Robert D. Foreman

Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction.

The interest for the antifibrillatory effect of vagal stimulation has been largely limited by the fact that this concept seemed restricted to acute experiments in anesthetized animals. To explore the potentially protective role of vagal stimulation in conscious animals we developed a chronically implantable device to be placed around the cervical right vagus. An anterior myocardial infarction was produced in 161 dogs; 1 month later an exercise stress test was performed on the 105 survivors. Toward the end of the test the circumflex coronary artery was occluded for 2 minutes. Fifty-nine (56%) dogs developed ventricular fibrillation and, before this test was repeated, were assigned either to a control group (n = 24) or to be instrumented with the vagal device (n = 35). Five dogs were excluded because of electrode malfunction. Compared with the heart rate level attained after 30 seconds of occlusion during exercise in the control test, vagal stimulation led to a decrease of approximately 75 beats/min (from 255 +/- 33 to 170 +/- 36 beats/min, p less than 0.001). In the control group 22 (92%) of 24 dogs developed ventricular fibrillation during the second exercise and ischemia test. By contrast, during vagal stimulation ventricular fibrillation occurred in only 3 (10%) of the 30 dogs tested and recurred in 26 (87%) during an additional exercise and ischemia test in the control condition (p less than 0.001 versus the vagal stimulation test; internal control analysis). Combined analysis of the tests performed in the control condition showed that ventricular fibrillation was reproducible in 48 (89%) of the 54 dogs tested. The protective effect of vagal stimulation was also significant in the group comparison analysis and even after exclusion of those four dogs in which ventricular fibrillation was not reproducible (92% versus 11.5%, control versus vagal stimulation, p less than 0.001). When heart rate was kept constant by atrial pacing, the vagally mediated protection was still significant (p = 0.015) as five (55%) of nine dogs survived the test. This study shows that vagal stimulation, performed shortly after the onset of an acute ischemic episode in conscious animals with a healed myocardial infarction, can effectively prevent ventricular fibrillation. This striking result seems to depend on multiple mechanisms having a synergistic action. The decrease in heart rate is an important but not always essential protective mechanism. The electrophysiological effects secondary to the vagally mediated antagonism of the sympathetic activity on the heart are likely to play a major role.

Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction.

We have suggested that among conscious dogs with a healed anterior wall myocardial infarction (MI) a depressed baroreflex sensitivity (BRS) carries a higher risk of developing ventricular fibrillation during a brief ischemic episode associated with an exercise stress test. The clinical and pathophysiological implications of our previous findings prompted the present study, which addressed three major questions: 1) Is, indeed, analysis of BRS after MI a specific and sensitive marker for sudden death-risk stratification? 2) Does MI modify BRS? 3) Does analysis of BRS before MI provide information about outcome during ischemic episodes occurring after MI? An anterior MI was produced in 301 dogs, and 4 weeks later, a 2-minute circumflex coronary artery occlusion beginning during the last minute of an exercise stress test could be performed in 192 animals. Ventricular fibrillation occurred in 106 (55%) dogs (susceptible to sudden death), whereas 86 (45%) dogs (resistant to sudden death) survived. BRS was assessed by the phenylephrine method and was expressed by the regression line relating RR intervals to blood-pressure changes. BRS was significantly lower among susceptible than among resistant dogs (9.1 +/- 6.0 vs. 17.7 +/- 6.5 msec/mm Hg, p less than 0.0001). The risk for sudden death increased from 20% (15 of 73 dogs) for a BRS greater than 15 msec/mm Hg to 91% (62 of 68 dogs) for a BRS less than 9 msec/mm Hg (p less than 0.001). An internal control study in 55 animals showed that BRS was reduced 4 weeks after MI compared with control conditions (13.5 +/- 6.7 vs. 17.8 +/- 6.6 msec/mm Hg, p less than 0.001) and that a reduction occurred in 73% of animals. Susceptible dogs and those that spontaneously died after MI had a lower BRS even before the MI (16.2 +/- 5.9 vs. 22.2 +/- 6.2 msec/mm Hg, p less than 0.001). The risk for sudden death after MI increased from 35% (nine of 26 dogs) for a BRS before MI greater than 20 msec/mm Hg to 85% (17 of 20 dogs) for a BRS before MI less than 14 msec/mm Hg (p less than 0.001). This study demonstrates that the presence of a reduced BRS is associated with a greater susceptibility to ventricular fibrillation during subsequent ischemic episodes. In the majority of dogs, BRS is reduced after an MI. The results in 192 conscious dogs with a healed MI indicate that analysis of BRS is a powerful tool for risk stratification not only after, but even before, the occurrence of an MI.

Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia.

