The cardiac molecular setting of metabolic syndrome in pigs reveals disease susceptibility and suggests mechanisms that exacerbate COVID-19 outcomes in patients

Olivia Ziegler,Denitsa Radeva,Makoto Hiromura,Kostadin Todorov,Simon C Robson,Jun Feng,Vladimir Gelev,Anny Usheva,Frank W Sellke,Boian S Alexandrov,Nivedita Sriram

doi:10.1038/s41598-021-99143-w

Abstract

Although metabolic syndrome (MetS) is linked to an elevated risk of cardiovascular disease (CVD), the cardiac-specific risk mechanism is unknown. Obesity, hypertension, and diabetes (all MetS components) are the most common form of CVD and represent risk factors for worse COVID-19 outcomes compared to their non MetS peers. Here, we use obese Yorkshire pigs as a highly relevant animal model of human MetS, where pigs develop the hallmarks of human MetS and reproducibly mimics the myocardial pathophysiology in patients. Myocardium-specific mass spectroscopy-derived metabolomics, proteomics, and transcriptomics enabled the identity and quality of proteins and metabolites to be investigated in the myocardium to greater depth. Myocardium-specific deregulation of pro-inflammatory markers, propensity for arterial thrombosis, and platelet aggregation was revealed by computational analysis of differentially enriched pathways between MetS and control animals. While key components of the complement pathway and the immune response to viruses are under expressed, key N6-methyladenosin RNA methylation enzymes are largely overexpressed in MetS. Blood tests do not capture the entirety of metabolic changes that the myocardium undergoes, making this analysis of greater value than blood component analysis alone. Our findings create data associations to further characterize the MetS myocardium and disease vulnerability, emphasize the need for a multimodal therapeutic approach, and suggests a mechanism for observed worse outcomes in MetS patients with COVID-19 comorbidity.

Highlights

Metabolic syndrome (MetS) is linked to an elevated risk of cardiovascular disease (CVD), the cardiac-specific risk mechanism is unknown
The phenotype observed in the pigs on high-fat, high-calorie diet meets all five metabolic syndrome diagnostic criteria in humans: obesity, elevated fasting blood sugar, elevated triglycerides and LDL, and increased blood pressure
LC–MS/MS was performed on parallel samples from six of the pigs, three metabolic syndrome (MetS) and three lean diet control pigs (LD), to verify RNA-seq results at the protein level

Summary

Introduction

Metabolic syndrome (MetS) is linked to an elevated risk of cardiovascular disease (CVD), the cardiac-specific risk mechanism is unknown. Hypertension, and diabetes (all MetS components) are the most common form of CVD and represent risk factors for worse COVID-19 outcomes compared to their non MetS peers. As part of MetS, hypertension, obesity, hyperglycemia and hyperlipidemia individually and synergistically, increase myocardial vulnerability and are associated with greater risk for death in patients with CVD; more recently components of MetS have been identified as a risk for worse COVID-19 outcomes[3]. Difficulties inherent in obtaining human myocardial tissue as well as differences in MetS treatment between humans and small animal models, further complicate the identification of the myocardium-specific risk factors in MetS

Methods

Results

Conclusion