Cardiac cells are exposed to continuously changing mechanical forces during contraction and relaxation of the myocardium. The cells’ mechanical environment and cardiac pathophysiology are closely inter-related. Hence, in the course of cardiac disease, the cells’ mechanical environment can change profoundly. Cells sense and adapt to mechanical stimuli because of specialized mechano-sensors mediating adaptive signalling cascades. In this context, mechano-sensitive ion channels (MSC) play an important role. Here, MSC are referred to as ion channels which are mechanically gated and/or mechanically modulated, i.e. their activity, localisation or expression can be modified by mechanical factors. Indeed, MSC have been shown to be remodelled in various cardiac diseases, e.g. melastatin-related transient receptor potential ion channels (TRPM4, 7) and vanilloid TRP (TRPV4) in arrhythmias, canonical TRP (TRPC6) in cardiac hypertrophy, heart failure and myocardial infarction, and ATP-sensitive potassium channels (K_ATP) as well as cystic fibrosis transmembrane conductance regulators (CFTR) in ischemic preconditioning. However, functional relevance of most MSC is still elusive and a comprehensive overview of MSC remodelling in the context of cardiac disease has not yet been proposed.

In this study, we hypothesize that human cardiac MSC gene expression is differentially regulated between heart chambers and between health conditions. We aim to get a better understanding of the involvement of MSC genes in cardiac pathophysiology, with a focus on finding putative targets for chamber-selective drug therapy.

To address this, we conducted a meta-analysis of previously published bulk RNA-sequencing datasets in which we were able to include non-diseased cardiac tissue samples and to consider a large number of patients.

We compared mRNA expression levels of 73 MSC genes and genes linked to tissue remodelling between human cardiac tissue samples. Reference atrial and ventricular tissue samples originated from donor hearts not suitable for transplantation (no cardiac disease). Diseased tissue samples were provided from patients with ischemic or dilative cardiomyopathy, coronary artery disease, heart valve disease, and atrial fibrillation. All patients requied cardiac surgery and gave informed consent for the respective study. The genes of interest were analysed for their chamber- and disease-selectivity.

We found that 21 MSC displayed chamber-selectivity by gene expression. Among these, TRPV4 showed right atria-preferential expression, whereas CACNA1B and KCNMB1 showed left atria-preferential expression. In diseased hearts, chamber-selective gene expression was lost for some MSC, but remained unaffected for others. Furthermore, 15 MSC genes exhibited differential expression related to cardiac diseases. Among those, expression of CHRNE was higher and expression of SCN9A was lower in heart failure compared to donor hearts. In atrial fibrillation, expression of PKD1 was higher and expression of KCNJ5 was lower compared to samples from patients in sinus rhythm.

This report gives an overview of MSC mRNA expression in cardiac health and disease and highlights the importance of this class of ion channels. By identifying candidate genes which show chamber-selectivity and/or disease-specificity at the mRNA level, novel potential molecular targets involved in mechano-transduction are featured.