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Chronic Atrial and Ventricular Pacing in the Mouse.

ABSTRACT: BACKGROUND:The mouse is the most widely used mammal in experimental biology. Although many clinically relevant in vivo cardiac stressors are used, one that has eluded translation is long-term cardiac pacing. Here, we present the first method to chronically simulate and simultaneously record cardiac electrical activity in conscious mobile mice. We then apply it to study right ventricular pacing induced electromechanical dyssynchrony and its reversal (resynchronization). METHODS AND RESULTS:The method includes a custom implantable bipolar stimulation and recording lead and flexible external conduit and electrical micro-commutator linked to a pulse generator/recorder. This achieved continuous pacing for at least 1 month in 77% of implants. Mice were then subjected to cardiac ischemia/reperfusion injury to depress heart function, followed by 4 weeks pacing at the right ventricle (dyssynchrony), right atrium (synchrony), or for 2 weeks right ventricle and then 2 weeks normal sinus (resynchronization). Right ventricular pacing-induced dyssynchrony substantially reduced heart and myocyte function compared with the other groups, increased gene expression heterogeneity (>10 fold) comparing septum to lateral walls, and enhanced growth and metabolic kinase activity in the late-contracting lateral wall. This was ameliorated by restoring contractile synchronization. CONCLUSIONS:The new method to chronically pace conscious mice yields stable atrial and ventricular capture and a means to dissect basic mechanisms of electromechanical physiology and therapy. The data on dyssynchrony and resynchronization in ischemia/reperfusion hearts is the most comprehensive to date in ischemic heart disease, and its similarities to nonischemic canine results support the translational utility of the mouse.

SUBMITTER: Stahlberg M

PROVIDER: S-EPMC6513021 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Chronic Atrial and Ventricular Pacing in the Mouse.

Ståhlberg Marcus M Nakagawa Ryo R Bedja Djahida D Zhu Guangshuo G Lin Brian L BL Saberi Amir A Lee Dong I DI Kass David A DA

Circulation. Heart failure 20190201 2

<h4>Background</h4>The mouse is the most widely used mammal in experimental biology. Although many clinically relevant in vivo cardiac stressors are used, one that has eluded translation is long-term cardiac pacing. Here, we present the first method to chronically simulate and simultaneously record cardiac electrical activity in conscious mobile mice. We then apply it to study right ventricular pacing induced electromechanical dyssynchrony and its reversal (resynchronization).<h4>Methods and res ...[more]

PMID: 30764638

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Project description:Sustained atrial tachycardia leads to multiple molecular and cellular effects collectively defined as atrial tachycardia remodeling (ATR). ATR is thought to play a major role in the self-perpetuating nature of atrial fibrillation (AF) and has been a subject of intense research in large mammalian models of AF. Recently, rodents are increasingly used to gain insight on the pathophysiology AF. However, little is known regarding the effects of rapid pacing on the atria of rats and mice mainly due to technical challenges in electrophysiological studies of unanesthetized rodents. Using an implantable device for electrophysiological studies in unanesthetized rodents we examine, on a daily basis, the effects of continuous rapid atrial pacing (RAP) for at least 4 consecutive days on the developed AF substrate of Sprague-Dawley rats and C57BL6 mice. AF induction protocol consisted 10 aggressive bursts (20 seconds, double diastolic threshold, 10 ms cycle length [CL]). This protocol failed to induce AF at baseline in both species, but repeatedly induced AF episodes in rats following 2 days of sustained RAP. Microarray study of left atrial tissue from rats exposed for 2 days to RAP (70 ms CL) vs control pacing (140 ms CL) identified 304 differentially expressed genes (155 upregulated and 149 downregulated). Real-time qt-PCR confirmed the validity of the microarray. Enrichment analysis and comparison with a dataset of atrial tissue from AF patients revealed indications of increased carbohydrate metabolism, and changes in pathways that are thought to have critical role in human AF including TGF-beta and IL-6 signaling. Among 19 commonly affected genes in comparison with human AF, downregulation of FOXP1 and upregulation of the KCNK2 gene encoding the Kir2.1 potassium channel were conspicuous finding suggesting NFAT activation. Further results in line with NFAT activation included reduced expression of MIR-26, MIR-101, which were linked to upregulation of the KCNK2 in human AF. Our results demonstrate electrophysiological evidence for AF promoting effects of RAP in rats and some important molecular similarities between the effects of RAP in large and small mammalian models. The effects of atrial tachypacing are well documented in large mammals but very little is know regarding the effects of tacypacing on the rodent atria.

