Contributed by Heidi L. Lujan and Stephen E. DiCarlo
Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201
Excessive sympathetic activity is responsible for, and/or contributes to, the morbidity and mortality associated with cardiovascular diseases (e.g. hypertension, stroke, heart failure, ischemic heart disease, ventricular arrhythmias). For example, myocardial ischemia provokes a powerful reflex increase in cardiac sympathetic efferent activity that directly promotes ventricular arrhythmias. Similarly, spinal cord injuries above thoracic level 6 (T6) are associated with episodic bouts of life-threatening hypertension as part of a condition known as autonomic dysreflexia (AD). Physiologically, AD is caused by a massive reflex sympathetic discharge triggered by a stimulus originating below the level of the spinal cord injury.
Importantly, interventions that reduce sympathetic activity protect against ventricular arrhythmias and AD. Accordingly, efforts to reduce sympathetic activity are the first-line therapy for these cardiovascular disorders. However, despite favorable effects, adverse complications (due to generalized sympatho-inhibition, e.g. fatigue, impotence; or specific sympatho-inhibition, e.g. Horner’s syndrome, paraesthesia, disruption of sexual, bladder or bowel function) limit compliance and patient satisfaction with these treatments.
However, targeted ablation of cardiac sympathetic neurons reduced the susceptibility to ventricular arrhythmias [2] and targeted ablation of mesenteric projecting sympathetic neurons reduced AD [1] while avoiding these complications.
Specifically, CTB-SAP (cholera toxin B conjugated to saporin; Cat. #IT-14), injected into the stellate ganglia, reduced the number of left ventricular sympathetic fibers (Figure 1), the number of sympathetic post-ganglionic neurons in the stellate ganglia, and virtually eliminated sympathetic pre-ganglionic neurons (SPNs) of spinal cord segments T1-T5 without altering afferent neurons. These structural neuroplastic changes were associated with a decreased susceptibility to ischemia-induced sustained ventricular tachycardia.
Furthermore, CTB-SAP injected into the celiac ganglion reduced the number of sympathetic post-ganglionic neurons in the celiac ganglia and virtually eliminated sympathetic pre-ganglionic neurons of spinal cord segments T5-T12 without altering afferent function. Similarly, these neuroplastic changes were associated with a reduced AD.
Thus CTB-SAP retrogradely transported from the peripheral ganglia is effective at ablating specific sympathetic neurons and reducing the susceptibility to ventricular arrhythmias and AD. Additional studies are required to further characterize the physiological responses to this procedure as well as determine if this new approach is safe and efficacious for the treatment of conditions associated with excess sympathetic activity.
Figure 1 presents tyrosine hydroxylase-immunoreactive sympathetic nerve fibers from the left ventricular free wall of rats that had CTB (left panel) or CTB-SAP (right panel) injected into both stellate ganglia. The CTB-SAP group showed a significant reduction in sympathetic nerve fibers compared to the CTB group.
Selected References: (back to top)
- Lujan HL, Palani G, Peduzzi JD and DiCarlo SE. Targeted ablation of mesenteric projecting sympathetic neurons reduces the hemodynamic response to pain in conscious, spinal cord-transected rats. Am J Physiol Regul Integr Comp Physiol 298: R1358-R1365, 2010.
- Lujan HL, Palani G, Zhang L and DiCarlo SE. Targeted Ablation of Cardiac Sympathetic Neurons Reduces the Susceptibility to Ischemia-Induced Sustained Ventricular Tachycardia in Conscious Rats. Am J Physiol Heart Circ Physiol 2010.