Mimicking the endogenous current of injury improves post-infarct cardiac remodeling

Abstract

Myocardial ischemia/reperfusion and infarction (I/R/I) is a leading cause of morbidity and mortality worldwide. The development of effective interventions for I/R/I has had only limited success due to the complex pathological processes of primary and secondary injury that follow I/R/I. Primary injury consists of cell death induced by the ischemic insult. Secondary injury results from activation of inflammatory processes that can induce secondary damage by apoptosis, lipid peroxidation, oxidative stress, or free radical formation. Thus the inflammatory and reparative response, after I/R/I, involves a complex, tightly controlled, and regulated cascade of events that lead to a replacement of the necrotic tissue with a collagen-rich scar. Timely activation and suppression of the inflammatory cascade and regulation of the reparative process is critical to prevent excessive tissue degradation, infarct expansion and heart failure. Accordingly, interventions that physiologically adjust the delicate balance between the essential and detrimental facets of inflammation are expected to provide new therapeutic opportunities. In this context, injury currents are endogenous, physiological mechanisms by which electrical fields interact with the innate immune system to modulate and restrain the inflammatory cascade and promote the reparative process. Accordingly, application of low intensity direct current (LIDC), by placing electrodes directly on the heart, and mimicking the current of injury is expected to enhance the complex biological mechanism of wound healing.

Introduction

In 1843, Dubois-Reymond measured a “current of injury” exiting human skin wounds. The current of injury emerging from wounds was later confirmed in subsequent studies [4], [21], [24], [34]. As the wound heals, the current of injury wanes [24]. This suggests that that the current of injury plays a significant role in wound healing [29], [38]. In fact, numerous studies have documented that the current of injury is an endogenous mechanism that promotes wound healing [29], [31], [37], [38], [41].

In 1880, Burdon-Sanderson described the effects of mechanical injury to the surface of the frog heart and noted that, during activity, the injured site was charged positively with respect to the non-injured surface. In the intervening years, many investigators have studied the effects of mechanical or ischemic injury on local extracellular electro-grams in the heart and established currents between the injured and non-injured myocardium [12], [25], [26], [28], [39], [43]. This current-of-injury mechanism is responsible for the deviation of the ST segment during myocardial injury resulting from myocardial ischemia and reperfusion. Under normal conditions, the ST segment is isoelectric because healthy myocardial cells attain approximately the same potential during the plateau phase of the ventricular action potential. Ischemia can reduce the resting membrane potential, shorten the duration of the action potential in the ischemic area, and decrease the rate of rise and amplitude of phase 0. These changes cause a voltage gradient between normal and ischemic zones that leads to current flow between these regions. These currents of injury are represented on the surface ECG by deviation of the ST segment.

Individuals who survive an acute myocardial infarction (AMI) are at risk of developing heart failure [33]. The development of heart failure is associated with changes in cardiac structure in the area of the infarction (increased chamber dilation, wall thinning and sphericity) as well as the non-infarcted regions of the ventricle (myocardial hypertrophy) and results in reduced cardiac function [11].

The process of cardiac repair, after an AMI, is a complex coordinated inflammatory reaction [16]. Specifically, complex and coordinated inflammatory reactions are required to ensure optimal repair and to prevent the development of adverse ventricular remodeling. Importantly, flaws and deviations in the temporal and spatial inflammatory reactions may have disastrous consequences [16]. For example, disproportionate early inflammation may augment matrix degradation causing cardiac rupture or activation of pro-apoptotic pathways causing additional loss of cardiomyocytes. Similarly, prolonged inflammatory reactions may impair collagen deposition leading to inadequate scar formation. Finally, failure to contain the inflammatory reaction may lead to extension of the inflammatory infiltrate into the non-infarcted myocardium enhancing fibrosis and worsening diastolic function [16].

Thus, the inflammatory reaction is necessary to protect the heart from disastrous consequences however an inappropriate inflammatory reaction may exacerbate the cardiac injury and alter the reparative process. Targeting the inflammatory reaction must focus on strategies that ensure optimal temporal and spatial regulation of the inflammatory response by preventing uncontrolled or prolonged inflammation [6], [8]. From this perspective, attempts should be made to activate an endogenous anti-inflammatory pathway. LIDC may be a therapeutic option for optimal temporal and spatial regulation of the inflammatory response by preventing uncontrolled or prolonged inflammation.

In 2002, electrical stimulation was approved for Medicare coverage as a wound-healing strategy [10]. The approval of electrical stimulation constitutes an indication of the growing acceptance and evidence for its application in wound healing [3]. Indeed, numerous reports support the use of electrical stimulation for enhancing wound healing [2], [5], [9], [13], [14], [17], [18], [19], [23], [27], [30], [35], [40], [45], [46]. The rational for the use of electrical stimulation for wound healing is the documentation that the injured tissue produces a current, the current of injury, which promotes healing. However, the current of injury gradually wanes resulting in delayed or limited wound healing [1], [7], [20], [22], [47]. Thus, external application of current mimicking the current of injury is expected to accelerate the healing process. Accordingly, low intensity direct current, by placing electrodes directly on the heart, is expected to mimic the natural electric field/current created following injury (injury current), and improve post-infarct cardiac remodeling (Fig. 1).

At the clinical level, this approach has the potential for a major impact because the technology for the application of LIDC is currently in use. Specifically, implantable cardiac defibrillators (ICD) are small battery powered electrical impulse generators that are implanted in patients at risk of sudden cardiac death. The generators typically include electrode wire(s) that pass via a vein into the apex of the right ventricle. The ICDs function as a permanent safeguard against sudden arrhythmias. It is likely that LIDC, with a similarly implanted DC generator, will mimic the natural electric field/current created following injury, and enhance the complex biological mechanism of wound healing.