Low-Level Transcutaneous Vagus Stimulation in ST Segment Elevation Myocardial Infarction: TREATMI Study

SPECIFIC AIMS:

1. Study the effects of TVNS on inflammation in patients with STEMI.
2. Determine the clinical impact of TVNS on 30, 3,6 and 12-month clinical outcomes in patients with STEMI.

B: BACKGROUND AND SIGNIFICANCE:

ST elevation myocardial infarction (STEMI) is the leading cause of death in United States.1 Improved survival following myocardial infarction has largely been due to the contribution of timely reperfusion strategies and advanced pharmacologic management (anti-coagulant and anti-platelet strategies).2 With acute myocardial infarction follows the accompaniment of a systemic and local inflammatory reaction involving both humoral and cell mediated inflammation, which is important in healing and scar formation.3,4 Reperfusion of ischemic myocardium sets the stage for an inflammatory response for the repair and remodeling of the ischemic territory. Experimental evidence has shown that the complement cascade plays an important role in triggering inflammation.3,4 These mechanisms drive the formation of the inflammasome resulting in the release of interleukin (IL)-1 activating expression of inflammatory mediators in necrotic myocardium.5 C-reactive protein (CRP) and IL-6 levels have been shown to correlate to infarction size post-percutaneous coronary intervention.6 Tumor necrosis factor (TNF- α) may be a predominant factor in up regulating the production of IL-6. The presence of significant levels of TNF- α post MI has been shown to correlate to infarct size and recurrent myocardial infarction.4,7 IL-10, an anti-inflammatory marker is important during the late phase of acute inflammation within myocardium in helping to inhibit inflammation while attenuating remodeling, increasing capillary density and improving left ventricular function.8 Expression of TGF-beta isoforms increases in necrotic myocardial regions and may exert anti-inflammatory effects by down regulating proinflammatory cytokine production, chemokine and adhesion molecule synthesis and promoting differentiation of inhibitory lymphocyte subsets. Lastly, TGF- β promotes matrix-stabilizing effects and is key in matrix remodeling and fibrosis in post myocardial infarction tissue and in chronic heart failure.5 Brunetti et. al. outlined the trend in inflammatory biomarkers such as CRP, ESR, and fibrinogen in patients presenting with STEMI receiving fibrinolytic therapy. They reported a peak level of such markers on day 2-3 post-STEMI.9 In a similar study by Brunetti et. al. it was also noted that higher TNF- α levels were associated with subsequent adverse cardiac events.10 Pudil et. al studied the variation in the levels of IL-6, CRP and TNF-alpha among 24 acute myocardial infarction (AMI) patients over 96 hours and determined that IL-6 and TNF- α levels were continually high during the 96 hours, however CRP increased later than IL-6 and peaked at 42 hrs after AMI.11 IL-6 levels seem to be elevated more so in the first 1-3 days following AMI with levels persistently elevated even 3 weeks after AMI.12 Inflammation plays a key role in atherogenesis and several complex interconnected pathways exist that modulate inflammation in STEMI. There remains an intense interest to identify anti-inflammatory therapies that may help reduce the risk of cardiovascular events. A recently published study with an anti-inflammatory agent Losmapimod ( p38 mitogen activated protein kinase), failed to demonstrate any improvement in clinical outcomes.13 It is thought that due to the interplay of several inflammatory cascades, targeting one particular pathway may not provide the desired impact on inflammatory milieu and clinical outcomes.

To the investigator's knowledge, there is no data that suggests that modulating the autonomic nervous system via TVNS (by increasing the parasympathetic tone and reducing the sympathetic nervous system activity) would lead to a reduction in the circulating pro-inflammatory cytokines in patients with STEMI. Since this concept has not been tested previously, the investigators embark on the idea of using autonomic modulation via TVNS to reduce the level of systemic inflammation that is rampant in patients admitted with STEMI.