Seven conscious dogs documented to be at high risk by the occurrence of ventricular fibrillation (VF) during acute myocardial ischemia were randomly assigned to 6 weeks of either daily exercise training or cage rest followed by exercise training. After 6 weeks of daily treadmill training, heart rate variability, a marker of vagal tone, increased by 74% (P < .001); baroreflex sensitivity, a marker of the capability to reflexly augment vagal activity, increased by 69% (P < .01); the repetitive extrasystole threshold, a marker of ventricular electrical stability, increased by 44% (P < .05). After exercise training, the incidence of ventricular fibrillation during acute myocardial ischemia decreased by 100%, as all animals survived. Neither passage of time nor heart rate level during ischemia contributed to the outcome. The most likely mechanism to explain the striking change in risk status is the shift in autonomic balance characterized by increased cardiac vagal activity, which was previously shown to have an antifibrillatory effect. These results suggest that exercise training in healthy individuals may decrease their likelihood of developing lethal arrhythmias during acute myocardial ischemia.

Physiology of Spinal Cord Stimulation: Review and Update

Spinal cord stimulation (SCS) was an outgrowth of the well‐known gate control theory presented by Melzack and Wall in 1965. Although the method has been used to treat chronic severe pain for more than three decades, very little was known about the physiological and biochemical mechanisms behind the beneficial effects until recently. We now know that SCS activates several different mechanisms to treat different types of pain such as neuropathic and ischemic. In general, these mechanisms seem most dependent on activation of only a few segments of the spinal cord. However, both animal studies and human observations have indicated that supraspinal circuits may contribute as well. In the treatment of neuropathic pain, intermittent SCS may give several hours of pain relief after cessation of the stimulation. This protracted effect indicates long‐lasting modulation of neural activity involving changes in the local transmitter systems in the dorsal horns. In ischemic pain, animal experiments demonstrate that inhibition of afferent activity in the spinothalamic tracts, long‐term suppression of sympathetic activity, and antidromic effects on peripheral reflex circuits may take part in the pain alleviation. Moderate SCS intensities seem to evoke sympathetic inhibition, but higher stimulation intensities may induce antidromically mediated release of vasoactive substances, eg, the calcitonin gene‐related peptide (CGRP), resulting in peripheral vasodilation. The anti‐ischemic effect of SCS in angina pectoris due to intermittent coronary ischemia probably occurs because application of SCS appears to result in a redistribution of cardiac blood supply, as well as a decrease in tissue oxygen demand. Recent studies indicate that SCS modulates the activity of cardiac intrinsic neurons thereby restricting the arrythmogenic consequences of intermittent local coronary ischemia. The present state of knowledge is briefly reviewed and recent research directions outlined.

Modulation of intrinsic cardiac neurons by spinal cord stimulation : implications for its therapeutic use in angina pectoris

OBJECTIVE Electrical stimulation of the dorsal aspect of the upper thoracic spinal cord is used increasingly to treat patients with severe angina pectoris refractory to conventional therapeutic strategies. Clinical studies show that spinal cord stimulation (SCS) is a safe adjunct therapy for cardiac patients, producing anti-anginal as well as anti-ischemic effects. However, little information is yet available about the underlying mechanisms involved. METHODS In order to determine its mechanism of action, the effects of SCS on the final common integrator of cardiac function, the intrinsic cardiac nervous system, was studied during basal states as well as during transient (2 min) myocardial ischemia. Activity generated by intrinsic cardiac neurons was recorded in 9 anesthetized dogs in the absence and presence of myocardial ischemia before, during and after stimulating the dorsal T1-T2 segments of the spinal cord at 66 and 90% of motor threshold using epidural bipolar electrodes (50 Hz; 0.2 ms; parameters within the therapeutic range used in humans). RESULTS The SCS suppressed activity generated by intrinsic cardiac neurons. No concomitant change in monitored cardiovascular indices was detected. Neuronal activity increased during transient ventricular ischemia (46%), as well as during the early reperfusion period (68% compared to control). Despite that, activity was suppressed during both states by SCS. CONCLUSIONS SCS modifies the capacity of intrinsic cardiac neurons to generate activity. SCS also acts to suppress the excitatory effects that local myocardial ischemia exerts on such neurons. Since no significant changes in monitored cardiovascular indices were observed during SCS, it is concluded that modulation of the intrinsic cardiac nervous system might contribute to the therapeutic effects of SCS in patients with angina pectoris.

Heart rate variability before and after myocardial infarction in conscious dogs at high and low risk of sudden death.

