Preclinical mouse models have identified the serotonin receptor 5-HT2B as a strong activator of cardiac hypertrophy and linked serotonin to the activation of specific cardiac transcription factors. In clinical studies, high levels of serotonin are a marker for cardiac decompensation. However, so far there is a limited understanding of serotonin dependent cardiac phenotypes and regulation of gene expression.

We performed a prospective cohort study in 59 patients diagnosed with a neuroendocrine tumor (NET) that were admitted to the Cardio-Oncology Unit of the Heidelberg University Hospital from 07/2016 to 03/2019. Cardiac systolic and diastolic functions were evaluated by transthoracic echocardiography. In addition, cardiac biomarkers (high-sensitive Troponin T (hs-cTnT), NT-proBNP and non-cardiac biomarkers (serotonin, 5-hydroxyindoleacetic acid (5-HIAA)) were analyzed. 

10 of 59 patients (16.9%) showed an impaired systolic dysfunction (LV-EF ≤ 50%) at the time of initial presentation whereas 20/59 (33.9%) patients showed a reduced diastolic function (E/e’ > 8). In 34/59 patients we measured a reduced global longitudinal strain (GLS > -20%). We further found a significant correlation of LV-thickness and serotonin levels over the observational time (p= 0.011). Maximal serotonin levels had an average of 9.61 µmol/l (reference < 2 µmol/l). Patients with high serotonin levels (mean concentration as a cutoff, n=23) showed a significant correlation to a reduced LVEF (Pearson Correlation: p=0.003, r=-0.63), hsTnT (Pearson Correlation: p=0.0004, r=0.79) and NT-proBNP (Pearson Correlation: p=0.043, r= 0.53). 

We further conducted RNA sequencing of peripheral blood samples (n=16) and correlated changes in gene expression with serotonin levels to potentially identify novel markers of serotonin induced cardiac dysfunction. By a stringent bioinformatic analysis, we identified 12 significantly dysregulated genes (DESeq2, FDR 0,1). This set of genes is predominantly involved in antigen presentation. Upregulation of HLA-DQB1, a member of the major histocompatibility complex II, correlated significantly with the serotonin levels in the blood (Spearman Correlation: p-value = 0.0276, rho=0.56673). Polymorphism and expressional changes in HLA-DQB1 are known to be associated with dilatative cardiomyopathy.

This cohort study of patients with NET provides first evidence for a potentially direct link between high serotonin levels and cardiac dysfunction. HLA-DQB1 dysregulation was further identified as a potential marker for serotonin driven cardiac remodelling.