Una Buckley

Autonomic Regulation Therapy in Heart Failure

Autonomic regulation therapy (ART) is a rapidly emerging therapy in the management of congestive heart failure secondary to systolic dysfunction. Modulation of the cardiac neuronal hierarchy can be achieved with bioelectronics modulation of the spinal cord, cervical vagus, baroreceptor, or renal nerve ablation. This review will discuss relevant preclinical and clinical research in ART for systolic heart failure. Understanding mechanistically what is being stimulated within the autonomic nervous system by such device-based therapy and how the system reacts to such stimuli is essential for optimizing stimulation parameters and for the future development of effective ART.

Targeted stellate decentralization: Implications for sympathetic control of ventricular electrophysiology☆

BACKGROUND Selective bilateral cervicothoracic sympathectomy has proven to be effective for managing ventricular arrhythmias in the setting of structural heart disease. In the procedure currently used, the caudal portions of both stellate ganglia along with thoracic chain ganglia down to T4 ganglia are removed. OBJECTIVE The purpose of this study was to define the relative contributions of the T1-T2 and T3-T4 paravertebral ganglia in modulating ventricular electrical function. METHODS In anesthetized vagotomized porcine subjects (n = 8), the heart was exposed via sternotomy along with right and left paravertebral sympathetic ganglia to the T4 level. A 56-electrode epicardial sock was placed over both ventricles to assess epicardial activation-recovery intervals (ARIs) in response to individually stimulating right and left stellate vs T3 paravertebral ganglia. Responses to T3 stimuli were repeated after surgical removal of the caudal portions of stellate ganglia and T2 bilaterally. RESULTS In intact preparations, stellate ganglion vs T3 stimuli (4 Hz, 4-ms duration) were titrated to produce equivalent decreases in global ventricular ARIs (right side: 85 ± 6 ms vs 55 ± 10 ms; left side: 24 ± 3 ms vs 17 ± 7 ms). Threshold of stimulus intensity applied to T3 ganglia to achieve threshold was 3 times that of T1 threshold. ARIs in unstimulated states were unaffected by bilateral stellate-T2 ganglion removal. After acute decentralization, T3 stimulation failed to change ARIs. CONCLUSION Preganglionic sympathetic efferents arising from the T1-T4 spinal cord that project to the heart transit through stellate ganglia via the paravertebral chain. Thus, T1-T2 surgical excision is sufficient to functionally interrupt central control of peripheral sympathetic efferent activity.

Bioelectronic neuromodulation of the paravertebral cardiac efferent sympathetic outflow and its effect on ventricular electrical indices

BACKGROUND Neuromodulation of the paravertebral ganglia by using symmetric voltage controlled kilohertz frequency alternating current (KHFAC) has the potential to be a reversible alternative to surgical intervention in patients with refractory ventricular arrhythmias. KHFAC creates scalable focal inhibition of action potential conduction. OBJECTIVE The purpose of this article was to evaluate the efficacy of KHFAC when applied to the T1-T2 paravertebral chain to mitigate sympathetic outflow to the heart. METHODS In anesthetized, vagotomized, porcine subjects, the heart was exposed via a midline sternotomy along with paravertebral chain ganglia. The T3 paravertebral ganglion was electrically stimulated, and activation recovery intervals (ARIs) were obtained from a 56-electrode sock placed over both ventricles. A bipolar Ag electrode was wrapped around the paravertebral chain between T1 and T2 and connected to a symmetric voltage controlled KHFAC generator. A comparison of cardiac indices during T3 stimulation conditions, with and without KHFAC, provided a measure of block efficacy. RESULTS Right-sided T3 stimulation (at 4 Hz) was titrated to produce reproducible ARI changes from baseline (52 ± 30 ms). KHFAC resulted in a 67% mitigation of T3 electrical stimulation effects on ARI (18.5 ± 22 ms; P < .005). T3 stimulation repeated after KHFAC produced equivalent ARI changes as control. KHFAC evoked a transient functional sympathoexcitation at onset that was inversely related to frequency and directly related to intensity. The optimum block threshold was 15 kHz and 15 V. CONCLUSION KHFAC applied to nexus (convergence) points of the cardiac nervous system produces a graded and reversible block of underlying axons. As such, KHFAC has the therapeutic potential for on-demand and reversible mitigation of sympathoexcitation.