Heart rate variability has been demonstrated both experimentally and clinically to be of prognostic importance in determining mortality after myocardial infarction. However, no paired studies have been reported to examine heart rate variability before and after myocardial infarction. The hypothesis was tested that low values of heart rate variability provided risk assessment both before and after myocardial infarction with use of an established canine model of sudden cardiac death. Risk for sudden death was assessed 1 month after myocardial infarction by a protocol in which exercise and myocardial ischemia were combined; dogs that developed ventricular fibrillation were classified at high risk for sudden death (susceptible) and the survivors were considered low risk (resistant). In resistant dogs, myocardial infarction did not affect any measure of heart rate variability: 1) mean RR interval, 2) standard deviation of the mean RR interval, and 3) the coefficient of variance (standard deviation/RR interval). By contrast, after myocardial infarction, susceptible dogs showed significant decrease in all measures of heart rate variability. Before myocardial infarction, no differences were seen between susceptible and resistant dogs. However, 30 days after infarction, epidemiologic analysis of the coefficient of variance showed high sensitivity and specificity (88% and 80%, respectively), predicting susceptibility. Therefore, results of analysis of 30 min of beat to beat heart period at rest 30 days after myocardial infarction are highly predictive for increased risk of sudden death.

Decreased activity of spontaneous and noxiously evoked dorsal horn cells during transcutaneous electrical nerve stimulation (TENS)

&NA; The purpose of this study was to examine the effects of TENS application to somatic receptive fields on spontaneous and noxiously evoked dorsal horn cell activity in &agr;‐chloralose‐anesthetized cat. Carbon‐filament microelectrodes were used to record extracellular action potentials from 83 spontaneously discharging cells. Using a commercial TENS unit (Medtronic Eclipse Model 7723), spontaneous cell activity was decreased in 54% (65%) of the cells. Twenty‐five (30%) did not respond and 4 (5%) increased activity. It was also shown that for 36 cells which were evoked with either manual pinch (19 cells) or manual clamp (17 cells), cell activity decreased during TENS application. This study shows that dorsal horn neurons which can potentially transmit noxious information to supraspinal levels, can have their cell activity decreased during TENS application to somatic receptive fields. This is consistent with the concept of the ‘gate control theory of pain’ in that less noxious information would be involved in the pain perception process.

The Appropriate Use of Neurostimulation of the Spinal Cord and Peripheral Nervous System for the Treatment of Chronic Pain and Ischemic Diseases: The Neuromodulation Appropriateness Consensus Committee

The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications.

Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies.

Spinal cord stimulation (SCS) is a widely used clinical technique to treat ischemic pain in peripheral, cardiac and cerebral vascular diseases. The use of this treatment advanced rapidly during the late 80s and 90s, particularly in Europe. Although the clinical benefits of SCS are clear and the success rate remains high, the mechanisms are not yet completely understood. SCS at lumbar spinal segments (L2-L3) produces vasodilation in the lower limbs and feet which is mediated by antidromic activation of sensory fibers and decreased sympathetic outflow. SCS at thoracic spinal segments (T1-T2) induces several benefits including pain relief, reduction in both frequency and severity of angina attacks, and reduced short-acting nitrate intake. The benefits to the heart are not likely due to an increase, or redistribution of local blood flow, rather, they are associated with SCS-induced myocardial protection and normalization of the intrinsic cardiac nervous system. At somewhat lower cervical levels (C3-C6), SCS induces increased blood flow in the upper extremities. SCS at the upper cervical spinal segments (C1-C2) increased cerebral blood flow, which is associated with a decrease in sympathetic activity, an increase in vasomotor center activity and a release of neurohumoral factors. This review will summarize the basic science studies that have contributed to our understanding about mechanisms through which SCS produces beneficial effects when used in the treatment of vascular diseases. Furthermore, this review will particularly focus on the antidromic mechanisms of SCS-induced vasodilation in the lower limbs and feet.

Stereotaxic delivery of corticosterone to the amygdala modulates colonic sensitivity in rats.

Episodes of anxiety are often associated with the onset or exacerbation of visceral pain in patients with irritable bowel syndrome (IBS). The central amygdaloid nucleus (CeA) is a key limbic structure involved in the expression of anxiety as well as a major site for regulating autonomic and visceral responses to stress. Previous experiments have shown that glucocorticoids can act directly at the CeA to increase the level of anxiety in rats. Therefore, the goal of this study was to examine the effect of stereotaxic delivery of corticosterone into the CeA on the development of visceral hypersensitivity by measuring visceromotor response to colorectal distention in rats. Stereotaxic delivery of corticosterone to the CeA increases indices of anxiety and produces a hypersensitive colon as demonstrated by an exaggerated visceromotor response to colorectal distention in the F344 rat strain. Our findings suggest that modulation of anxiety by manipulating amygdala function with corticosterone induced colonic hypersensitivity via descending neuronal pathways from the CeA.