Intermittent Vagus Nerve Stimulation Reflexively Modulates Heart Rate Variability in Rats With Chronic Ischemic Heart Failure

Abstract

Heart disease is the leading cause of death in the developed world. Despite major strides made in the past decade regarding the treatment and prevention of heart disease, cardiac injury due to acute myocardial infarct (MI) remains a difficult and complicated problem to solve. When enough tissue damage occurs in the myocardium, the ability of the heart to circulate blood is reduced and the organ changes shape in a maladaptive attempt to compensate for its lack of pumping capacity, ultimately leading to an even greater lack of circulatory output known as heart failure. Such tissue damage begins for a great number of patients the downward spiral termed ‘heart failure’ which culminates almost certainly at death. At rest, the heart rate of healthy individuals exhibits spontaneous variation as a result of respiratory-driven neural modulation of sinus node function (respiratory sinus arrhythmia, RSA). Heart rate variability (HRV) is defined as time-domain variations of the R-R intervals in the electrocardiogram. HRV driven primarily by RSA is strongly influenced by cholinergic nerve activity in and on the heart. Depressed parasympathetic activity within the autonomic nervous system resulting from cardiovascular disease has been linked to significantly diminished HRV in humans suffering with chronic heart failure (CHF). CHF is associated with autonomic dysregulation characterized by a sustained increase in sympathetic activity and decrease in parasympathetic activity [1]. Mainstream methods of nervous system modulation include beta-blockers, aldosterone agonists, and ACE inhibitors. Recently, modulation of parasympathetic activity through cardiac vagal nerve stimulation (VNS) has emerged as a potential therapy for CHF. VNS has been shown to prevent cardiac remodeling, eventually leading to an improved prognosis of HF rats after initial MI [2]. VNS also inhibited sudden cardiac death in dogs with MI [3] and markedly suppressed arrhythmias in conscious rats [4]. Chronic VNS may even improve quality of life and LV function in CHF patients with severe systolic dysfunction [5]. Recently, lowlevel VNS was implemented to reduce atrial tachyarrhythmia in ambulatory dogs [6]. Implantable VNS stimulators are currently undergoing human clinical trials for possible future use as a CHF therapy [8]. While human trials may be advancing, little is still known about the underlying antiarrhythmic mechanisms of VNS. VNS may indeed present a very promising future therapy for patients suffering from CHF, but further work is necessary to develop a reliable and efficacious treatment. Here we investigated changes induced in in-vivo MI heart rat model by means of chronic VNS. Specifically, we focused on changes in heart rate, and HRV. The objective of this paper was to investigate the changes induced in in-vivo MI heart rat model by means of chronic VNS. Specifically, we focused on changes in heart rate, and HRV that followed after chronic stimulation in 8-week animal study. Because VNS will soon be used for human CHF therapy, we must know how clinically relevant parameters such as HRV respond to VNS therapy and specifically, how they may change over time.