Basic research models for the study of underlying mechanisms of electrical neuromodulation and ischemic heart-brain interactions

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The study of mechanisms of action underlying the use of electrical neuromodulation for angina and myocardial ischemia may illuminate heart-brain interactions that influence these conditions. To investigate these mechanisms of action, we initiated a neurocardiology program in the 1990s. This review discusses the experimental models we have studied to unravel the heart-brain interactions involved in the use of electrical neuromodulation for ischemic disease.




In the industrialized world, average life expectancy has nearly doubled since the 19th century. One of the consequences of this increase in life span is that the sequelae of diseases also have increased. For coronary artery disease (CAD), one of the most prevalent diseases in the western world, this has resulted in an amplification of the number of patients suffering from heart failure, arrhythmias, and refractory angina. Much progress has recently been made in nonpharmacologic therapies for these deleterious consequences of CAD, such as cardiac resynchronization for heart failure, implantable defibrillators for ventricular arrhythmias, and electrical neuromodulation by means of spinal cord stimulation for chronic angina that is refractory to conventional strategies.

For patients suffering from severe angina secondary to end-stage CAD who have no other options to alleviate their complaints, electrical neuromodulation may be the preferred adjunctive treatment.1 Although spinal cord stimulation is still not approved by the US Food and Drug Administration for treatment of refractory angina, it is is accepted in the American College of Cardiology/American Heart Association guidelines for chronic stable angina, with a class II indication, and is frequently used for this indication in Europe.2

However, to understand underlying mechanisms of therapies such as electrical neuromodulation—executed through either transcutaneous electrical nerve stimulation or spinal cord stimulation—for angina pectoris and to improve the effect and safety of these therapies, clinical questions concerning neuromodulation must be evaluated in experimental models. The outcomes of these preclinical experimental studies subsequently need to be assessed in humans.

Although therapeutic improvements from implantable devices would not have been possible without experimental work, any experimentation must be avoided if it is not approved by the relevant ethics committee(s) or is not conducted in keeping with standard guidelines. For this reason it is sometimes more feasible, when appropriate, to make use of simulation models—for instance, to study regularization of atrial fibrillation by means of a device.3,4

Figure 1. Our preclinical neurocardiology research program. Several experimental approaches, ranging from neuroanatomy to molecular biological studies of cardiac nociceptor mRNA expression, have been employed to unravel mechanisms of heart-brain interaction and electrical neuromodulation. For explanations of project numbers, see the text.

So, on the one hand it is challenging to use electrical neuromodulation as a tool to study heart-brain interactions in general; on the other hand, electrical neuromodulation may be used to study its own underlying mechanisms of action, more specifically on characteristics of angina and myocardial ischemia. To investigate these mechanisms of action of electrical neuromodulation, we initiated a neurocardiology program in the 1990s (Figure 1). This article will discuss the experimental models we have studied to unravel the heart-brain interactions involved. We studied electrical neuromodulation both in patients and in experimental animals. However, the lack of knowledge about fundamental aspects of cardiovascular regulating circuitry and cardiac pain, as well as the lack of an animal model for angina pectoris, is the background for the various projects we have conducted concerning heart-brain interactions.


In 1772, Heberden described to physicians in England the clinical symptoms of exercise-induced chest discomfort, with its emotional component and vaguely distributed projection on the chest, as follows: “The seat of it, and sense of strangling and anxiety with which it is attended, may make it not improperly be called angina pectoris.”5 Since then, it has been demonstrated repeatedly that strong emotional distress frequently precedes or is associated with complaints of pain in the chest. Further, emotional suffering has been associated with increased mortality in patients with CAD. We and others, unfortunately, were confronted with very limited knowledge of the precise locations of the origin of emotions in the limbic structures of the forebrain. Even less was known about the relationship of these brain structures and the heart, owing to technical limitations in the field of neuroanatomical tract tracing, among other reasons. As a result, the nervous pathways from the heart, through which signals are propagated to the brain in order to activate emotional components, were not accurately identified. We therefore initiated Project 1 to study, in a rat model, neuroanatomical characterization of the neuronal circuitry controlling cardiac activity, specifically during cardiac distress.

In the area of identifying efferent neural pathways from the heart, we were the first to publish an experimental setup making use of a neurotropic herpesvirus from the Bartha strain of the pseudorabies virus (PRV).6 Following injections of PRV into the left and right myocardium or into atrial tissue, PRV infects the neurons that innervate the injection site and is then transported in the neural network, where the virus may cross at least four synapses. This transneuronal retrograde viral pathway labeling method with PRV provided us the opportunity to study cardiovascular controlling networks. The distribution of the PRV-infected cells was studied immunocytochemically after survival times of 3 to 6 days. Right ventricular infection showed labeling in the same nuclei as left ventricular labeling, but the number of PRV-positive cells was always higher and the localization of PRV within the nuclei differed. These obvious signs for differentiation within the nuclei suggest differential neuronal pathways to various parts of the heart.

Following injection of PRV at different cardiac sites, differences in density and localization of PRV-positive cells were found predominantly in higher-order neurons that are known to be involved in cardiac control. Transection of the spinal cord at Th1, performed to reveal selectively the parasympathetic neuronal networks, reduced the number of labeled cells, specifically in the periaqueductal gray matter. Virus-labeled sympathetic preganglionic cells were found in the Th1–Th7 thoracic intermediolateral cell groups, with some additional infections at Th8–Th11 after inoculations of the ventricular myocardium. The rostral parts of the insular cortex appeared to be linked selectively to sympathetic innervation of the heart.6

From the experiments we hypothesized that, according to the type of lesion, the pattern of cardiac innervation may account for a specific malfunctioning. Subsequently, the subendocardial clustered parasympathetic nerves make these nerves more vulnerable for myocardial damage than the superficial spread of sympathetic nerves. In this respect, the identification of three preganglionic parasympathetic nuclei in cardiac control—ie, the dorsal motor nucleus of the vagus (20% labeling), the nucleus ambiguus, and the periambiguus—constituted the most striking findings.

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