blinded, randomized controlled trial.

BACKGROUND: The addition of epinephrine in irrigation fluid and the intravenous or local administration of tranexamic acid have independently been reported to decrease bleeding, thereby improving surgeons' visualization during arthroscopic shoulder procedures. No study has compared the effect of intravenous tranexamic acid, epinephrine in the irrigation fluid, or the combination of both tranexamic acid and epinephrine on visual clarity during shoulder arthroscopy with a placebo group. We hypothesized that intravenous tranexamic acid is more effective than epinephrine mixed in the irrigation fluid in improving visualization during shoulder arthroscopy, with no additive effect when both are used. METHODS: Patients aged ≥18 years undergoing shoulder arthroscopy were randomized into one of 4 study arms: (1) saline irrigation fluid (placebo); (2) epinephrine (0.33 mL of 1:1000 per liter) mixed in irrigation fluid (EPI); (3) 1 g intravenous tranexamic acid (TXA); and (4) epinephrine and tranexamic acid combined (TXA + EPI). Visualization was rated intraoperatively on a scale from 0, indicating poor clarity, to 3, indicating excellent clarity, every 15 minutes and overall. The primary outcome measure was the overall rating of visualization. A stepwise linear regression was performed using visualization as the dependent variable and independent variables including presence or absence of epinephrine and tranexamic acid, surgery duration, complexity, mean arterial pressure, increase in pump pressure, and volume of irrigation fluid. RESULTS: One hundred twenty-eight patients (mean age 56 years) were randomized. Mean visual clarity for the placebo, TXA, EPI, and TXA + EPI groups were 2.0 (±0.6), 2.0 (±0.6), 2.6 (±0.5), and 2.7 (±0.5), respectively (P < .001). The presence or absence of epinephrine was the most significant predictor of visual clarity (P < .001). Tranexamic acid presence or absence had no effect. No adverse events were recorded in any of the groups. CONCLUSION: Intravenous tranexamic acid is not an effective alternative to epinephrine in irrigation fluid to improve visualization during routine arthroscopic shoulder surgeries, and there is no additive effect when both are used.

Artificial intelligence in shoulder and elbow surgery: overview of current and future applications.

Artificial intelligence (AI) is amongst the most rapidly growing technologies in orthopedic surgery. With the exponential growth in healthcare data, computing power, and complex predictive algorithms, this technology is poised to aid providers in data processing and clinical decision support throughout the continuum of orthopedic care. Understanding the utility and limitations of this technology is vital to practicing orthopedic surgeons, as these applications will become more common place in everyday practice. AI has already demonstrated its utility in shoulder and elbow surgery for imaging-based diagnosis, predictive modeling of clinical outcomes, implant identification, and automated image segmentation. The future integration of AI and robotic surgery represents the largest potential application of AI in shoulder and elbow surgery with the potential for significant clinical and financial impact. This editorial's purpose is to summarize common AI terms, provide a framework to understand and interpret AI model results, and discuss current applications and future directions within shoulder and elbow surgery.

Racial and gender disparities in utilization of outpatient total shoulder arthroplasties.

BACKGROUND: Utilization in outpatient total shoulder arthroplasties (TSAs) has increased significantly in recent years. It remains largely unknown whether utilization of outpatient TSA differs across gender and racial groups. This study aimed to quantify racial and gender disparities both nationally and by geographic regions. METHODS: 168,504 TSAs were identified using Medicare fee-for-service inpatient and outpatient claims data and beneficiary enrollment data from 2020 to 2022Q4. The percentage of outpatient cases, defined as cases discharged on the same day of surgery, was evaluated by racial and gender groups and by different census divisions. A multivariate logistics regression model controlling for patient sociodemographic information (White vs. non-White race, age, gender, and dual eligibility for both Medicare and Medicaid), hierarchical condition category (HCC) score, hospital characteristics, year fixed effects, and patient residency state fixed effects was performed. RESULTS: The TSA volume per 1000 beneficiaries was 2.3 for the White population compared with 0.8, 0.6, and 0.3 for the Black, Hispanic, and Asian population, respectively. A higher percentage of outpatient TSAs were in White patients (25.6%) compared with Black patients (20.4%) (P < .001). The Black TSA patients were also younger, more likely to be female, more likely to be dually eligible for Medicaid, and had higher HCC risk scores. After controlling for patient sociodemographic characteristics and hospital characteristics, the odds of receiving outpatient TSAs were 30% less for Black than the White group (odds ratio 0.70). Variations were observed across different census divisions, with South Atlantic (0.67, P < .01), East North Central (0.56, P < .001), and Middle Atlantic (0.36, P < .01) being the 4 regions observed with significant racial disparities. Statistically significant gender disparities were also found nationally and across regions, with an overall odds ratio of 0.75 (P < .001). DISCUSSION: Statistically significant racial and gender disparities were found nationally in outpatient TSAs, with Black patients having 30% (P < .001) fewer odds of receiving outpatient TSAs than White patients, and female patients with 25% (P < .001) fewer odds than male patients. Racial and gender disparities continue to be an issue for shoulder arthroplasties after the adoption of outpatient TSAs.

