Cardiomyocyte-specific disruption of the circadian BMAL1-REV-ERBα/ß regulatory network impacts distinct miRNA species in the murine heart.

Circadian disruption increases cardiovascular disease (CVD) risk, through poorly understood mechanisms. Given that small RNA species are critical modulators of cardiac physiology/pathology, we sought to determine the extent to which cardiomyocyte circadian clock (CCC) disruption impacts cardiac small RNA species. Accordingly, we collected hearts from cardiomyocyte-specific Bmal1 knockout (CBK; a model of CCC disruption) and littermate control (CON) mice at multiple times of the day, followed by small RNA-seq. The data reveal 47 differentially expressed miRNAs species in CBK hearts. Subsequent bioinformatic analyses predict that differentially expressed miRNA species in CBK hearts influence processes such as circadian rhythmicity, cellular signaling, and metabolism. Of the induced miRNAs in CBK hearts, 7 are predicted to be targeted by the transcriptional repressors REV-ERBα/ß (integral circadian clock components that are directly regulated by BMAL1). Similar to CBK hearts, cardiomyocyte-specific Rev-erbα/ß double knockout (CM-RevDKO) mouse hearts exhibit increased let-7c-1-3p, miR-23b-5p, miR-139-3p, miR-5123, and miR-7068-3p levels. Importantly, 19 putative targets of these 5 miRNAs are commonly repressed in CBK and CM-RevDKO heart (of which 16 are targeted by let-7c-1-3p). These observations suggest that disruption of the circadian BMAL1-REV-ERBα/ß regulatory network in the heart induces distinct miRNAs, whose mRNA targets impact critical cellular functions.

Diastolic function: modeling left ventricular untwisting as a damped harmonic oscillator.

Objective.We developed a method using cardiovascular magnetic resonance imaging to model the untwisting of the left ventricle (LV) as a damped torsional harmonic oscillator to estimate shear modulus (intrinsic myocardial stiffness) and frictional damping, then applied this method to evaluate the torsional stiffness of patients with resistant hypertension (RHTN) compared to a control group.Approach.The angular displacement of the LV during diastole was measured. Myocardial shear modulus and damping constant were determined by solving a system of equations modeling the diastolic untwisting as a damped, unforced harmonic oscillator, in 100 subjects with RHTN and 36 control subjects.Main Results.Though overall torsional stiffness was increased in RHTN (41.7 (27.1-60.7) versus 29.6 (17.3-35.7) kdyn*cm;p = 0.001), myocardial shear modulus was not different between RHTN and control subjects (0.34 (0.23-0.50) versus 0.33 (0.22-0.46) kPa;p= 0.758). RHTN demonstrated an increase in overall diastolic frictional damping (6.13 ± 3.77 versus 3.35 ± 1.70 kdyn*cm*s;p< 0.001), but no difference in damping when corrected for the overlap factor (74.3 ± 25.9 versus 68.0 ± 24.0 dyn*s/cm3;p = 0.201). There was an increase in the polar moment (geometric component of stiffness; 11.47 ± 6.95 versus 7.58 ± 3.28 cm4;p<0.001).Significance.We have developed a phenomenological method, estimating the intrinsic stiffness and relaxation properties of the LV based on restorative diastolic untwisting. This model finds increased overall stiffness in RHTN and points to hypertrophy, rather than tissue- level changes, as the major factor leading to increased stiffness.

Diabetes-Related Cardiac Dysfunction.

The proposal that diabetes plays a role in the development of heart failure is supported by the increased risk associated with this disease, even after correcting for all other known risk factors. However, the precise mechanisms contributing to the condition referred to as diabetic cardiomyopathy have remained elusive, as does defining the disease itself. Decades of study have defined numerous potential factors that each contribute to disease susceptibility, progression, and severity. Many recent detailed reviews have been published on mechanisms involving insulin resistance, dysregulation of microRNAs, and increased reactive oxygen species, as well as causes including both modifiable and non-modifiable risk factors. As such, the focus of the current review is to highlight aspects of each of these topics and to provide specific examples of recent advances in each area.