Advances in heart failure (HF) therapeutics over the last 20 years have led to widespread acceptance and use of oral antagonists of the renin–angiotensin–aldosterone (RAAS) and sympathetic nervous (SNS) systems [1, 2] in patients with a depressed ejection fraction. In addition, implantable cardioverter defibrillators and cardiac resynchronization devices (CRT) have been widely adopted in both practice guidelines and clinical care [3–5]. Nevertheless, with the aging of the population and rising disease prevalence, interest in the development of newer approaches has continued, and several are now under investigation [6, 7]. The need for novel paradigms is further highlighted by the fact that intensification of antagonism of the RAAS has not been shown to reduce mortality [8–10], and other pharmacologic and device approaches including anticytokine therapy, epicardial constraining devices, and novel stimulation technologies have not been convincingly associated with improvements in hard clinical outcomes [11–13]. There are also multiple clinical scenarios that suggest areas of unmet need in HF such as CRT non-responders and patients who are not candidates for CRT due to narrow complex QRS morphologies [14, 15]. Thus, there continues to be a need for innovative therapies for patients with heart failure.

One area of recent focus in heart failure research has been the role of autonomic imbalance. In particular, there is increasing evidence that in addition to increased sympathetic activation, parasympathetic withdrawal may also contribute to the pathogenesis of heart failure [16]. However, while beta-blockade has found its place as a leading disease modifying therapy that impacts the sympathetic nervous system, far less is known about methods to augment parasympathetic function.

In this context, the topics of vagus nerve anatomy, physiology and influence on cardiac function are reviewed in detail in the current issue of Heart Failure Reviews. These papers form a foundation for understanding the clinical potential of a new intervention, vagus nerve stimulation (VNS). Pre-clinical data (including models of acute ischemia and chronic failure) and phase II experience in Europe with VNS are reviewed as are other potential ways to influence vagus nerve function.

The current issue begins with a historical overview of experimental physiologic and clinical-translational work performed by Dr. Peter Schwartz and colleagues, on parasympathetic–sympathetic interactions in both ischemic heart disease and heart failure [17]. Drs. Chapleau and Sabharwal provide a highly detailed review of the concepts of cardiovagal tone, parasympathetic modulation, parasympathetic re-activation, and reflex changes in heart rate and the methods used to assess them [18]. Normal vagus nerve anatomy is described in an elegant paper by Bibevski and Dunlap, who discuss the multitude of potential sites that might contribute to impaired parasympathetic nerve activity and offer evidence that points to specific locations of the defects, including the post-ganglionic nicotinic acetylcholine receptor [19]. The potential mechanisms that mediate the effects of VNS in heart failure are discussed by Li and Olshansky, who review the influence of efferent and afferent limbs of the parasympathetic system on inflammation, as well as the role of nitric oxide [20]. Vagus nerve stimulation is also a focus of several other papers, including a comprehensive review by Zhang and Mazgalev on the impact of stimulation on atrial fibrillation, atrioventricular conduction, and ventricular arrhythmia generation [21]. An overview of the safety of VNS is provided by Cohen and Georgievskaya who first describe the impact of various forms of nerve injury (compressive, inflammatory, and electrical) and then present a histopathological evaluation of the effects of stimulation on the vagus nerve itself, using tissue derived from pre-clinical studies [22]. These safety assessments are important in light of the data generated by Sabbah [23] demonstrating that VNS has a beneficial effect on left ventricular remodeling in the canine infarct model [23]. Indeed, these experimental data provided ample support for the initiation of human studies, including a recently completed open label study in patients with left ventricular dysfunction and advanced heart failure symptoms despite optimal medical therapy [7, 24]. VNS is of course only one methodology by which parasympathetic tone can theoretically be increased. In a review of pharmacologic studies, Desai and colleagues describe often conflicting data that have been published on the impact of conventional heart failure medications on indices of parasympathetic system function. They also outline the limitations of human studies including the use of surrogate end points such as heart rate variability [25].

The long arc from anatomic and physiologic studies to pre-clinical experiments to clinical trials in humans is summarized by de Ferrari and Schwartz in a thoughtful concluding paper [26]. Taken together, the articles presented in this issue of heart failure reviews suggest that augmentation of parasympathetic tone is an attractive therapeutic target in patients with heart failure and a depressed ejection fraction. Nevertheless, as highlighted by a number of the contributors, important gaps in knowledge remain. Therefore, despite preliminary efficacy signals, the final evaluation of VNS requires the ultimate test: a large clinical trial.