The Impact of Acute Exercise on Hemostasis and Angiogenesis Mediators in Patients With Continuous-Flow Left Ventricular Assist Devices: A Prospective Observational Pilot Study.

Impaired primary hemostasis and dysregulated angiogenesis, known as a two-hit hypothesis, are associated with gastrointestinal (GI) bleeding in patients with continuous-flow left ventricular assist devices (CF-LVADs). Exercise is known to influence hemostasis and angiogenesis in healthy individuals; however, little is known about the effect in patients with CF-LVADs. The objective of this prospective observational study was to determine whether acute exercise modulates two-hit hypothesis mediators associated with GI bleeding in patients with a CF-LVAD. Twenty-two patients with CF-LVADs performed acute exercise either on a cycle ergometer for approximately 10 minutes or on a treadmill for 30 minutes. Blood samples were taken pre- and post-exercise to analyze hemostatic and angiogenic biomarkers. Acute exercise resulted in an increased platelet count (p < 0.00001) and platelet function (induced by adenosine diphosphate, p = 0.0087; TRAP-6, p = 0.0005; ristocetin, p = 0.0009). Additionally, high-molecular-weight vWF multimers (p < 0.00001), vWF collagen-binding activity (p = 0.0012), factor VIII (p = 0.034), angiopoietin-1 (p = 0.0026), and vascular endothelial growth factor (p = 0.0041) all increased after acute exercise. This pilot work demonstrates that acute exercise modulated two-hit hypothesis mediators associated with GI bleeding in patients with CF-LVADs.

Frailty and transcatheter valve intervention: A narrative review.

Frailty is a common clinical syndrome that portends poor peri-procedural outcomes and increased mortality following transcatheter valve interventions. We reviewed frailty assessment tools in transcatheter intervention cohorts to recommend a pathway for preprocedural frailty assessment in patients referred for transcatheter valve procedures, and evaluated current evidence for frailty interventions and their efficacy in transcatheter intervention. We recommend the use of a frailty screening instrument to identify patients as frail, with subsequent referral for comprehensive geriatric assessment in these patients, to assist in selecting appropriate patients and then optimizing them for transcatheter valve interventions. Interventions to reduce preprocedural frailty are not well defined, however, data from limited cohort studies support exercise-based interventions to increase functional capacity and reduce frailty in parallel with preprocedural medical optimization.

Integrating Computational and Biological Hemodynamic Approaches to Improve Modeling of Atherosclerotic Arteries.

Atherosclerosis is the primary cause of cardiovascular disease, resulting in mortality, elevated healthcare costs, diminished productivity, and reduced quality of life for individuals and their communities. This is exacerbated by the limited understanding of its underlying causes and limitations in current therapeutic interventions, highlighting the need for sophisticated models of atherosclerosis. This review critically evaluates the computational and biological models of atherosclerosis, focusing on the study of hemodynamics in atherosclerotic coronary arteries. Computational models account for the geometrical complexities and hemodynamics of the blood vessels and stenoses, but they fail to capture the complex biological processes involved in atherosclerosis. Different in vitro and in vivo biological models can capture aspects of the biological complexity of healthy and stenosed vessels, but rarely mimic the human anatomy and physiological hemodynamics, and require significantly more time, cost, and resources. Therefore, emerging strategies are examined that integrate computational and biological models, and the potential of advances in imaging, biofabrication, and machine learning is explored in developing more effective models of atherosclerosis.

Apixaban in bridge to transplant and destination LVAD - rationale and study design: the ApixiVAD trial.

