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PART FIVE  METHODS FOR SYMPTOMATIC CONTROL

shares some mechanisms with “ischemic preconditioning” but, notably, does not cause cardiac ischemia. 129 In order to mimic the development of chronic ischemic heart disease in an animal model of myocardial ischemia, progressive occlusion of the arterial blood supply by a device or creation of cardiac infarction of moderate size could be used, after which a period of acute ischemia provocation with or without SCS could be programmed. In one early canine study, a slowly expanding material lining the inside of a metal constrictor ring was implanted around the proximal left circumflex coronary artery of a group of dogs. 124 This technique progressively reduces blood flow through the artery and facilitates the development of collaterals creating a collateral-dependent myocardial ischemia substrate. In sub­ sequent acute experiments, the exposed heart was paced at a basal rate of 150 beats per minute. An ECG plaque was used to record from multiple sites on the left ventricle supplied by the left coronary artery occluded by the constrictor. In order to stress the heart, either angiotensin II, administered via the local arterial supply to the right atrial ganglionated plexus, was used, or rapid ventricular pacing applied via a standard pace­ maker. Both these maneuvers produced an elevation of the ST segments that was markedly attenuated during SCS. In a similar way, ST-segment responses were largely unchanged when rapid ventricular pacing (240 beats per minute during 60 seconds) was induced during SCS. These experiments indicate that SCS may attenuate the deleterious effects that stressors, especially chemical activation of the intrinsic cardiac nervous system, exert on a myocardium with reduced reserve capacity. This ob­ servation led to the conclusion that SCS produces anti-ischemic effects that contribute to improved cardiac function. Further evidence to support the anti-ischemic effects of SCS on the heart is the observation that preemptive SCS appears to have a protective effect on the myocardium, which makes it more resistant to critical ischemia as demonstrated by rabbit experiments with left anterior descending (LAD) artery occlu­ sion lasting 30 minutes. In these studies, the infarct size was markedly reduced by preemptive SCS. However, the protective effects of SCS therapy were lost if SCS was begun after ischemia induction. 129 Patients with SCS therapy for chronic therapy-re­ sistant angina are recommended to use their stimulators at low amplitude most of the day or at least for 6 to 8 hours and to increase the amplitude when needed during an angina attack or when physical stress is expected to produce angina. Thus, the validity of this clinical recommendation is substantiated by experimental data. In experimental cardiology, there is a well-known phenome­ non that a short ischemic episode preceding a longer occlusion of a coronary vessel induces complicated protective processes in the myocardium that diminishes the resulting infarct size. This phenomenon is called ischemic preconditioning, and the details are still not completely known (e.g., Foreman 130 ). Re­ cent studies indicate that SCS-induced local release of cate­ cholamines in the myocardium may trigger protective changes related to mechanisms behind such ischemic preconditioning but without producing any signs of ischemic changes in the heart. There are also other signs indicating that SCS may in­ duce a state similar to that following a short ischemic period, for example, by activating protein kinase C, a substance which is pivotal in ischemic preconditioning. 129 An important part of the “general common pathways” in the communication between the CNS and the heart is the intrinsic cardiac nervous system (ICNS). The ICNS is located in the car­ diac ganglionated plexuses covered by epicardial fat pads situ­ ated on the myocardium. 131 The ICNS plexuses are composed of mixed somatosensory, sympathetic, and parasympathetic fibers. The ICNS plays a critical role in coordinating regional cardiac function and providing rapid reflex coordination of autonomic

neuronal inflow to the heart. In critical ischemia, the ICNS is vigorously activated. 126 The ICNS responds to ischemic stress by marked activity increase even if the ischemic region is situated far away from the neuron population. 125 If the increased activity persists, it may result in spreading dysrhythmias that may lead to more generalized ischemia and/or to ventricular fibrillation. Several experimental studies have clearly shown that SCS may potently inhibit and stabilize the activity of the ICNS especially during a critical ischemic challenge. In patients with angina, SCS can relieve the symptoms and signs of ischemia for long periods after the stimulation is ter­ minated which may relate to prolonged effects of SCS on ICNS activity observed at least up to 45 to 60 minutes after SCS stim­ ulation off in dogs. 131 Modulation of the ICNS may be one mechanism that pro­ tects the heart from more severe ischemic threats due to gen­ eralized arrhythmias. Others have confirmed the observation that experimental animals display less arrhythmia during isch­ emic provocation when being subjected to SCS. Experiments by Lopshire et al. 132 demonstrated that SCS might improve car­ diac function in canine heart failure following an experimental myocardial infarction and continued stress by HF pacing over 8 weeks. In addition, acute experiments with experimental oc­ clusion of the LAD carried out with or without SCS on land­ race pigs showed that the stimulation provided positive effects as displayed in the vectorized ECG. 133 In several of the studies mentioned earlier, the ischemic chal­ lenge induced arrhythmias, but in virtually all studies, these were less severe during SCS treatment. This observation was recently supported by a new study. 134 The use of SCS for angina reached a peak in the 1990s and early 2000s (when it was the best indication for SCS with out­ comes . 80% of patients clearly helped by the therapy), but thereafter, the use of this technique has diminished consider­ ably also in Europe due largely to increased use of stenting. It also should be noted that angina pectoris is presently not a U.S. Food and Drug Administration (FDA)-approved indica­ tion for SCS in the United States. Some of the pathways and mechanisms behind beneficial effects of SCS on cardiac function discussed earlier are sche­ matically summarized in Figure 96.5, which illustrates the mechanisms and neurotransmitters known or hypothesized to be involved in the effects of SCS in angina. The treatment of visceral pain is a relatively new application for SCS, and investigators have proposed that SCS might exert its positive effect on visceral pain (and dysfunction) by moderat­ ing the so-called “brain–gut” axis (the neural circuitry thought to control the interface among visceral afferent sensation, intes­ tinal motor function, and the brain). 130,135–137 In fact, moving an active SCS electrode along the neuraxis demonstrates that electric activation occurs at various levels; thus, in addition to its beneficial effects on pain and ischemia, SCS inhibits the viscerosomatic reflexes involved with the par­ ticular spinal segmental level being stimulated (Fig. 96.6). Some rodent studies in experimental colonic pain 137,138 demonstrated that SCS applied with conventional clinical stim­ ulation parameters significantly decreased the painful symp­ toms (measured by monitoring of abdominal contractions as response to balloon inflation in the distal colon). Based on these observations, first a case of irritable bowel symptom was successfully treated by SCS, 139 and thereafter, a prospective ran­ domized clinical study in a small series confirmed the beneficial findings in a pilot study. 140 In fact, as shown in Figure 96.6, SCS might have many as yet unexplored positive effects on visceral problems. MECHANISMS OF SPINAL CORD STIMULATION IN VISCERAL ABDOMINAL PAIN