William E. Schwartzman

Background: Postoperative sinus tachycardia is a poorly understood complication following the Fontan procedure. The molecular signaling cascades triggering acute tachycardia remain uncharacterized, limiting therapeutic innovation. Here, we present a retrospective study leveraging serum proteomics and machine learning to identify the molecular drivers of postoperative Fontan sinus tachycardia. Methods: We integrated a clinically relevant ovine Fontan model with continuous telemetric heart rate monitoring and human patient data. Serum proteomics coupled with least absolute shrinkage and selection operator and Boruta machine learning algorithms were used to identify protein panels predictive of postoperative sinus tachycardia. Cross‐species validation was performed by comparing proteomic signatures from sheep and pediatric patients undergoing Glenn or Fontan surgery. Results: Ovine Fontan animals demonstrated significant heart rate elevation beginning on postoperative day 1, peaking at postoperative day 3 (159.4±11.7 bpm versus preoperative, 105.3±10.5 bpm; P =0.0002), before trending toward baseline by postoperative day 10. This pattern was mirrored in human patients with a more modest magnitude. Surgical controls did not exhibit tachycardia. The principal component most correlated with heart rate (principal component 1: r =0.78, P =2.2×10 ⁻⁴ ) was enriched for inflammatory and neural pathways. The Boruta algorithm identified an 11‐protein panel with strong predictive power (area under the receiver operating characteristic curve, 0.963). Cross‐species comparison demonstrated that angiotensinogen, angiotensin‐converting enzyme, and pentraxin 3 were similarly dysregulated in both species postoperatively. Conclusions: This study provides molecular evidence implicating a dysregulated neurohormonal–inflammatory axis in acute postoperative Fontan sinus tachycardia and establishes a foundation for developing targeted diagnostics and therapeutics for this complication.

Background: Post-operative tachycardia is a common and poorly understood complication following the Fontan procedure. Post-operative factors such as surgical scarring and venous hypertension can contribute to tachycardia risk, but the specific molecular signaling cascades triggering acute tachycardia remain uncharacterized, limiting therapeutic innovation and leaving clinicians with only reactive management strategies. Here, we present a retrospective translational study leveraging serum proteomics and machine learning to identify the molecular drivers of post-operative Fontan tachycardia. Methods: We integrated a clinically relevant ovine animal model of the Fontan circulation with continuous telemetric heart rate monitoring and human patient data. Serum proteomics coupled with machine learning algorithms (LASSO and Boruta) were employed to identify protein panels predictive of post-operative tachycardia. Cross-species validation was performed by comparing proteomic signatures from sheep and pediatric patients undergoing Glenn or Fontan surgery. Results: Ovine Fontan animals demonstrated significant heart rate elevation beginning on post-operative day (POD) 1, peaking at POD 3 (159.4 ± 11.7 bpm vs. pre-operative 105.3 ± 10.5 bpm, p<0.0001), before trending toward baseline by POD 10. This pattern was mirrored in human pediatric patients, though with a more modest magnitude. Surgical controls did not exhibit tachycardia, indicating the response was specific to the Fontan procedure. Proteomic analysis identified distinct separation between pre- and post-operative serum profiles. Principal component analysis revealed that the principal components most correlated with heart rate (PC1: r=0.79, p=6.5×10⁻⁶; PC8: r=0.40, p=0.04) were significantly enriched for inflammatory and neural pathways. We leveraged the Boruta algorithm to identify a seven-protein panel (ACE, ANGT, ITIH4, SELENOP, W5PHP7, PTX3, and F5) with superior predictive power (AUC=0.926). A cross-species comparison between human and sheep demonstrated that three proteins, angiotensinogen (ANGT), angiotensin-converting enzyme (ACE), and pentraxin 3 (PTX3), were similarly dysregulated in both species post-operatively. Conclusions: This study provides the first direct molecular evidence implicating a dysregulated neurohormonal-inflammatory axis as a principal driver of acute post-operative Fontan tachycardia. The identified protein signature offers novel mechanistic insights and establishes a foundation for developing targeted diagnostics and therapeutics to predict and mitigate this significant clinical complication.

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Advancements in congenital heart surgery have heightened the importance of durable biomaterials for adult survivors. Dystrophic calcification poses a significant risk to the long-term viability of prosthetic biomaterials in these procedures. Herein, we describe the natural history of calcification in the most frequently used vascular conduits, expanded polytetrafluoroethylene grafts. Through a retrospective clinical study and an ovine model, we compare the degree of calcification between tissue-engineered vascular grafts and polytetrafluoroethylene grafts. Results indicate superior durability in tissue-engineered vascular grafts, displaying reduced late-term calcification in both clinical studies (p < 0.001) and animal models (p < 0.0001). Further assessments of graft compliance reveal that tissue-engineered vascular grafts maintain greater compliance (p < 0.0001) and distensibility (p < 0.001) than polytetrafluoroethylene grafts. These properties improve graft hemodynamic performance, as validated through computational fluid dynamics simulations. We demonstrate the promise of tissue engineered vascular grafts, remaining compliant and distensible while resisting long-term calcification, to enhance the long-term success of congenital heart surgeries.

A retrospective review of the UNOS/OPTN Database was performed from 1 October 1987–31 December 2019. Recipients were classified as LSu (15+ years survival without GF/ReTx), normal survival (3–15 years) and short survival (<3 years). In total, 22,646 patients were identified. Groups were assessed with comparative statistics in addition to a multivariate analysis which included recipient, donor, transplant characteristics and select post-transplant complications. LSu recipients were younger, more commonly female, healthier and more commonly had cystic fibrosis, pulmonary vascular disease or bilateral lung transplantation. LSu donors were younger, healthier and lacked clinical infection. Recipients with restrictive lung disease, single lung transplant and dialysis postoperatively were less likely to be LSu. Several recipient, donor and transplant characteristics are associated with long lung transplantation survival. While some factors cannot be altered, others related to donor selection and posttransplant management can potentially be influenced. Understanding these characteristics and employing discretion in donor selection, in appropriate recipients, may optimize the longevity of transplanted lungs.

Intracortical neural probes are both a powerful tool in basic neuroscience studies of brain function and a critical component of brain computer interfaces (BCIs) designed to restore function to paralyzed patients. Intracortical neural probes can be used both to detect neural activity at single unit resolution and to stimulate small populations of neurons with high resolution. Unfortunately, intracortical neural probes tend to fail at chronic timepoints in large part due to the neuroinflammatory response that follows implantation and persistent dwelling in the cortex. Many promising approaches are under development to circumvent the inflammatory response, including the development of less inflammatory materials/device designs and the delivery of antioxidant or anti-inflammatory therapies. Here, we report on our recent efforts to integrate the neuroprotective effects of both a dynamically softening polymer substrate designed to minimize tissue strain and localized drug delivery at the intracortical neural probe/tissue interface through the incorporation of microfluidic channels within the probe. The fabrication process and device design were both optimized with respect to the resulting device mechanical properties, stability, and microfluidic functionality. The optimized devices were successfully able to deliver an antioxidant solution throughout a six-week in vivo rat study. Histological data indicated that a multi-outlet design was most effective at reducing markers of inflammation. The ability to reduce inflammation through a combined approach of drug delivery and soft materials as a platform technology allows future studies to explore additional therapeutics to further enhance intracortical neural probes performance and longevity for clinical applications.

(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain–machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application.