Abstract 17637: Lacking MicroRNA-1’s Biophysical Action Causes Heart Failure Revealed by a Newly Developed Biplane Echocardiography of Mouse Heart

MicroRNA-1 (miR1) is the most abundant microRNA in the heart and plays a key role in maintaining cardiac homeostasis through a well-known RNAi mechanism. Recently, we found a novel biophysical function of miR1 to physically bind to and modulate cardiac ion channels. A human single nucleotide polymorphism-hSNP14A/G (rs776480338) of miR1, in which the 14th nucleotide “A” is mutated to “G”, specifically abolishes the biophysical modulation while maintaining the RNAi. However, the physiological significance of microRNA’s biophysical action remains unknown. To study this, we created a single-nucleotide 14A/G mutation on miR1-1 and miR1-2 genes by using CRISPR/Cas9 and developed 14G-mutated homozygous (14G-Homo, miR1-1 14G/G:miR1-2 14G/G) transgenic mice. In addition, we also developed a new echocardiography methodology that can consistently record clear 4-chamber views of mouse hearts, allowing integration of 4-chamber and long axis views for the clinically recommended Biplane Simpson’s assessment of left ventricular (LV) function. Validation via Cardiac Magnetic Resonance (CMR) revealed that the Biplane method is more accurate than M-mode analysis for precise assessments of mouse LV functional parameters. These findings were highlighted in practice by monitoring both Wild Type (WT) and 14G-Homo mice at 2, 3, and 4 months of age, in which M-mode consistently overestimated LV parameters. Moreover, the clarity of the 4 chamber images enables many cardiac analyses that were previously not feasible for the mouse heart, such as the mitral valve color doppler that revealed turbulent blood flow into the LV of 14G-Homo mice. With the 4-chamber view methodology, we also studied the right ventricular (RV) function by assessing fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) and found that cardiac functional deterioration of 14G-Homo mice most likely originated in the LV, followed by RV deteriorations and development of heart failure. In conclusion, our study demonstrated that the biophysical action of miR1 is essential to cardiac homeostasis. Additionally, our new imaging methodology enables more clinically comparable analyses which significantly improve translational implications of mouse cardiac research.