AIMS: Use of novel anticoagulation in mechanical circulatory support is controversial. We report the rationale and design of the ApixiVad pilot trial, a pilot study testing the safety of apixaban as an anticoagulant in patients bridged to transplant (BTT) or for destination (DT) with Heartmate 3 (HM3) left ventricular assist device (LVAD). METHODS AND RESULTS: Apixaban has been used in small non-randomized cohorts in LVAD patients and shown to be effective in ex vivo studies. The ApixiVAD study examines apixaban use in a multicentre, international, open-label, randomized, controlled trial aiming to include 50 BTT or DT HM3 patients with a 1:1 randomization ratio. This event-driven study has a maximum follow-up period of 24 months with interim analysis at 6 months. The primary outcome is death, thromboembolic events and major bleeding, including operative bleeding and immediate transplant outcomes. The secondary outcome focuses on patients' quality of life related to anticoagulation. This investigator-driven pilot study is not powered to determine the non-inferiority of apixaban. An increase in primary outcome in the apixaban group of 20% will be considered a signal of harm. CONCLUSIONS: A positive outcome in the ApixiVAD study would provide the basis for future, larger, pivotal anticoagulation trials in LVAD patients.

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.

Mental Imagery to Reduce Alcohol-related harm in patients with alcohol use disorder and alcohol-related liver damaGE: the MIRAGE randomised pilot trial results.

OBJECTIVE: The healthcare burden of alcohol-related liver disease (ARLD) is increasing. ARLD and alcohol use disorder (AUD) is best managed by reduction or cessation of alcohol use, but effective treatments are lacking. We tested whether people with ARLD and AUD admitted to hospital could be recruited to and retained in a trial of Functional Imagery Training (FIT), a psychological therapy that uses mental imagery to reduce alcohol craving. We conducted a multicentre randomised pilot trial of treatment as usual (TAU) versus FIT+TAU in people admitted to hospital with ARLD and AUD. DESIGN: Participants were randomised to TAU (a single session of brief intervention) or FIT+TAU (TAU with one hospital-based FIT session then eight telephone sessions over 6 months). Pilot outcomes included recruitment rate and retention at day 180. Secondary outcomes included fidelity of FIT delivery, alcohol use, and severity of alcohol dependence. RESULTS: Fifty-four participants (mean age 49; 63% male) were recruited and randomised, 28 to TAU and 26 to FIT+TAU. The retention rate at day 180 was 43%. FIT was delivered adequately by most alcohol nurses. 50% of intervention participants completed FIT sessions 1 and 2. There were no differences in alcohol use or severity of alcohol dependence between treatment groups at day 180. CONCLUSION: Participants with ARLD and AUD could be recruited to a trial of FIT versus FIT+TAU. However, retention at day 180 was suboptimal. Before conducting a definitive trial of FIT in this patient group, modifications in the intervention and recruitment/retention strategy must be tested. TRIAL REGISTRATION NUMBER: ISRCTN41353774.

Use of removable support boot versus cast for early mobilisation after ankle fracture surgery: cost-effectiveness analysis and qualitative findings of the Ankle Recovery Trial (ART).

OBJECTIVES: To estimate the cost-effectiveness of using a removable boot versus a cast following ankle fracture from the National Health Service and Personal Social Services (NHS+PSS) payer and societal perspectives and explore the impact of both treatments on participants' activities of daily living. DESIGN: Cost-effectiveness analyses and qualitative interviews performed alongside a pragmatic multicentre randomised controlled trial. SETTING: Eight UK NHS secondary care trusts. PARTICIPANTS: 243 participants (60.5% female, on average 48.2 years of age (SD 16.4)) with ankle fracture. Qualitative interviews with 16 participants. Interventions removable air boot versus plaster cast 2 weeks after surgery weight bearing as able with group-specific exercises. PRIMARY AND SECONDARY OUTCOME MEASURES: Quality-adjusted life years (QALYs) estimated from the EQ-5D-5L questionnaire, costs and incremental net monetary benefit statistics measured 12 weeks after surgery, for a society willing-to-pay £20 000 per QALY. RESULTS: Care in the boot group cost, on average, £88 (95% CI £22 to £155) per patient more than in the plaster group from the NHS+PSS perspective. When including all societal costs, the boot saved, on average, £676 per patient (95% CI -£337 to £1689). Although there was no evidence of a QALY difference between the groups (-0.0020 (95% CI -0.0067 to 0.0026)), the qualitative findings suggest participants felt the boot enhanced their quality of life. Patients in the boot felt more independent and empowered to take on family responsibilities and social activities. CONCLUSIONS: While the removable boot is slightly more expensive than plaster cast for the NHS+PSS payer at 12 weeks after surgery, it reduces productivity losses and the need for informal care while empowering patients. Given that differences in QALYs and costs to the NHS are small, the decision to use a boot or plaster following ankle surgery could be left to patients' and clinicians' preferences. TRIAL REGISTRATION NUMBER: ISRCTN15497399, South Central-Hampshire A Research Ethics Committee (reference 14/SC/1409).

