Pulsed field ablation in patients with cardiac implantable electronic devices: an ex vivo assessment of safety.

BACKGROUND: Pulse field ablation (PFA) is a novel catheter ablation technology with potential safety benefits due to its tissue selectivity. It has the potential to directly damage or interact with the functionality of cardiac implantable electronic devices (CIEDs) in the form of electromagnetic interference (EMI). The aim of our study was to assess the impact of PFA on CIEDs. METHODS: PFA lesions (45 per CIED) were applied from the Farapulse system to CIEDs (< 5 cm from the lead tip and < 15 cm from the generator). All devices were checked before and after PFA application for proper sensing and pacing functionality as well as for integrity of shock circuits in ICDs using a heart simulator. Moreover, devices were then interrogated for any spontaneous reprogramming, mode switching or other EMI effects. RESULTS: In total, 44 CIEDs were tested (16 pacemaker, 21 ICDs, 7 CRT-P/D) with 1980 PFA applications. There was no change in device settings, functionality and electrical parameters, and there was no macroscopic damage to the devices. The risk of damage to the electric components or leads on a patient-based analysis is 0/44 (95% CI 0-8%) and on a PFA pulse-based analysis is 0/1980 (95% CI 0-0.2%). Clinically relevant EMI appeared with oversensing and pacing inhibition but not tachycardia detection. CONCLUSIONS: Bipolar PFA appears safe and does not result in damage to CIEDs or leads. Clinically relevant EMI does occur, but appropriate peri-procedural programming may mitigate this. In vivo studies are needed to confirm our findings.

Unraveling the molecular dynamics of sugammadex-rocuronium complexation: A blueprint for cyclodextrin drug design.

Sugammadex, marketed as Bridion™, is an approved cyclodextrin (CD) based drug for the reversal of neuromuscular blockade in adults undergoing surgery. Sugammadex forms an inclusion complex with the neuromuscular blocking agent (NMBA) rocuronium, allowing rapid reversal of muscle paralysis. In silico methods have been developed for studying CD inclusion complexes, aimed at accurately predicting their structural, energetic, dynamic, and kinetic properties, as well as binding constants. Here, a computational study aimed at characterizing the sugammadex-rocuronium system from the perspective of docking calculations, free molecular dynamics (MD) simulations, and biased metadynamics simulations with potential of mean force (PMF) calculations is presented. The aim is to provide detailed information about this system, as well as to use it as a model system for validation of the methods. This method predicts results in line with experimental evidence for both the optimal structure and the quantitative value for the binding constant. Interestingly, there is a less profound preference for the orientation than might be assumed based on electrostatic interactions, suggesting that both orientations may exist in solution. These results show that this technology can efficiently analyze CD inclusion complexes and could be used to facilitate the development and optimization of novel applications for CDs.

Survival does not differ by annual center transplant volume-A Pediatric Heart Transplant Society Registry study.

BACKGROUND: There are conflicting data regarding the relationship between center volume and outcomes in pediatric heart transplantation. Previous studies have not fully accounted for differences in case mix, particularly in high-risk congenital heart disease (CHD) groups. We aimed to evaluate the relationship between center volume and outcomes using the Pediatric Heart Transplant Society (PHTS) Registry and explore how case mix may affect outcomes. METHODS: A retrospective cohort study of all pediatric patients in the PHTS Registry who received a heart transplant from 2009 to 2018 was performed. Centers were divided into 5 groups based on average yearly transplant volume. The primary outcome was time to death or graft loss and outcomes were compared using Kaplan-Meier analysis. RESULTS: There were 4583 cases among 55 centers included. There was no difference in time to death or graft loss by center volume in the entire cohort (p = .75), in patients with CHD (p = .79) or in patients with cardiomyopathy (p = .23). There was also no difference in time to death or graft loss by center size in patients undergoing transplant after Norwood, Glenn or Fontan (log rank p = .17, p = .31, and p = .10 respectively). There was a statistically significant difference in outcomes by center size in the positive crossmatch group (p < .0001), though no discernible pattern related to high or low center volume. CONCLUSIONS: Outcomes are similar among transplant centers of all sizes, including for high-risk patient groups with CHD. Future work is needed to understand how patient-specific risk factors may vary among centers of various sizes and whether this influences patient outcomes.

