Adipose tissue dysfunction, inflammation, and insulin resistance alternative pathways to cardiac remodelling in schizophrenia. A multimodal, case-control study

Background Cardiovascular disease is the leading cause of excess mortality in schizophrenia. Patients with schizophrenia show evidence of increased concentric cardiac remodelling (CCR), defined as an increase in left-ventricular mass over end-diastolic volumes. CCR is a predictor of cardiac disease, but the molecular pathways leading to this in schizophrenia are unknown. We aimed to explore the relevance of hypertensive and non-hypertensive pathways to CCR, and their potential molecular underpinnings in schizophrenia. Methods and findings In this multimodal case-control study we collected cardiac and whole-body fat magnetic resonance imaging (MRI), clinical measures, and blood levels of several cardiometabolic biomarkers known to potentially cause CCR from individuals with schizophrenia, alongside healthy controls (HCs) matched for age, sex, ethnicity, and body surface area. Of 50 participants, 34 (68%) were male. Participants with schizophrenia showed increases in cardiac concentricity (d=0.71, 95%CI: 0.12,1.30; p=0.01), indicative of CCR, but showed no differences in overall content or regional distribution of adipose tissue compared to HCs. Despite the cardiac changes, participants with schizophrenia did not demonstrate activation of the hypertensive CCR pathway; however, they showed evidence of adipose dysfunction: adiponectin was reduced (d=-0.69, 95%CI: -1.28,-0.10; p=0.02), with evidence of activation of downstream pathways including hypertriglyceridemia, elevated C-reactive protein, fasting glucose, and alkaline phosphatase. Conclusions People with schizophrenia showed adipose tissue dysfunction compared to BMI-matched HCs. The presence of non-hypertensive CCR and a dysmetabolic phenotype may contribute to excess cardiovascular risk in schizophrenia. If our results are confirmed, acting on this pathway could reduce cardiovascular risk and resultant lifeyears lost in people with schizophrenia