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.

Longitudinal analysis left ventricular chamber responses under durable LVAD support.

BACKGROUND: Left ventricular assist device (LVAD) support offers remodeling potential in some patients. Our goal was to use noninvasively derived pressure-volume (PV) loops to understand the effect of demographic and device variables on serial changes in cardiac function under pump support. METHODS: Thirty-two consecutive Medtronic HeartWare Ventricular Assist Device (HVAD) patients (mean 55.9 ± 12.3 years, 81.3% male) were prospectively recruited. Single-cycle ventricular pressure and volume were estimated using a validated algorithm. PV loops (n = 77) and corresponding cardiac chamber dynamics were derived at predefined postimplant timepoints (1, 3, 6 months). Changes in PV loop parameters sustained across the 6-month period were characterized using mixed-effects modeling. The influence of demographic and device variables on the observed changes was assessed. RESULTS: Across a 6-month period, the mean ventricular function parameters remained stable. Significant predictors of monthly improvement of stroke work include: lower pump speeds (2400 rpm vs 2500-2800 rpm) [0.0.051 mm Hg/liter/month (p = 0.001)], high pulsatility index (>1.0 vs <1.0) [0.052 mm Hg/liter/month (p = 0.012)], and ischemic cardiomyopathy indication for LVAD implantation (vs nonischemic) [0.0387 mm Hg/liter/month (p = 0.007)]. Various other cardiac chamber function parameters including cardiac power, peak systolic pressure, and LV elastance also showed improvements in these cohorts. CONCLUSIONS: Factors associated with improvement in ventricular energetics and hemodynamics under LVAD support can be determined with noninvasive PV loops. Understanding the basis of increasing ventricular load to optimize myocardial remodeling may prove valuable in selecting eligible recovery candidates.

Strain Assessment in Aortic Stenosis: Pathophysiology and Clinical Utility.

Contemporary echocardiographic criteria for grading aortic stenosis severity have remained relatively unchanged, despite significant advances in noninvasive imaging techniques over the last 2 decades. More recently, attention has shifted to the ventricular response to aortic stenosis and how this might be quantified. Global longitudinal strain, semiautomatically calculated from standard two-dimensional echocardiographic images, has been the focus of extensive research. Global longitudinal strain is a sensitive marker of subtle hypertrophy-related impairment in left ventricular function and has shown promise as a relatively robust prognostic marker, both independently and when added to severity classification systems. Herein we review the pathophysiological basis underpinning the potential utility of global longitudinal strain in the assessment of aortic stenosis, as well as its potential role in quantifying myocardial recovery and prognostic discrimination following aortic valve replacement.

Safety and Performance of the Aortix Device in Acute Decompensated Heart Failure and Cardiorenal Syndrome.