Cyclodextrins: Establishing building blocks for AI-driven drug design by determining affinity constants in silico.

Cyclodextrins (CDs) are cyclic carbohydrate polymers that hold significant promise for drug delivery and industrial applications. Their effectiveness depends on their ability to encapsulate target molecules with strong affinity and specificity, but quantifying affinities in these systems accurately is challenging for a variety of reasons. Computational methods represent an exceptional complement to in vitro assays because they can be employed for existing and hypothetical molecules, providing high resolution structures in addition to a mechanistic, dynamic, kinetic, and thermodynamic characterization. Here, we employ potential of mean force (PMF) calculations obtained from guided metadynamics simulations to characterize the 1:1 inclusion complexes between four different modified ßCDs, with different type, number, and location of substitutions, and two sterol molecules (cholesterol and 7-ketocholesterol). Our methods, validated for reproducibility through four independent repeated simulations per system and different post processing techniques, offer new insights into the formation and stability of CD-sterol inclusion complexes. A systematic distinct orientation preference where the sterol tail projects from the CD's larger face and significant impacts of CD substitutions on binding are observed. Notably, sampling only the CD cavity's wide face during simulations yielded comparable binding energies to full-cavity sampling, but in less time and with reduced statistical uncertainty, suggesting a more efficient approach. Bridging computational methods with complex molecular interactions, our research enables predictive CD designs for diverse applications. Moreover, the high reproducibility, sensitivity, and cost-effectiveness of the studied methods pave the way for extensive studies of massive CD-ligand combinations, enabling AI algorithm training and automated molecular design.

Emergency Department Use and Hospital Mortality Among Heart Transplant Recipients in the United States.

BACKGROUND: Annual heart transplant (HT) volumes have increased, as have post-HT outpatient care needs. Data on HT-related emergency department (ED) visits are limited. METHODS AND RESULTS: A retrospective analysis of 177 450 HT patient ED visits from the 2009 to 2018 Nationwide Emergency Department Sample was conducted. HT recipients, primary diagnoses, and comorbidities associated with ED visits were identified via International Classification of Diseases, Ninth Revision (ICD-9) and International Classification of Diseases, Tenth Revision (ICD-10) codes. Multivariable logistic regression was used to predict outcomes of hospital admission and death. HT volumes and HT-related ED visits increased from 2009 to 2018. Infection was the most common primary diagnosis (24%), and cardiac primary diagnoses represented 10% of encounters. Hospital admissions occurred in 48% of visits, but overall mortality was low (1.6%). Length of stay was 3.1 days (interquartile range, 1.6-5.9 days), and comorbidity burden was high: 42% had hypertension, 38% had diabetes, and 31% had ≥2 comorbidities. Those aged ≥65 years had significantly higher odds of admission (odds ratio [OR], 2.14 [95% CI, 1.97-2.33]) and death (OR, 2.06 [95% CI, 1.61-2.62]). Comorbidities increased odds of admission (OR, 1.62 [95% CI, 1.51-1.75]) but not death. Renal primary diagnosis had the highest risk of admission (OR, 4.1 [95% CI, 3.6-4.6]), but cardiac primary diagnosis had the highest odds of death (OR, 11.6 [95% CI, 9.1-14.8]). CONCLUSIONS: HT-related ED visits increased from 2009 to 2018 with high admission rates but low in-hospital mortality, suggesting an opportunity to improve prehospital care. Older patients and those with cardiac primary diagnoses had the highest risk of death. The observed contrast between predictors of admission and mortality signals a need for further study to improve risk stratification and outpatient care strategies.

Date fruit melanin is primarily based on (-)-epicatechin proanthocyanidin oligomers.