Project description:BackgroundRecent studies suggested that the left bundle branch area pacing (LBBAP) has a better efficacy to reduce QRS duration and produce a lower pacing threshold than the conventional right ventricular outflow tract septal pacing (RVOP), which resulted in a better cardiac function and ventricular synchronization. However, whether the LBBAP has a better efficacy in improving left atrial structure, function in pace-dependent patients compared with RVOP has not been well studied.ObjectiveThe purpose of this study was to compare the atrial outcomes of pace-dependent patients who received LBBAP or RVOP procedures.Methods and resultsA total of 72 patients (including II° AVB, high AVB, and III° AVB, excluding atrial fibrillation patients with atrioventricular block) consecutively enrolled in this single-center prospective clinical study and randomly assigned to the RVOP group and the LBBP group with 36 patients. All patients were pace-dependent. The changes in echocardiogram, speckle-tracking echocardiography, brain natriuretic peptide (BNP), and 6-min walking distance were documented and compared between two groups at baseline, 7 days, 1, 3, and 6 months after the implantation. There were no significant differences in baseline characteristics between the two groups. The results of the study were as following: (1) left atrial structure index: Our study indicated that there are no significant differences in left atrial anteroposterior dimension (LAAPD), left atrial superoinferior dimension, and left atrial mediolateral dimension between two groups. While the LAAPD in the LBBAP group was significantly reduced at 6 months after implantation ([38.22 ± 2.17] mm vs. [34.13 ± 1.59] mm, p < .05). (2) Left atrial strain index: We observed that the S% was significantly improved in both groups at 3 and 6 months after implantation but more prominent in the LBBAP group at 6 months (36.94 ± 11.67 vs. 25.87 ± 8.93, p = .01). SRs, SRe were improved in the RVOP group at 6 months after implantation but was further significantly increased in the LBBAP group. Similarly, the SRa in the LBBAP group was significantly better than the RVOP group after 6 months (-2.11 ± 0.75 vs. -2.51 ± 0.70, p = .04). (3) Left atrial ejection index: LAEF% in the LBBAP group was significantly improved compared with the RVOP group (60.02 ± 1.88 vs. 53.65 ± 2.45, p = .047) and baseline (60.02 ± 1.88 vs. 49.68 ± 2.75, p < .05) at 6 months after the surgery. (4) Left ventricular ejection index: The LVEF% in the LBBAP group was significantly increased than the RVOP group after 6 months (69.14 ± 4.99 vs. 64.60 ± 4.84, p = .01) and the BNP level was significantly lower in the LBBAP group compared with the RVOP group at 7 days, 1, 3, and 6 months after implantation (p < .05). (5) 6-min walking distance: the 6-min walking distance was significantly increased at 3 and 6 months after implantation compared with that before (p < .05) in both groups, but was more prominent in LBBAP groups ([483.03 ± 11.02] m vs. [431.09 ± 10.69] m,p < .05).ConclusionCompared with the traditional RVOP, the LBBAP procedure increased left atrial myocardial stress as well as left atrial ejection in pace-dependent patients at follow-up to 6 months.

Dataset Information

Chronic Atrial and Ventricular Pacing in the Mouse.

Publications

Chronic Atrial and Ventricular Pacing in the Mouse.

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