BACKGROUND: Cardiorenal syndrome (CRS) complicates 33% of acute decompensated heart failure (ADHF) admissions, and patients with persistent congestion at discharge have high 30-day event rates. OBJECTIVES: The purpose of this study was to evaluate a novel catheter-deployed intra-aortic entrainment pump (IAEP) in patients with ADHF with CRS and persistent congestion. METHODS: A multicenter (n = 14), nonrandomized, single-arm, safety and feasibility study of IAEP therapy was conducted. Within patient changes (post-pre IAEP therapy) in fluid loss, hemodynamics, patient-reported dyspnea, and serum biomarkers were assessed using Wilcoxon signed-rank testing. RESULTS: Of 21 enrolled patients, 18 received Aortix therapy. Mean ± SD patient age was 60.3 ± 7.9 years. The median left ventricular ejection fraction was 22.5% (25th-75th percentile: 10.0%-53.5%); 27.8% had a left ventricular ejection fraction ≥50%. Pre-therapy, patients received 8.7 ± 4.1 days of loop diuretic agents and 44% were on inotropes. Pump therapy averaged 4.6 ± 1.6 days, yielding net fluid losses of 10.7 ± 6.5 L (P < 0.001) and significant (P < 0.01) reductions in central venous pressure (change from baseline: -8.5 mm Hg [25th-75th percentile: -3.5 to -10.0 mm Hg]), pulmonary capillary wedge pressure (-11.0 mm Hg [25th-75th percentile: -5.0 to -14.0 mm Hg]), and serum creatinine (-0.2 mg/dL [25th-75th percentile: -0.1 to -0.5 mg/dL]) with improved estimated glomerular filtration rate (+5.0 mL/min/1.73 m2 [25th-75th percentile: 2.0-9.0 mL/min/1.73 m2]) and patient-reported dyspnea score (+16 [25th-75th percentile: 3-37]). Dyspnea scores, natriuretic peptides, and renal function improvements persisted through 30 days. CONCLUSIONS: This pilot study of patients with ADHF, persistent congestion, and worsening renal function due to CRS supports the potential for safely achieving decongestion using IAEP therapy. These initial promising results provide the basis for future randomized clinical trials of this novel pump. (An Evaluation of the Safety and Performance of the Aortix System for Intra-Aortic Mechanical Circulatory Support in Patients with Cardiorenal Syndrome [The Aortix CRS Pilot Study]; NCT04145635).

Major adverse kidney events predict reduced survival in ventricular assist device supported patients.

AIMS: There is limited data describing major adverse kidney events (MAKE) in patients supported with ventricular assist devices (VAD). We aim to describe the association between MAKE and survival, risk factors for MAKE, and renal trajectory in VAD supported patients. METHODS AND RESULTS: We conducted a single-centre retrospective analysis of consecutive VAD implants between 2010 and 2019. Baseline demographics, biochemistry, and adverse events were collected for the duration of VAD support. MAKE was defined as the first event to occur of sustained drop (>50%) in estimated glomerular filtration rate (eGFR), progression to stage V chronic kidney disease, initiation or continuation of renal replacement therapy beyond implant admission or death on renal replacement therapy at any time. One-hundred and seventy-three patients were included, median age 56.8 years, 18.5% female, INTERMACS profile 1 or 2 in 75.1%. Thirty-seven patients experienced MAKE. On multivariate analysis, post-implant clinical right ventricular failure and the presence of chronic haemolysis, defined by the presence of schistocytes on blood film analysis, were significantly associated with increased risk of MAKE (adjusted odds ratio 9.88, P < 0.001 and adjusted odds ratio 3.33, P = 0.006, respectively). MAKE was associated with reduced survival (hazard ratio 4.80, P < 0.001). Patients who died or experienced MAKE did not demonstrate the expected transient 3-month improvement in eGFR, seen in other cohorts. CONCLUSIONS: MAKE significantly impacts survival. In our cohort, MAKE was predicted by post-implant right ventricular failure and chronic haemolysis. The lack of early eGFR improvement on VAD support may indicate higher risk for MAKE.

Disease trajectories following myocardial infarction: insights from process mining of 145 million hospitalisation episodes.