Plant-based melanin seems to be abundant, but it did not receive scientific attention despite its importance in plant biology and medicinal applications, e.g. photoprotection, radical scavenging, antimicrobial properties, etc. Date fruit melanin (DM) has complex, graphene-like, polymeric structure that needs characterization to understand its molecular properties and potential applications. This study provides the first investigation of the possible molecular composition of DM. High performance size-exclusion chromatography (HPSEC) suggested that DM contains oligomeric structures (569-3236 Da) and transmission electron microscopy (TEM) showed agglomeration of these structures in granules of low total porosity (10-1000 Å). Nuclear magnetic resonance (NMR) spectroscopy provided evidence for the presence of oligomeric proanthocyanidins and electron paramagnetic resonance (EPR) spectroscopy revealed a g-factor in the range 2.0034-2.005. Density functional theory (DFT) calculations suggested that the EPR signals can be associated with oligomeric proanthocyanidin structures having 4 and above molecular units of (-)-epicatechin. The discovery of edible melanin in date fruits and its characterization are expected to open a new area of research on its significance to nutritional and sensory characteristics of plant-based foods.

Echocardiographic image collection and evaluation in infants with CHD: lessons learned from the imaging core lab for the Residual Lesion Score study.

Many factors affect patient outcome after congenital heart surgery, including the complexity of the heart disease, pre-operative status, patient specific factors (prematurity, nutritional status and/or presence of comorbid conditions or genetic syndromes), and post-operative residual lesions. The Residual Lesion Score is a novel tool for assessing whether specific residual cardiac lesions after surgery have a measurable impact on outcome. The goal is to understand which residual lesions can be tolerated and which should be addressed prior to leaving the operating room. The Residual Lesion Score study is a large multicentre prospective study designed to evaluate the association of Residual Lesion Score to outcomes in infants undergoing surgery for CHD. This Pediatric Heart Network and National Heart, Lung, and Blood Institute-funded study prospectively enrolled 1,149 infants undergoing 5 different congenital cardiac surgical repairs at 17 surgical centres. Given the contribution of echocardiographic measurements in assigning the Residual Lesion Score, the Residual Lesion Score study made use of a centralised core lab in addition to site review of all data. The data collection plan was designed with the added goal of collecting image quality information in a way that would permit us to improve our understanding of the reproducibility, variability, and feasibility of the echocardiographic measurements being made. There were significant challenges along the way, including the coordination, de-identification, storage, and interpretation of very large quantities of imaging data. This necessitated the development of new infrastructure and technology, as well as use of novel statistical methods. The study was successfully completed, but the size and complexity of the population being studied and the data being extracted required more technologic and human resources than expected which impacted the length and cost of conducting the study. This paper outlines the process of designing and executing this complex protocol, some of the barriers to implementation and lessons to be considered in the design of future studies.

Successful implementation of telehealth visits in the paediatric heart failure and heart transplant population.

The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a working group at the beginning of 2020 during the COVID-19 pandemic, with the aim of using telehealth as an alternative medium to provide quality care to a high-acuity paediatric population receiving advanced cardiac therapies. An algorithm was developed to determine appropriateness, educational handouts were developed for both patients and providers, and post-visit surveys were collected. Telehealth was found to be a viable modality for health care delivery in the paediatric heart failure and transplant population and has promising application in the continuity of follow-up, medication titration, and patient education/counselling domains.

Hypertension: An Important But Reversible Cause of Systolic Dysfunction in a Cohort of Pediatric Patients.