Cost-Effectiveness of Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation in the Australian Health Care System.

BACKGROUND: Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation. METHOD: A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance. RESULTS: In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost-utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk. CONCLUSIONS: CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management.

Assessment of formalin preserved and fresh frozen quadriceps tendon graft-suture constructs for load to failure testing: a biomechanical cadaveric study.

PURPOSE: Fresh-frozen specimen availability and cost may be a barrier for initiation of biomechanical studies where soft tissue is used in a construct with other medical devices. The impact of soft tissue preservation method on the outcomes of biomechanical studies in the specific case of graft-suture constructs is relatively unexplored. This study aimed to observe peak loads and failure modes in biomechanical testing of fresh-frozen (FF) versus formalin embalmed (FE) quadriceps tendon (QT) graft-suture constructs for soft tissue fixation in ACLR and assess suitability of FE QT graft constructs for load-to-fail testing. METHODS: Twenty QT grafts were harvested from human cadaver specimens. Ten grafts came from fresh-frozen donors and 10 from embalmed donors. All grafts were prepared with the modified Prusik knot using a braided composite suture and subjected to tensile loading. Comparisons between the biomechanical properties of the graft-suture constructs were made with unpaired t tests with α = 0.05. RESULTS: FE and FF constructs displayed similar peak loads and failure modes. FF constructs had greater elongation after pre-tensioning than FE (7.3 vs. 5.5 mm, p = 0.02) and greater elongation after cyclic loading than FE constructs (17.5 vs. 10.5 mm, p = 0.01). Hysteresis was greater for FF constructs at the 50th, 100th, 150th, and 200th cycle (p = 0.02, p = 0.07, p < 0.001, p = 0.004, respectively). FE constructs were stiffer than fresh-frozen (103 vs. 84 N/mm, p < 0.001). CONCLUSION: FE constructs were significantly stiffer but displayed similar peak load and failure mode to FF which was reflective of the strength of the suture material. FE grafts can offer an alternative to FF grafts in graft-suture constructs for biomechanical studies where load at failure and knot security and strength is of main interest.

Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. METHODS: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. RESULTS: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P=0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P=0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P=0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. CONCLUSIONS: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. REGISTRATION: HREC/13/SVH/66 and HREC/17/SVH/80. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12618000672257.

Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial.

BACKGROUND: Dietary restriction of sodium has been suggested to prevent fluid overload and adverse outcomes for patients with heart failure. We designed the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events. METHODS: SODIUM-HF is an international, open-label, randomised, controlled trial that enrolled patients at 26 sites in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand). Eligible patients were aged 18 years or older, with chronic heart failure (New York Heart Association [NYHA] functional class 2-3), and receiving optimally tolerated guideline-directed medical treatment. Patients were randomly assigned (1:1), using a standard number generator and varying block sizes of two, four, or six, stratified by site, to either usual care according to local guidelines or a low sodium diet of less than 100 mmol (ie, <1500 mg/day). The primary outcome was the composite of cardiovascular-related admission to hospital, cardiovascular-related emergency department visit, or all-cause death within 12 months in the intention-to-treat (ITT) population (ie, all randomly assigned patients). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT02012179, and is closed to accrual. FINDINGS: Between March 24, 2014, and Dec 9, 2020, 806 patients were randomly assigned to a low sodium diet (n=397) or usual care (n=409). Median age was 67 years (IQR 58-74) and 268 (33%) were women and 538 (66%) were men. Between baseline and 12 months, the median sodium intake decreased from 2286 mg/day (IQR 1653-3005) to 1658 mg/day (1301-2189) in the low sodium group and from 2119 mg/day (1673-2804) to 2073 mg/day (1541-2900) in the usual care group. By 12 months, events comprising the primary outcome had occurred in 60 (15%) of 397 patients in the low sodium diet group and 70 (17%) of 409 in the usual care group (hazard ratio [HR] 0·89 [95% CI 0·63-1·26]; p=0·53). All-cause death occurred in 22 (6%) patients in the low sodium diet group and 17 (4%) in the usual care group (HR 1·38 [0·73-2·60]; p=0·32), cardiovascular-related hospitalisation occurred in 40 (10%) patients in the low sodium diet group and 51 (12%) patients in the usual care group (HR 0·82 [0·54-1·24]; p=0·36), and cardiovascular-related emergency department visits occurred in 17 (4%) patients in the low sodium diet group and 15 (4%) patients in the usual care group (HR 1·21 [0·60-2·41]; p=0·60). No safety events related to the study treatment were reported in either group. INTERPRETATION: In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events. FUNDING: Canadian Institutes of Health Research and the University Hospital Foundation, Edmonton, Alberta, Canada, and Health Research Council of New Zealand.

Yield of Repeat Endoscopy for Barrett's Esophagus After Normal Index Endoscopy.

