DYRK1B expression is increased in patients with impaired cardiac contractility

Introduction

Despite ongoing progress in therapeutic developments, cardiovascular disease remains a major challenge for healthcare systems. This highlights the need for new therapeutic strategies and pharmacological targets. In this regard, the dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) was recently linked to an impaired cardiac contractility and myocardial hypertrophy in mice. The purpose of our work was to study myocardial DYRK1B expression in clinically well-characterized patients with a high cardiovascular risk.

Methods

In our cross-sectional study, we analyzed 159 patients undergoing elective coronary artery bypass surgery. Sleep-disordered breathing (including hypoxia parameters) was assessed with polygraphy the night prior to surgery. Human right atrial appendage biopsies obtained intraoperatively were utilized for experimental analyses. Following RNA isolation and reverse transcription, we quantified the myocardial DYRK1B expression with qPCR (normalized to the housekeeper gene ACTB). Based on the median DYRK1B expression level (1.098% of ACTB), we stratified the patients into two cohorts: those with a DYRK1B expression below the median (n=79) and those with an expression equal to or higher than the median (n=80). The risk for an increased DYRK1B expression was calculated by logistic regression analyses to explore the effect of various clinical parameters on myocardial DYRK1B expression.

Results

Of the 159 patients included, 136 were male. The study cohort had a mean age of 66.1 years and an average body-mass-index (BMI) of 28.5 kg/m². A left ventricular ejection fraction (LVEF) <55% was associated with an >5-fold increased risk for an elevated (≥median) DYRK1B expression (Figure 1A). Similarly, also the left ventricular end-diastolic diameter was associated with an increased DYRK1B  expression. We the divided the patients into four groups, based on the LVEF range (Figure 1B). Notably, in patients with an LVEF <45%, we found a 3-fold increased myocardial DYRK1B expression compared to patients with an LVEF of ≥45%. 
Besides the association with ejection fraction, analysis of the nocturnal polygraphs revealed the presence of sleep-disordered breathing (SDB), defined as AHI≥15, was associated with a >3-fold increased risk for an elevated DYRK1B expression (Figure 1A). Accordingly, there was a significant positive correlation between the oxygen desaturation index (ODI) and the myocardial DYRK1B expression, indicating that hypoxia may be involved in DYRK1B regulation (Figure 1C).

As illustrated in Figure 1A, there are several clinical variables that are associated with an either increased or decreased DYRK1B expression. To account for that, we performed a multivariate regression analysis incorporating important clinical covariates that correlated with the
DYRK1B expression in the univariate model. Notably, only the LVEF remained a significant variable in the multivariate model and was therefore independent of other potential confounders.

Conclusion

We found an increased myocardial DYRK1B expression in patients with an impaired LVEF, which was independent of potential clinical confounders. Future studies will aim to further study and test DYRK1B as a molecular target for therapeutic strategies against heart failure with a reduced ejection fraction.