Cardiac dysfunction due to hypertension (CDHTN) in pediatrics is not well described. We aimed to describe the presentation and outcomes of pediatric CDHTN and identify clinical features associated with resolution of dysfunction. A single-center retrospective cohort study of patients ≤ 21 years with CDHTN from January 2005-September 2020 was performed. Patients with systolic dysfunction without another cause, blood pressure > 95th percentile, and physician judgment that dysfunction was secondary to hypertension were included. Demographics, clinical characteristics, echocardiographic findings, and outcomes were examined using Fisher's exact and Mann-Whitney U tests. Multiple correspondence analysis was used to explore the relationship of resolution of dysfunction to clinical features. Thirty-four patients were analyzed at a median age of 10.9 (IQR 0.3-16.9) years. Patients were divided into groups < 1 year (n = 12) and ≥ 1 year (n = 22). Causes of hypertension were varied by age, with renovascular disease most common in infants (42%) and medical renal disease most common in older patients (77%). Echocardiography demonstrated mild LV dilation (median LV end-diastolic z-score 2.6) and mild LV hypertrophy (median LV mass z-score 2.4). Most patients (81%) had resolution of dysfunction, particularly infants (92%). One patient died and one patient was listed for heart transplant. None required mechanical circulatory support (MCS). No clinical features were statistically associated with resolution of dysfunction. Hypertension is an important but reversible cause of systolic dysfunction in children. Patients are likely to recover with low mortality and low utilization of MCS or transplantation. Further studies are needed to confirm features associated with resolution of dysfunction.

Selective Removal of 7KC by a Novel Atherosclerosis Therapeutic Candidate Reverts Foam Cells to a Macrophage-like Phenotype.

The removal of the toxic oxidized cholesterol, 7-ketocholesterol (7KC), from cells through the administration of therapeutics has the potential to treat atherosclerosis and various other pathologies. While cholesterol is a necessary building block for homeostasis, oxidation of cholesterol can lead to the formation of toxic oxysterols involved in various pathologies, the most prominent of which is 7KC, which is formed through the non-enzymatic oxidation of cholesterol. Oxidized LDL (oxLDL) particles, highly implicated in heart disease, contain high levels of 7KC, and molecular 7KC is implicated in the pathogenesis of numerous diseases, including multiple sclerosis, hypercholesterolemia, sickle cell anemia, and multiple age related diseases. Of particular interest is the role of 7KC in the progression of atherosclerosis, with several studies associating elevated levels of 7KC with the etiology of the disease or in the transition of macrophages to foam cells. This research aims to elucidate the molecular mechanisms of UDP-003, a novel therapeutic, in mitigating the harmful effects of 7KC in mouse and human monocyte and macrophage cell lines. Experimental evidence demonstrates that administration of UDP-003 can reverse the foam cell phenotype, rejuvenating these cells by returning phagocytic function and decreasing both reactive oxygen species (ROS) and intracellular lipid droplet accumulation. Furthermore, our data suggests that the targeted removal of 7KC from foam cells with UDP-003 can potentially prevent and reverse atherosclerotic plaque formation. UDP-003 has the potential to be the first disease-modifying therapeutic approach to treating atherosclerotic disease.

Outcomes after initial heart failure consultation in Fontan patients.

BACKGROUND: Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care. METHODS: This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as "too late" (death or declined for transplant due to being too sick) and/or "care escalation" (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. "Late referral" was defined as those referred too late and/or had care escalation. RESULTS: Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8-21.5, p=0.004). CONCLUSIONS: Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.

Cardiologist-Directed Sedation Management in Patients Undergoing Transvenous Lead Extraction: A Single-Centre Retrospective Analysis.

BACKGROUND: The demand for transvenous lead extraction (TLE) has increased. In line with this, the safety of such procedures has also increased. Traditionally, TLE is performed under resource-intensive general anaesthesia. This study aims to evaluate the safety and outcomes of Cardiologist-lead deep sedation for TLE. METHODS: We retrospectively analysed 328 TLE procedures performed under deep sedation from 2016 to 2019. TLE procedures were performed by experienced electrophysiologists. Sedation was administered by a specifically trained cardiologist (bolus midazolam/fentanyl and propofol infusion). Procedural sedation data including blood pressure, medication administration and sedation time were collected. Complications related to sedation and the operative component of the procedure were analysed retrospectively. RESULTS: The sedation-associated complication rate during TLE was 22.0%. The most common complication (75% of complications) was hypotension requiring noradrenaline, followed by bradycardia requiring atropine (13% of complications). Additionally, the unplanned presence of an anaesthesiologist was needed in one case (0.3%). Deep sedation was achieved with midazolam (mean dose 42.9 ± 26.5 µg/kg), fentanyl (mean dose 0.4 ± 0.6 µg/kg) and propofol (mean dose 3.5 ± 1.2 mg/kg/h). There was no difference in medication dosage between those with a sedation-associated complication and those without. Sedation-associated complications appeared significantly more in patients with reduced LVEF (p = 0.01), renal impairment (p = 0.01) and a higher American Society of Anaesthesiologists (ASA) class (p = 0.01). CONCLUSION: Deep sedation for TLE can be safely performed by a specifically trained cardiologist, with a transition to general anaesthesia required in only 0.3% of cases. We continue to recommend the on-call availability of an anaesthesiologist and cardiac surgeon in case of major complications.

