Evidence showing lipotoxicity worsens outcomes in covid-19 patients and insights about the underlying mechanisms
Rodrigo Cartin-Ceba,
Biswajit Khatua,
Bara El-Kurdi,
Shubham Trivedi,
Sergiy Kostenko,
Zaid Imam,
Ryan Smith,
Christine Snozek,
Sarah Navina,
Vijeta Sharma,
Bryce McFayden,
Filip Ionescu,
Eugene Stolow,
Sylvia Keiser,
Aziz Tejani,
Allison Harrington,
Phillip Acosta,
Saatchi Kuwelker,
Juan Echavarria,
Girish B. Nair,
Adam Bataineh,
Vijay P. Singh
Affiliations
Rodrigo Cartin-Ceba
Division of Pulmonary Medicine and Department of Critical Care Medicine, Mayo Clinic, Phoenix, AZ, USA; Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
Biswajit Khatua
Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
Bara El-Kurdi
Department of Gastroenterology and Hepatology, University of Texas Health, San Antonio, TX, USA
Shubham Trivedi
Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
Sergiy Kostenko
Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
Zaid Imam
Section of Gastroenterology and Hepatology, Department of Internal Medicine, William Beaumont Hospital at Royal Oak, Royal Oak, MI, USA
Ryan Smith
Mayo Clinic Alix School of Medicine, Phoenix, AZ, USA
Christine Snozek
Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, AZ, USA
Sarah Navina
Clin-Path Associates, Phoenix, AZ, USA
Vijeta Sharma
Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
Bryce McFayden
Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
Filip Ionescu
Department of Internal Medicine, William Beaumont Hospital at Royal Oak, Royal Oak, MI, USA
Eugene Stolow
Department of Internal Medicine, University of Texas Health, San Antonio, TX, USA
Sylvia Keiser
Department of Internal Medicine, University of Texas Health, San Antonio, TX, USA
Aziz Tejani
Department of Internal Medicine, University of Texas Health, San Antonio, TX, USA
Allison Harrington
Department of Gastroenterology and Hepatology, University of Texas Health, San Antonio, TX, USA
Phillip Acosta
Department of Internal Medicine, University of Texas Health, San Antonio, TX, USA
Saatchi Kuwelker
Department of Internal Medicine, University of Texas Health, San Antonio, TX, USA
Juan Echavarria
Department of Gastroenterology and Hepatology, University of Texas Health, San Antonio, TX, USA
Girish B. Nair
Section of Pulmonary and Critical Care Medicine, William Beaumont Hospital at Royal Oak, Royal Oak, MI, USA
Adam Bataineh
Department of Internal Medicine, University College of London Hospital, London, UK
Vijay P. Singh
Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA; Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA; Corresponding author
Summary: We compared three hospitalized patient cohorts and conducted mechanistic studies to determine if lipotoxicity worsens COVID-19. Cohort-1 (n = 30) compared COVID-19 patients dismissed home to those requiring intensive-care unit (ICU) transfer. Cohort-2 (n = 116) compared critically ill ICU patients with and without COVID-19. Cohort-3 (n = 3969) studied hypoalbuminemia and hypocalcemia’s impact on COVID-19 mortality. Patients requiring ICU transfer had higher serum albumin unbound linoleic acid (LA). Unbound fatty acids and LA were elevated in ICU transfers, COVID-19 ICU patients and ICU non-survivors. COVID-19 ICU patients (cohort-2) had greater serum lipase, damage-associated molecular patterns (DAMPs), cytokines, hypocalcemia, hypoalbuminemia, organ failure and thrombotic events. Hypocalcemia and hypoalbuminemia independently associated with COVID-19 mortality in cohort-3. Experimentally, LA reacted with albumin, calcium and induced hypocalcemia, hypoalbuminemia in mice. Endothelial cells took up unbound LA, which depolarized their mitochondria. In mice, unbound LA increased DAMPs, cytokines, causing endothelial injury, organ failure and thrombosis. Therefore, excessive unbound LA in the circulation may worsen COVID-19 outcomes.
