Cardiac troponin I directly binds and inhibits mitochondrial ATP synthase with a noncanonical role in the post-ischemic heart.

Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress.

Extracellular release of damaged mitochondria induced by prehematopoietic stem cell transplant conditioning exacerbates GVHD.

Despite therapeutic advancements, graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT). In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing pathogen-associated molecular patterns, result in activation of host antigen-presenting cells (APCs) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space.

"Big Data" Analyses Underlie Clinical Discoveries at the Aortic Institute.

This issue of the () focuses on Big Data and precision analytics in medical research. At the Aortic Institute at Yale New Haven Hospital, the vast majority of our investigations have emanated from our large, prospective clinical database of patients with thoracic aortic aneurysm (TAA), supplemented by ultra-large genetic sequencing files. Among the fundamental clinical and scientific discoveries enabled by application of advanced statistical and artificial intelligence techniques on these clinical and genetic databases are the following: .

Bicuspid aortopathy does not require earlier surgical intervention.

Objectives: Guidelines for surgical correction of patients with ascending thoracic aortic aneurysm (ATAA) with a bicuspid aortic valve (BAV) have oscillated over the years. In this study, we outline the natural history of the ascending aorta in patients with BAV and trileaflet aortic valve (TAV) ATAA followed over time, to ascertain if their behavior differs and to determine if a different threshold for intervention is required.

Methods: Aortic diameters and long-term complications (ie, adverse aortic events) of 2428 patients (554 BAV and 1874 TAV) with ATAA before operative repair were reviewed.

Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy.

Background: Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury, including sepsis-induced myocardial dysfunction (SIMD). However, the mechanisms behind p53 localization to the mitochondria have not been well established. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization.

A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury.

Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of protein kinase C delta (δPKC) with a pan-inhibitor (δV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac troponin I (cTnI), a key sarcomeric protein in cardiomyocyte contraction, is phosphorylated by δPKC during reperfusion.

A machine learning approach for predicting complications in descending and thoracoabdominal aortic aneurysms.

Objective: To use machine learning to predict rupture, dissection, and all-cause mortality for patients with descending and thoracoabdominal aortic aneurysms in an effort to improve on diameter-based surgical intervention criteria.

Methods: Retrospective data from 1083 patients with descending aortic diameters 3.0 cm or greater were collected, with a mean follow-up time of 3.

Drp1/Fis1-Dependent Pathologic Fission and Associated Damaged Extracellular Mitochondria Contribute to Macrophage Dysfunction in Endotoxin Tolerance.

Objectives: Recent publications have shown that mitochondrial dynamics can govern the quality and quantity of extracellular mitochondria subsequently impacting immune phenotypes. This study aims to determine if pathologic mitochondrial fission mediated by Drp1/Fis1 interaction impacts extracellular mitochondrial content and macrophage function in sepsis-induced immunoparalysis.

Design: Laboratory investigation.

Machine Learning Applied to Electronic Health Records: Identification of Chemotherapy Patients at High Risk for Preventable Emergency Department Visits and Hospital Admissions.

Purpose: Acute care use (ACU) is a major driver of oncologic costs and is penalized by a Centers for Medicare & Medicaid Services quality measure, OP-35. Targeted interventions reduce preventable ACU; however, identifying which patients might benefit remains challenging. Prior predictive models have made use of a limited subset of the data in the electronic health record (EHR).

Developing machine learning models to personalize care levels among emergency room patients for hospital admission.

Objective: To develop prediction models for intensive care unit (ICU) vs non-ICU level-of-care need within 24 hours of inpatient admission for emergency department (ED) patients using electronic health record data.

Materials And Methods: Using records of 41 654 ED visits to a tertiary academic center from 2015 to 2019, we tested 4 algorithms-feed-forward neural networks, regularized regression, random forests, and gradient-boosted trees-to predict ICU vs non-ICU level-of-care within 24 hours and at the 24th hour following admission. Simple-feature models included patient demographics, Emergency Severity Index (ESI), and vital sign summary.

Machine learning: principles and applications for thoracic surgery.

Objectives: Machine learning (ML) has experienced a revolutionary decade with advances across many disciplines. We seek to understand how recent advances in ML are going to specifically influence the practice of surgery in the future with a particular focus on thoracic surgery.

Methods: Review of relevant literature in both technical and clinical domains.

Use Characteristics and Triage Acuity of a Digital Symptom Checker in a Large Integrated Health System: Population-Based Descriptive Study.

Background: Pressure on the US health care system has been increasing due to a combination of aging populations, rising health care expenditures, and most recently, the COVID-19 pandemic. Responses to this pressure are hindered in part by reliance on a limited supply of highly trained health care professionals, creating a need for scalable technological solutions. Digital symptom checkers are artificial intelligence-supported software tools that use a conversational "chatbot" format to support rapid diagnosis and consistent triage.

The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective.

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD.

Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy.

Unlabelled: Mitochondrial dysfunction is a key contributor to septic cardiomyopathy. Although recent literature implicates dynamin related protein 1 (Drp1) and its mitochondrial adaptor fission 1 (Fis1) in the development of pathologic fission and mitochondrial failure in neurodegenerative disease, little is known about the role of Drp1/Fis1 interaction in the context of sepsis-induced cardiomyopathy. Our study tests the hypothesis that Drp1/Fis1 interaction is a major driver of sepsis-mediated pathologic fission, leading to mitochondrial dysfunction in the heart.