Short-term disruption in regional left ventricular electrical conduction patterns increases interstitial matrix metalloproteinase activity

Abstract

Increased matrix metalloproteinase (MMP) abundance occurs with adverse left ventricular (LV) remodeling in a number of cardiac disease states, including those induced by long-standing arrhythmias. However, whether regionally contained aberrant electrical activation of the LV, with consequent dyskinesia, alters interstitial MMP activation remained unknown. Electrical activation of the LV of pigs (n ϭ 10, 30 -35 kg) was achieved by pacing (150 beats/min) at left atrial and LV sites such that normal atrioventricular activation (60 min) was followed by regional early LV activation for 60 min within 1.5 cm of the paced site and restoration of normal atrioventricular pacing for 120 min. Regional shortening (piezoelectric crystals) and interstitial MMP activity (microdialysis with MMP fluorogenic substrate) at the LV pacing site and a remote LV site were monitored at 30-min intervals. During aberrant electrical stimulation, interstitial MMP activity at the paced site was increased (122 Ϯ 4%) compared with the remote region (100%, P Ͻ 0.05). Restoration of atrioventricular pacing after the 60-min period of aberrant electrical activation normalized segmental shortening (8.5 Ϯ 0.4%), but MMP activity remained elevated (121 Ϯ 6%, P Ͻ 0.05). This study demonstrates that despite the restoration of mechanical function, disturbances in electrical conduction, in and of itself, can cause acute increases in regional in vivo MMP activation and, therefore, contribute to myocardial remodeling. myocardium; interstitium ACUTE AS WELL AS CHRONIC ACTIVATION of matrix metalloproteinases (MMPs) within the myocardium can disrupt the integrity of the extracellular matrix (ECM) and, consequently, affect interstitial protein content, stability, and bioactive signaling pathways (9,14,19). Mechanical stimuli, such as abnormal myocardial stress and strain patterns, can also result in MMP induction (8,12,20). In this context, Garcia et al. (11) demonstrated that acute arrhythmias can disrupt electrical activation pathways and, therefore, induce alterations in the stretch/ contraction patterns of the myocardium and serve as a primary impetus for MMP activation and a potential nidus for stimuli to propagate a remodeling process. For example, previous studies (1, 22) have shown that short-duration disruption of electrical conduction induced in the atria can progress to the development of a sustained arrhythmia with associated remodeling of the myocardium. However, whether and to what degree an increase in MMP induction as a result of acute changes in electrical activation persist after the restoration of normal conduction patterns remain unknown. Therefore, the present study was designed to test the hypothesis that short-term (i.e., acute) alterations in the electrical activation of the myocardium would cause in vivo MMP activation and that the restoration of electrical conduction would normalize interstitial MMP activity. METHODS Instrumentation. Animals were treated and cared for in accordance with the National Institutes of Health Guide for the C...

Ventricular pacing-induced loss of contractile function and development of epicardial inflammation

“…Alternatively, the use of a greater electrical current during suprathreshold stimulation may also be sufficient to trigger the degranulation of neutrophils. This hypothesis is supported by the results of Mukherjee et al (12), where 60 min of LV pacing in the presence of dyskinesis was sufficient to trigger MMP activation and collagen degradation.…”

“…The differences likely arise from variations used in the implementation of the zymography technique and the large number of samples examined. A recent study (12) reported on increases in Values are means Ϯ SE; n ϭ 9 for the nonpaced group, 5 for the subthreshold group, and 9 for the suprathreshold group. HR, heart rate; LVSP, left ventricular (LV) systolic pressure; LVEDP, LV end-diastolic pressure; ϩdP/dt, increase of LV pressure; ϪdP/dt, decrease of LV pressure; N/A, not applicable.…”

“…A mechanism that can account for loss of contractile function relates to increases in MMP activity and the resulting degradation of collagen (8,12). Damage to the extracellular matrix superstructure can lead to myocyte slippage and loss of contractile function (8,20).…”

Targeted Imaging of the Spatial and Temporal Variation of Matrix Metalloproteinase Activity in a Porcine Model of Postinfarct Remodeling

“…Some in vitro models have shown that fibroblasts grown on mechanically relaxed collagen I produced high levels of MMP-2 and MT1-MMP 26 , while others have shown that cyclic stretching of myofibroblasts causes increased MT-MMP activity 27 . Altering the mechanical activation pattern of a region of the LV free wall in vivo increased MMP-9 levels, interstitial MMP activity, and increased collagen degradation 19, 28 . Rohde et.…”

“…A specific global MMP fluorogenic substrate (Enzo Life Sciences BML-P126; excitation 330 nm; emission 405 nm) was utilized to measure MMP activity within the tissue homogenates 19, 20 . Briefly, 30 μM of the fluorogenic MMP substrate was incubated with myocardial tissue extract (25 μg) and fluorescence of the cleaved substrate recorded (FLUOstar, BMG Labtech, Durham, NC).…”