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2017 Cardiovascular Research Day Abstract Book

11 Cardiac Specific Rad

11 Cardiac Specific Rad Deletion Enhances Cardiac Function through Safe, Stable Positive Inotropic Support Brooke Ahern 1 • Bryana Levitan 2 • Mihir Shah 1 • Andrea Sebastian 1 • Zach Bessinger 3 • Radu Paul Mihail 3 • Landon Simpson 4 • Nathan Jacobs, PhD 3 • Douglas Andres, PhD 4 • Jonathan Satin, PhD 1 1Physiology, University of Kentucky • 2 Gill Heart and Vascular Institute, University of Kentucky • 3Computer Science, University of Kentucky • 4 Biochemistry, University of Kentucky Graduate Student Background: The cardiac L-type Calcium Channel (LTCC) is a heteromultimeric protein complex. Rad interacts with the main pore forming subunit (CaV1.2) and auxiliary subunit CaVβ2. Rad modifies LTCC function and Rad protein levels are reduced by pathological stimuli. Global, constitutive deletion of Rad results in an increase in calcium handling and improved ejection fraction without progression to heart failure. Goals: It is unknown if the effects of global Rad deletion are also exhibited in cardiac-specific Rad deletion, and if the effects are preserved long-term. Our hypothesis is that cardiac-specific Rad ablation causes positive inotropic effects that are maintained over time. Methods and Results: We crossed Radfl/fl onto αMHC-MerCreMer mice to create a cardiacrestricted inducible Rad knockout (cRadKO). Mice were induced for gene deletion at ~3 months of age. We assessed cardiac structure and function through echocardiography from 7 days through 9 months after cRadKO induction. Ejection fraction improved in females in comparison to wild type 7 days post knock out (762% vs. 594%; cRadKO n=16 vs. WT n=7, respectively; p=0.001). Improved function was stable for 9 months in females (774% vs. 587%;cRadKO vs. WT, respectively; p=0.01). Similar results were found in males. The key mechanism for improved function includes elevated trigger Ca2+ in cardiomyocytes measured as a Ca2+-transient departure velocity (48.72.4 units/s vs. 38.13.4 units/s; cRadKO n=8 vs. WT n=10, respectively; p=.014). Cellular Ca2+ synchrony was preserved in cRadKO despite chronic elevated Ca2+ homeostasis. Conclusion: Cardiomyocyte Rad deletion preserves increased ejection fraction over time through a mechanism including increased calcium handling resulting in safe, stable positive inotropic support for heart function. 27

12 Auditory Entrainment of Respiration and RR Intervals Dibyajyoti Biswal, PhD 1 • Javad Mohammad Mollakazemi, PhD 1 • Sridevi Thyagarajan, PhD 1 • Joyce Evans, PhD 1 • Abhijit Patwardhan, PhD 1 1 Biomedical Engineering, University of Kentucky Graduate Student Introduction:- It is known that music has palliative effect in a number of patients. Listening to music is also known to evoke autonomically regulated cardiovascular and respiratory responses. In adults, these responses are a combination of sensory input and cognition. While it is known that listening to music evokes measurable responses in cardiovascular and respiratory variables, much is unknown in terms of causal links between these responses and the mechanisms by which they get entrained. Our overall objective is to determine the causal links between auditory stimuli, respiration and cardiovascular regulatory variables. Materials and Methods:- The study was approved by the Institutional Review Board at the University of Kentucky. Subjects gave informed consent. Subjects (n=8, equal numbers of males and females, age 18 to 35) sat in a comfortable chair and listened to songs through a pair of circumaural headphones. An internet based audio acuity test was administered to each subject to rule out overt hearing loss. The following measurements were made: non-invasive continuous finger blood pressure (Portapres, Finapres), ECG (lead II, Spacelabs), Respiration (abdominal and thoracic, AMI Inductotrace) and EEG. Results of analyses using EEG is reported elsewhere. All signals were digitized on-line at a rate of 1000 samples/second. To align the physiological data with the music, a square wave pulse was inserted at the beginning of the songs. For each study, the subject was asked to provide a song of their choice which in their opinion “moves” them. Data were collected during 5 trials in each study: control (10 minutes), songs of slow and fast tempo, the song of the subject’s choice, and a phase scrambled version of the song of the subjects’ choice. Each song was 3-4 minutes long. To minimize cognitive response, we scrambled the phase of the song of the subject’s chosen song by segmenting the songs and scrambling the phase spectrum of that segment while preserving the magnitude spectrum. From the recorded data, time series of RR intervals were generated. These time series and the respiratory signals were low pass filtered (cut off 5Hz) and subsampled at a rate of 10 samples/second. From the subsampled data auto-spectra of RR intervals and respiration, coherencies and transfer functions between these signals were computed using Welch’s method. Results and Discussion:- The most pronounced effect during listening to songs was in respiration. In all but one subject, the mean respiratory rate increased relative to control while listening to songs. In addition to an increase in mean rate, the power distribution in the autospectra of respiration markedly narrowed during auditory stimulation. Similar changes were seen in RR interval spectra, the so called HF power, i.e. respiratory region power, was more narrowly distributed while listening to songs. Coherence between RR intervals and respiration exhibited a broad band increase during listening to songs as compared with control. Although there was a slight tendency during phase scrambled song for respiratory spectra to move closer to those during control, these differences were not very robust. Conclusion:- Our results show that auditory stimulation does entrain respiration as well as RR interval. Taken together, these results suggest that RR intervals were entrained by respiration while listening to both slow and fast tempo songs. The increase in average coherencies suggests entrainment of respiration to auditory stimulation which in turn entrains RR intervals. Further analyses using phase synchronization indexes would be useful to better reveal the causal links in these entrainment processes. Supported by a grant from the National Science Foundation (EPSCoR RII Track-2). 28

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