BACKGROUND: Knowledge of post-myocardial infarction (MI) disease risk to date is limited-yet the number of survivors of MI has increased dramatically in recent decades. We investigated temporally ordered sequences of all conditions following MI in nationwide electronic health record data through the application of process mining. METHODS: We conducted a national retrospective cohort study of all hospitalisations (145,670,448 episodes; 34,083,204 individuals) admitted to NHS hospitals in England (1st January 2008-31st January 2017, final follow-up 27th March 2017). Through process mining, we identified trajectories of all major disease diagnoses following MI and compared their relative risk (RR) and all-cause mortality hazard ratios (HR) to a risk-set matched non-MI control cohort using Cox proportional hazards and flexible parametric survival models. FINDINGS: Among a total of 375,669 MI patients (130,758 females; 34.8%) and 1,878,345 matched non-MI patients (653,790 females; 34.8%), we identified 28,799 unique disease trajectories. The accrual of multiple circulatory diagnoses was more common amongst MI patients (RR 4.32, 95% CI 3.96-4.72) and conferred an increased risk of death (HR 1.32, 1.13-1.53) compared with matched controls. Trajectories featuring neuro-psychiatric diagnoses (including anxiety and depression) following circulatory disorders were markedly more common and had increased mortality post MI (HR ranging from 1.11 to 1.73) compared with non-MI individuals. INTERPRETATION: These results provide an opportunity for early intervention targets for survivors of MI-such as increased focus on the psychological and behavioural pathways-to mitigate ongoing adverse disease trajectories, multimorbidity, and premature mortality. FUNDING: British Heart Foundation; Alan Turing Institute.

DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies.

BACKGROUND: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. METHODS: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. RESULTS: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. CONCLUSIONS: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management.

Safety and tolerability of sodium-glucose cotransporter-2 inhibitors in bridge-to-transplant patients supported with centrifugal-flow left ventricular assist devices.

BACKGROUND: The safety and tolerability of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with end-stage heart failure supported with left-ventricular-assist-devices (LVADs), irrespective of diabetes mellitus, is not known. METHODS: A retrospective analysis of 31 outpatients implanted with LVADs as bridge-to-transplant (BTT) was conducted. Patients with biventricular support, aged under 18 years, who were discharged from the index hospitalisation, or were prescribed SGLT2i prior to their first outpatient clinic were excluded. Patient demographics, laboratory studies, pump haemodynamic and adverse event data was collected. RESULTS: Sixteen (51.6%) of 31 patients were prescribed SGLT2i over median 101.5 days (37.5-190.8). No patients discontinued SGLT2i use or reported attributable adverse symptoms. No significant differences between patients prescribed SGLT2i compared to those SGLT2i-naïve were seen in: [1] renal function; [2] weight; [3] mean arterial pressure. There were numerically lower infection-related (n = 4 vs 7, HR 0.32 (0.08-1.28), p = 0.11) and haemocompatibility-related (n = 3 vs 4, HR 0.52 (0.09-2.83), p = 0.45) adverse events in the SGLT2i group, albeit non-significant. CONCLUSIONS: We found SGLT2i to be safe and well-tolerated in the BTT LVAD cohort with no significant difference in rates of infection or haemocompatibility-related adverse events with SGLT2i use. Larger studies will inform further beneficial effects of SGLT2i prescription in this cohort.

How do mechanical circulatory support patients die? Autopsy findings for left-ventricular assist device/total artificial heart nonsurvivors.