Impact of Ventricular Dysfunction and Atrioventricular Valve Regurgitation on Pre-Fontan Attrition.

BACKGROUND: There is a significant incidence of pre-Fontan attrition-defined as failure to undergo Fontan completion-after superior cavopulmonary connection. This study investigated the impact of at least moderate ventricular dysfunction (VD) and atrioventricular valve regurgitation (AVVR) on pre-Fontan attrition. METHODS: This single-center retrospective cohort study included all infants who underwent Norwood palliation from 2008 to 2020 and subsequently underwent superior cavopulmonary connection. Pre-Fontan attrition was defined as death, listing for heart transplantation before Fontan completion, or unsuitability for Fontan completion. The study's secondary outcome was transplant-free survival. RESULTS: Pre-Fontan attrition occurred in 34 of 267 patients (12.7%). Isolated VD was not associated with attrition. However, patients with isolated AVVR had 5 times the odds of attrition (odds ratio, 5.4; 95% CI 1.8-16.2), and patients with both VD and AVVR had 20 times the odds of attrition (odds ratio, 20.1; 95% CI 7.7-52.8) compared with patients without VD or AVVR. Only patients with both VD and AVVR had significantly worse transplant-free survival compared with patients without VD or AVVR (hazard ratio, 7.7; 95% CI 2.8-21.6). CONCLUSIONS: The additive effect of VD and AVVR is a powerful contributor to pre-Fontan attrition. Future research investigating therapies that can mitigate the degree of AVVR may help improve Fontan completion rates and long-term outcomes.

Anatomic, histologic, and mechanical features of the right atrium: implications for leadless atrial pacemaker implantation.

BACKGROUND: Leadless pacemakers (LPs) may mitigate the risk of lead failure and pocket infection related to conventional transvenous pacemakers. Atrial LPs are currently being investigated. However, the optimal and safest implant site is not known. OBJECTIVES: We aimed to evaluate the right atrial (RA) anatomy and the adjacent structures using complementary analytic models [gross anatomy, cardiac magnetic resonance imaging (MRI), and computer simulation], to identify the optimal safest location to implant an atrial LP human. METHODS AND RESULTS: Wall thickness and anatomic relationships of the RA were studied in 45 formalin-preserved human hearts. In vivo RA anatomy was assessed in 100 cardiac MRI scans. Finally, 3D collision modelling was undertaken assessing for mechanical device interaction. Three potential locations for an atrial LP were identified; the right atrial appendage (RAA) base, apex, and RA lateral wall. The RAA base had a wall thickness of 2.7 ± 1.6 mm, with a low incidence of collision in virtual implants. The anteromedial recess of the RAA apex had a wall thickness of only 1.3 ± 0.4 mm and minimal interaction in the collision modelling. The RA lateral wall thickness was 2.6 ± 0.9 mm but is in close proximity to the phrenic nerve and sinoatrial artery. CONCLUSIONS: Based on anatomical review and 3D modelling, the best compromise for an atrial LP implantation may be the RAA base (low incidence of collision, relatively thick myocardial tissue, and without proximity to relevant epicardial structures); the anteromedial recess of the RAA apex and lateral wall are alternate sites. The mid-RAA, RA/superior vena cava junction, and septum appear to be sub-optimal fixation locations.

Expanding use of the HeartMate 3 ventricular assist device in pediatric and adult patients within the Advanced Cardiac Therapies Improving Outcomes Network (ACTION).

