Intermittent pacing therapy favorably modulates infarct remodeling

Abstract

Despite early revascularization, remodeling and dysfunction of the left ventricle (LV) after acute myocardial infarction (AMI) remain important therapeutic targets. Intermittent pacing therapy (IPT) of the LV can limit infarct size, when applied during early reperfusion. However, the effects of IPT on post-AMI LV remodeling and infarct healing are unknown. We therefore investigated the effects of IPT on global LV remodeling and infarct geometry in swine with a 3-day old AMI. For this purpose, fifteen pigs underwent 2 h ligation of the left circumflex coronary artery followed by reperfusion. An epicardial pacing lead was implanted in the peri-infarct zone. After three days, global LV remodeling and infarct geometry were assessed using magnetic resonance imaging (MRI). Animals were stratified into MI control and IPT groups. Thirty-five days post-AMI, follow-up MRI was obtained and myofibroblast content, markers of extracellular matrix (ECM) turnover and Wnt/frizzled signaling in infarct and non-infarct control tissue were studied. Results showed that IPT had no significant effect on global LV remodeling, function or infarct mass, but modulated infarct healing. In MI control pigs, infarct mass reduction was principally due to a 26.2 ± 4.4% reduction in infarct thickness (P ≤ 0.05), whereas in IPT pigs it was mainly due to a 35.7 ± 4.5% decrease in the number of infarct segments (P ≤ 0.05), with no significant change in infarct thickness. Myofibroblast content of the infarct zone was higher in IPT (10.9 ± 2.1%) compared to MI control (5.4 ± 1.6%; P ≤ 0.05). Higher myofibroblast presence did not coincide with alterations in expression of genes involved in ECM turnover or Wnt/frizzled signaling at 5 weeks follow-up. Taken together, IPT limited infarct expansion and altered infarct composition, showing that IPT influences remodeling of the infarct zone, likely by increasing regional myofibroblast content.

Keywords: Infarct expansion; Infarct geometry; Infarct healing; Myocardial infarction; Myofibroblasts; Swine.

Fig. 1

Effect of IPTVVI on infarct geometry. Percent changes in infarct geometry from 3 days baseline values at 5-week follow-up in eight MI control (white bars) and six IPTVVI (gray bars) swine. Shown are changes in infarct mass, infarct thickness, total number of infarcted segments, number of infarcted slices, and average circumferential infarct length. Data are mean ± SEM; *P ≤ 0.05 vs. corresponding BL; ^† P ≤ 0.05, ^†† P ≤ 0.10, vs. change in MI control

Fig. 2

IPTVVI increases myofibroblast presence in the infarct region. Left panel αSMA stained infarct tissue of two MI control and two IPTVVI swine (magnification ×20). Brown staining indicates myofibroblasts. Right panel percent αSMA-positive cells in infarct tissue from eight MI control (white bar) and six IPTVVI (gray bar) swine. Data are mean ± SEM; *P ≤ 0.05 vs. MI control

Fig. 3

Circulating levels of markers of extracellular matrix and inflammation. Markers for extracellular matrix and inflammation in arterial plasma of five control (white bars) and five IPTVVI (gray bars) swine. Data are mean ± SEM; *P ≤ 0.05 vs. MI control