Biventricular Pacing Cardiac Contractility Modulation Improves Cardiac Contractile Function via Upregulating SERCA2 and miR-133 in a Rabbit Model of Congestive Heart Failure

Abstract

Objective: To compare the effects of biventricular electrical pacing and conventional single-ventricular pacing for cardiac contractility modulation (CCM) on cardiac contractile function and to delineate the underlying molecular mechanisms. Methods: Forty rabbits were divided into four groups before surgery: healthy control, HF sham, HF left ventricular pacing CCM (LVP-CCM), and HF biventricular pacing CCM (BVP-CCM) groups with n=10 for each group. A rabbit model of chronic heart failure was established by ligating ascending aortic root of rabbits. Then electrical stimulations during the absolute refractory period were delivered to the anterior wall of left ventricle in the LVP-CCM group and on the anterior wall of both left and right ventricles in the BVP-CCM group lasting six hours per day for seven days. Changes in ventricular structure, cardiac function and electrocardiogram were monitored before and after CCM stimulation. Results: Compared with the sham-operated group, heart weight, heart weight index, LV end-systolic diameter (LVESD), LV end-diastolic diameter (LVEDD) in the LVP-CCM and BVP-CCM groups were significantly decreased (p<0.05), while LV ejection fraction (LVEF) and fractional shortening fraction (FS) were increased (p<0.05). Notably all these changes were consistently found to be greater in BVP-CCM than in LVP-CCM. Moreover, plasma BNP levels were highest in the HF sham-control group, followed by the LVP-CCM group, and lowest in the BVP-CCM group (p<0.05). Furthermore, sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) protein levels were upregulated by 1.7 and 2.4 fold, along with simultaneous upregulation of a cardiac-enriched microRNA miR-133 levels by 2.6 and 3.3 fold, in LVP-CCM and BVP-CCM, respectively, compared to sham. Conclusions: Biventricular pacing CCM is superior to conventional monoventricular pacing CCM, producing greater improvement cardiac contractile function. Greater upregulation of SERCA2 and miR-133 may account, at least partially, for the improvement by BVP-CCM.

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

“…It has also been reported that CCM has a favorable effect on cardiac remodeling by echocardiography and histological assessment and normalizes expressions of key cytoskeleton proteins and matrix metalloproteinase (MMPs) [13][14][15]. Our previous study has demonstrated that CCM could normalize the expression of SERCA2a/phospholamban and miR-133 in CHF rabbits, which contributes to the multiaspect cardioprotective action of CCM [16].…”

“…The rabbit model of CHF induced in the present study was previously described in detail [16]. Briefly, following the induction of anesthesia in rabbit via ear vein administration of 3% sodium pentobarbital at 1 ml/ kg body weight, the thoracic cavity was opened.…”

“…As detailed previously, the signals consisted of a biphasic square-wave pulses with phase duration=2 ms, stimulus amplitude=7 V, and 30 ms delay after R-wave sensing [16]. CCM signals lasted 6 hours per day for consecutive 4 weeks.…”

“…Emerging evidences showed miR-133 could improve the fibrosis process by regulating the expression levels of TGF-β1 and CTGF [22,23]. We have previously demonstrated that CCM unregulated miR-133 level, which benefited cardiac function [16]. In this study, we sought to investigate the potential relationship between CCM and TGF-β1/Smad3 signaling pathway in a rabbit model of CHF and to explore the role of CCM in myocardial fibrosis.…”

Non-Coding RNAs in Cardiac Aging

“…Mature miRNAs through pairing to the 3′-untranslated (3′UTR) region to inhibit target genes mRNA translation or promote mRNA degradation [24]. As a class of regulatory molecules, miRNAs participate in many physiological and pathological processes including heart development [25], regeneration [26], hypertrophy [27], contractility [28] and fibrosis [29]. MiRNAs have recently emerged as important regulators of cellular senescence and aging.…”