BACKGROUND: We report current outcomes in patients supported with the HeartMate 3 (HM3) ventricular assist device in a multicenter learning network. METHODS: The Advanced Cardiac Therapies Improving Outcomes Network database was queried for HM3 implants between 12/2017 and 5/2022. Clinical characteristics, postimplant course, and adverse events were collected. Patients were stratified according to body surface area (BSA) (<1.4 m2, 1.4-1.8 m2, and >1.8 m2) at device implantation. RESULTS: During the study period, 170 patients were implanted with the HM3 at participating network centers, with median age 15.3years; 27.1% were female. Median BSA was 1.68 m2; the smallest patient was 0.73 m2 (17.7 kg). Most (71.8%) had a diagnosis of dilated cardiomyopathy. With a median support time of 102.5days, 61.2% underwent transplantation, 22.9% remained supported on device, 7.6% died, and 2.4% underwent device explantation for recovery; the remainder had transferred to another institution or transitioned to a different device type. The most common adverse events included major bleeding (20.8%) and driveline infection (12.9%); ischemic and hemorrhagic stroke were encountered in 6.5% and 1.2% of patients, respectively. Patients with BSA <1.4 m2 had a higher incidence of infection, renal dysfunction, and ischemic stroke. CONCLUSIONS: In this updated cohort of predominantly pediatric patients supported with the HM3 ventricular assist device, outcomes are excellent with <8% mortality on device. Device-related adverse events including stroke, infection, and renal dysfunction were more commonly seen in smaller patients, highlighting opportunities for improvements in care.

Taking ACTION: A Prognostic Tool for Pediatric Ventricular Assist Device Mortality.

We sought to develop a contemporary risk assessment tool for use in pediatric ventricular assist device (VAD) candidates to estimate risk for mortality on the device using readily available preimplantation clinical data. Training and testing datasets were created from Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry data on patients supported with a VAD from 2012 to 2021. Potential risk factors for mortality were assessed and incorporated into a simplified risk prediction model utilizing an open-source, gradient-boosted decision tree machine learning library, known as random forest. Predictive performance was assessed by the area under the receiver operating characteristic curve in the testing dataset. Nine significant risk factors were included in the final predictive model which demonstrated excellent discrimination with an area under the curve of 0.95. In addition to providing a framework for establishing pediatric-specific risk profiles, our model can help inform team expectations, guide optimal patient selection, and ultimately improve patient outcomes.

Reduced incidence of cardiac rejection in multi-organ transplants: A propensity matched study.

BACKGROUND: Rejection remains a primary cause of graft loss after heart transplant (HT). Recognizing the immunomodulation of multi-organ transplant can enhance our understanding of the mechanisms of cardiac rejection. METHODS: This retrospective cohort study identified patients from the UNOS database with isolated heart (H, N = 37 433), heart-kidney (HKi, N = 1516), heart-liver (HLi, N = 286), and heart-lung (HLu, N = 408) transplants from 2004 to 2019. Propensity score matching reduced baseline differences between groups. Outcomes included risk of rejection prior to transplant hospital discharge and within 1 year, and mortality within 1 year of transplant. RESULTS: In the propensity score matched data, the relative risk of being treated for rejection prior to transplant hospital discharge was 61% lower for HKi (RR .39, 95% CI .29, .53) and 87% lower for HLi (RR .13, 95% CI .05, .37) compared to H. Similarly, the probability of being treated for rejection in the first year after transplant remained lower in HKi (RR .45, 95% CI .35, .57) and HLi (RR .13, 95% CI .06, .28) compared to H. The 1-year survival analysis revealed an equivalent risk of death in HKi (HR .84, 95% CI .68, 1.03) and HLi (HR 1.41, 95% CI .83, 2.41) compared to H, while HLu had a higher risk of death in the first year after transplant (HR 1.65, 95% CI 1.17, 2.33). CONCLUSIONS: Recipients of HKi and HLi experience a reduced risk of rejection when compared to H, but an equivalent risk of 1 yr mortality. These findings have important implications for the future of HT medicine.