Device-Based Sympathetic Nerve Regulation for Cardiovascular Diseases

Sympathetic overactivation plays an important role in promoting a variety of pathophysiological processes in cardiovascular diseases (CVDs), including ventricular remodeling, vascular endothelial injury and atherosclerotic plaque progression. Device-based sympathetic nerve (SN) regulation offers a new therapeutic option for some CVDs. Renal denervation (RDN) is the most well-documented method of device-based SN regulation in clinical studies, and several large-scale randomized controlled trials have confirmed its value in patients with resistant hypertension, and some studies have also found RDN to be effective in the control of heart failure and arrhythmias. Pulmonary artery denervation (PADN) has been clinically shown to be effective in controlling pulmonary hypertension. Hepatic artery denervation (HADN) and splenic artery denervation (SADN) are relatively novel approaches that hold promise for a role in cardiovascular metabolic and inflammatory-immune related diseases, and their first-in-man studies are ongoing. In addition, baroreflex activation, spinal cord stimulation and other device-based therapies also show favorable outcomes. This review summarizes the pathophysiological rationale and the latest clinical evidence for device-based therapies for some CVDs.

Interaction Between the Intestinal Microbial Community and Transcriptome Profile in Common Carp (Cyprinus carpio L.)

In a previous study, we found that the growth performance of the new strain of Huanghe carp is related to gene expression and bacterial community in the gut. In order to better understand the relationship between the gene expression level and bacterial abundance in the gut, we studied the growth performance, gut bacterial structure, and transcriptome profile in the 4th generation of the new carp strain (selection group) at harvesting time, and compared them with the control line (traditional Huanghe carp). Body weight, depth, width, and length increased 14.58, 7.14, 5.04, and 5.07%, respectively. The gut microbiome of the selection group also exhibited significantly higher species diversity parameters (Shannon, Simpson, and chao1). Both PCA and phylogenetic analyses divided all gut samples into two parts: control and selection group. Aeromonas was the dominant taxon in the control group, followed by Firmicutes and Roseomonas; in the selection group, Roseomonas was the dominant taxon, followed by Firmicutes and then Aeromonas. Among the 249 significantly differentially expressed genes, 194 were downregulated and 55 were upregulated. Functional GO annotation produced 13 terms in the biological process, 8 in the cellular component, and 7 in the molecular function categories. KEGG annotation indicated that most of these genes were associated with the immune-related pathways. A total of 2,892 pairs of genes (245) and baceterial genera (256) were analyzed using Pearson’s correlation analysis. Most of the identified associations were mapped to the immune system, bacterial community, and cell differentiation categories. The top-10 bacterial genera identified by these analyses were Methylocystis, Ohtaekwangia, Roseomonas, Shewanella, Lutispora, GpVI, Desulfovibrio, Candidatus_Berkiella, Bordetella, and Azorhizobium. Genes paired with bacteria flora were divided into four functional categories: immune, growth, adipocyte differentiation, and nerve regulation. These genes may be related to the comparatively fast growth and high muscle polyunsaturated fatty acid content of the Huanghe carp new strain. Meanwhile, nerve regulation-related genes may be a reflection of the microbiota-gut-brain axis. These results illustrate that gut bacterial community structure is associated with the growth performance and gene expression in the Huanghe carp new strain.

Abstract 327: Attenuated Beta-Adrenergic Response in the Tric-a Knock Out Mice

Trimeric intracellular cation (TRIC) channels are expressed on the surface of sarcoplasmic reticulum (SR) and regulate calcium release from ryanodine receptors (RyRs). In a previous study, Tric-a knock out (KO) mice showed diminished calcium release from RyRs following increased calcium-influx via L-type calcium channels, which results in enhanced vascular resistance and non-dipper type hypertension. Decreased activation of RyR1 by PKA in skeletal myocytes in Tric-a KO mice is also known. However, physiological importance of TRIC channels on cardiac rhythm formation and its importance on the sympathetic nerve regulation are still obscure. Therefore, we aimed to clarify the effects of Tric-a ablation on cardiac pace making using Tric-a KO mice. We measured systolic blood pressure (SBP) with tail-cuff method, ECG and spontaneous action potential with microelectrode in the Tric-a KO and wild type (WT) mice. Isoproterenol or propranolol was used for sympathetic nerve manipulation. Furthermore, we evaluated heart rate variability (HRV). Tric-a KO mice tended to show limited responses to isoproterenol (0.3 mg/kg) than the WT mice (-27 ± 6 and -32 ± 6 mmHg, n = 10, p =0.70), and to propranolol (4 ± 6 and 13 ± 7 mmHg, n = 5~6, p =0.48). In ECG analysis, ablation of Tric-a gene resulted in significantly decreased heart rate changes to isoproterenol (23 ± 6 and 99 ± 15 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). Response to propranolol was also significantly decreased in the Tric-a KO mice (-28 ± 20 and -122 ± 14 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). In the action potential recordings, Tric-a KO mice showed significantly decreased sinus rate changes to 1 microM isoproterenol (35 ± 9 and 71 ± 10 bpm, Tric-a KO and WT mice, respectively, n = 6~8, p <0.05). In HRV analysis, low-frequency/high-frequency (LF/HF) ratio tended to be lower in the Tric-a KO mice than the WT mice under the administration of isoproterenol (0.22 ± 0.31 and 0.65 ± 0.16 bpm, Tric-a KO and WT mice, respectively, n = 9~11, p =0.16), suggesting lower sympathetic nerve tonus in the Tric-a KO mice. In conclusion, our data indicates that Tric-a KO mice showed attenuated responses to beta-adrenergic stimulus, which indicates involvement of TRIC-A channels in sympathetic nerve regulation.