INTRODUCTION: Guidelines suggest 1-time screening with esophagogastroduodenoscopy (EGD) for Barrett's esophagus (BE) in individuals at an increased risk of esophageal adenocarcinoma (EAC). We aimed to estimate the yield of repeat EGD performed at prolonged intervals after a normal index EGD. METHODS: We conducted a national retrospective analysis within the U S Veterans Health Administration, identifying patients with a normal index EGD between 2003 and 2009 who subsequently had a repeat EGD. We tabulated the proportion with a new diagnosis of BE, EAC, or esophagogastric junction adenocarcinoma (EGJAC) and conducted manual chart review of a sample. We fitted logistic regression models for the odds of a new diagnosis of BE/EAC/EGJAC. RESULTS: We identified 71,216 individuals who had a repeat EGD between 1 and 16 years after an index EGD without billing or cancer registry codes for BE/EAC/EGJAC. Of them, 4,088 had a new billing or cancer registry code for BE/EAC/EGJAC after the repeat EGD. On manual review of a stratified sample, most did not truly have new BE/EAC/EGJAC. A longer duration between EGD was associated with greater odds of a new diagnosis (adjusted odds ratio [aOR] for each 5 years 1.31; 95% confidence interval [CI] 1.19-1.44), particularly among those who were younger during the index EGD (ages 19-29 years: aOR 3.92; 95% CI 1.24-12.4; ages 60-69 years: aOR 1.19; 95% CI 1.01-1.40). DISCUSSION: The yield of repeat EGD for BE/EAC/EGJAC seems to increase with time after a normal index EGD, particularly for younger individuals. Prospective studies are warranted to confirm these findings.

Extracorporeal Membrane Oxygenation for Graft Dysfunction Early After Heart Transplantation: A Systematic Review and Meta-analysis.

INTRODUCTION: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a prevailing option for the management of severe early graft dysfunction. This systematic review and individual patient data (IPD) meta-analysis aims to evaluate (1) mortality, (2) rates of major complications, (3) prognostic factors, and (4) the effect of different VA-ECMO strategies on outcomes in adult heart transplant (HT) recipients supported with VA-ECMO. METHODS AND RESULTS: We conducted a systematic search and included studies of adults (≥18 years) who received VA-ECMO during their index hospitalization after HT and reported on mortality at any timepoint. We pooled data using random effects models. To identify prognostic factors, we analysed IPD using mixed effects logistic regression. We assessed the certainty in the evidence using the GRADE framework. We included 49 observational studies of 1477 patients who received VA-ECMO after HT, of which 15 studies provided IPD for 448 patients. There were no differences in mortality estimates between IPD and non-IPD studies. The short-term (30-day/in-hospital) mortality estimate was 33% (moderate certainty, 95% confidence interval [CI] 28%-39%) and 1-year mortality estimate 50% (moderate certainty, 95% CI 43%-57%). Recipient age (odds ratio 1.02, 95% CI 1.01-1.04) and prior sternotomy (OR 1.57, 95% CI 0.99-2.49) are associated with increased short-term mortality. There is low certainty evidence that early intraoperative cannulation and peripheral cannulation reduce the risk of short-term death. CONCLUSIONS: One-third of patients who receive VA-ECMO for early graft dysfunction do not survive 30 days or to hospital discharge, and one-half do not survive to 1 year after HT. Improving outcomes will require ongoing research focused on optimizing VA-ECMO strategies and care in the first year after HT.

The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study.

AIMS: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. METHODS: Two prospective studies on heart failure patients were undertaken. The first was a cross-sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12-week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. RESULTS: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P < .03) and III (P < .001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P < .05). The pharmacokinetics of heart failure patients with and without T2DM were similar. CONCLUSIONS: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM.

Quality care close to home: Objectives and early outcomes of a second paediatric heart transplant service in Australia.

AIM: We describe the experience of a new paediatric heart transplant (HT) centre in Australia. New South Wales offers quaternary paediatric cardiac services including comprehensive care pre- and post-HT; however, perioperative HT care has previously occurred at the national paediatric centre or in adult centres. Internationally, perioperative HT care is highly protocol-driven and a majority of HT occurs in low volume centres. Establishing a low volume paediatric HT centre in New South Wales offers potential for quality HT care close to home. METHODS: Retrospective review of programme data for the first 12 months was undertaken. Patient selection was audited against the programme's intended initiation criteria. Longitudinal patient data on outcomes and complications were obtained from patient medical records. RESULTS: The programme's initial phase offered HT to children with non-congenital heart disease and no requirement for durable mechanical circulatory support. Eight patients met criteria for HT referral. Three underwent interstate transfer to the national paediatric centre. Five children (13-15 years, weight 36-85 kg) underwent HT in the new programme. Individual predicted 90-day mortality was 1.3-11.6%, with increased risk for recipients transplanted from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and with restrictive/hypertrophic cardiomyopathies. Survival at 90 days and for duration of follow-up is 100%. Observed programme benefits include mitigation of family dislocation and improved continuity of care within a family-centred programme. CONCLUSION: Audit of the first 12 months' activity of a second paediatric HT centre in Australia demonstrates adherence to proposed patient selection criteria and excellent 90-day patient outcomes. The programme demonstrates feasibility of care close to home, providing continuity for all patients including those requiring increased rehabilitation and psychosocial support post-transplantation.