BACKGROUND: Although life saving for end-stage heart failure patients, permanent mechanical circulatory support (MCS) is often the proximate cause of death in those that do not survive to transplant. Autopsy remains the gold standard for diagnosing causes of death and a vital tool for better understanding underlying pathology of nonsurvivors. The aim of this study was to determine the frequency and outcomes of autopsy investigations and compare these with premortem clinical assessment. METHODS: The autopsy findings and medical records of all patients who underwent left ventricular assist device (LVAD) or total artificial heart (TAH) insertion between June 1994 and April 2022 as a bridge to transplant, but subsequently died pre-heart transplantation were reviewed. RESULTS: A total of 203 patients had a LVAD or TAH implanted during the study period. Seventy-eight patients (M=59, F=19) died prior to transplantation (age 55 [14] years, INTERMACS=2). Autopsies were conducted in 26 of 78 patients (33%). Three were limited studies. The leading contributor to cause of death was respiratory (14/26), either nosocomial infection or associated with multiorgan failure. Intracranial hemorrhage was the second most common cause of death (8/26). There was a major discrepancy rate of 17% and a minor discrepancy rate of 43%. Autopsy study added a total of 14 additional contributors of death beyond clinical assessment alone (Graphical Abstract). CONCLUSIONS: Over an observational period of 26years, the frequency of autopsy was low. To improve LVAD/TAH patient survival to transplant, better understanding as to cause of death is required. Patients with MCS have complex physiology and are at high risk of infection and bleeding complications.

Machine learning prediction of progressive subclinical myocardial dysfunction in moderate aortic stenosis.

Background: Moderate severity aortic stenosis (AS) is poorly understood, is associated with subclinical myocardial dysfunction, and can lead to adverse outcome rates that are comparable to severe AS. Factors associated with progressive myocardial dysfunction in moderate AS are not well described. Artificial neural networks (ANNs) can identify patterns, inform clinical risk, and identify features of importance in clinical datasets. Methods: We conducted ANN analyses on longitudinal echocardiographic data collected from 66 individuals with moderate AS who underwent serial echocardiography at our institution. Image phenotyping involved left ventricular global longitudinal strain (GLS) and valve stenosis severity (including energetics) analysis. ANNs were constructed using two multilayer perceptron models. The first model was developed to predict change in GLS from baseline echocardiography alone and the second to predict change in GLS using data from baseline and serial echocardiography. ANNs used a single hidden layer architecture and a 70%:30% training/testing split. Results: Over a median follow-up interval of 1.3 years, change in GLS (≤ or >median change) could be predicted with accuracy rates of 95% in training and 93% in testing using ANN with inputs from baseline echocardiogram data alone (AUC: 0.997). The four most important predictive baseline features (reported as normalized % importance relative to most important feature) were peak gradient (100%), energy loss (93%), GLS (80%), and DI < 0.25 (50%). When a further model was run including inputs from both baseline and serial echocardiography (AUC 0.844), the top four features of importance were change in dimensionless index between index and follow-up studies (100%), baseline peak gradient (79%), baseline energy loss (72%), and baseline GLS (63%). Conclusions: Artificial neural networks can predict progressive subclinical myocardial dysfunction with high accuracy in moderate AS and identify features of importance. Key features associated with classifying progression in subclinical myocardial dysfunction included peak gradient, dimensionless index, GLS, and hydraulic load (energy loss), suggesting that these features should be closely evaluated and monitored in AS.

Nonoptimal component placement of the human connectome supports variable brain dynamics.

Neural systems are shaped by multiple constraints, balancing region communication with the cost of establishing and maintaining physical connections. It has been suggested that the lengths of neural projections be minimized, reducing their spatial and metabolic impact on the organism. However, long-range connections are prevalent in the connectomes across various species, and thus, rather than rewiring connections to reduce length, an alternative theory proposes that the brain minimizes total wiring length through a suitable positioning of regions, termed component placement optimization. Previous studies in nonhuman primates have refuted this idea by identifying a nonoptimal component placement, where a spatial rearrangement of brain regions in silico leads to a reduced total wiring length. Here, for the first time in humans, we test for component placement optimization. We show a nonoptimal component placement for all subjects in our sample from the Human Connectome Project (N = 280; aged 22-30 years; 138 females), suggesting the presence of constraints-such as the reduction of processing steps between regions-that compete with the elevated spatial and metabolic costs. Additionally, by simulating communication between brain regions, we argue that this suboptimal component placement supports dynamics that benefit cognition.