Bioelectronic block of paravertebral sympathetic nerves mitigates post–myocardial infarction ventricular arrhythmias

BACKGROUND Autonomic dysfunction contributes to induction of ventricular tachyarrhythmia (VT). OBJECTIVE To determine the efficacy of charge-balanced direct current (CBDC), applied to the T1-T2 segment of the paravertebral sympathetic chain, on VT inducibility post-myocardial infarction (MI). METHODS In a porcine model, CBDC was applied in acute animals (n = 7) to optimize stimulation parameters for sympathetic blockade and in chronic MI animals (n = 7) to evaluate the potential for VTs. Chronic MI was induced by microsphere embolization of the left anterior descending coronary artery. At termination, in anesthetized animals and following thoracotomy, an epicardial sock array was placed over both ventricles and a quadripolar carousel electrode positioned underlying the right T1-T2 paravertebral chain. In acute animals, the efficacy of CBDC carousel (CBDCC) block was assessed by evaluating cardiac function during T2 paravertebral ganglion stimulation with and without CBDCC. In chronic MI animals, VT inducibility was assessed by extrasystolic (S1-S2) stimulations at baseline and under >66% CBDCC blockade of T2-evoked sympathoexcitation. RESULTS CBDCC demonstrated a current-dependent and reversible block without impacting basal cardiac function. VT was induced at baseline in all chronic MI animals. One animal died after baseline induction. Of the 6 remaining animals, only 1 was reinducible with simultaneous CBDCC application (P < .002 from baseline). The ventricular effective refractory period (VERP) was prolonged with CBDCC (323 ± 26 ms) compared to baseline (271 ± 32 ms) (P < .05). CONCLUSIONS Axonal block of the T1-T2 paravertebral chain with CBDCC reduced VT in a chronic MI model. CBDCC prolonged VERP, without altering baseline cardiac function, resulting in improved electrical stability.

Effect of Thoracic Epidural Anesthesia on Ventricular Excitability in a Porcine Model

Background: Imbalances in the autonomic nervous system, namely, excessive sympathoexcitation, contribute to ventricular tachyarrhythmias. While thoracic epidural anesthesia clinically suppresses ventricular tachyarrhythmias, its effects on global and regional ventricular electrophysiology and electrical wave stability have not been fully characterized. The authors hypothesized that thoracic epidural anesthesia attenuates myocardial excitability and the proarrhythmic effects of sympathetic hyperactivity. Methods: Yorkshire pigs (n = 15) had an epidural catheter inserted (T1 to T4) and a 56-electrode sock placed on the heart. Myocardial excitability was measured by activation recovery interval, dispersion of repolarization, and action potential duration restitution at baseline and during programed ventricular extrastimulation or left stellate ganglion stimulation, before and 30 min after thoracic epidural anesthesia (0.25% bupivacaine). Results: After thoracic epidural anesthesia infusion, there was no change in baseline activation recovery interval or dispersion of repolarization. During programmed ventricular extrastimulation, thoracic epidural anesthesia decreased the maximum slope of ventricular electrical restitution (0.70 ± 0.24 vs. 0.89 ± 0.24; P = 0.021) reflecting improved electrical wave stability. Thoracic epidural anesthesia also reduced myocardial excitability during left stellate ganglion stimulation–induced sympathoexcitation through attenuated shortening of activation recovery interval (−7 ± 4% vs. −4 ± 3%; P = 0.001), suppression of the increase in dispersion of repolarization (313 ± 293% vs. 185 ± 234%; P = 0.029), and reduction in sympathovagal imbalance as measured by heart rate variability. Conclusions: Our study describes the electrophysiologic mechanisms underlying antiarrhythmic effects of thoracic epidural anesthesia during sympathetic hyperactivity. Thoracic epidural anesthesia attenuates ventricular myocardial excitability and induces electrical wave stability through its effects on activation recovery interval, dispersion of repolarization, and the action potential duration restitution slope.

Implantable cardioverter defibrillators: even better than we thought?

This editorial refers to ‘The effect of duration of follow-up and presence of competing risk on lifespan-gain from implantable cardioverter defibrillator therapy: who benefits the most?’[†][1], by C. Raphael et al ., on page 1676. In certain parts of the world, cardiologists struggle on a daily basis to convince government-run health services to allow them to implant defibrillators into patients who have guideline indications for a device. The general opinion of the wider health service is that implantable cardiac defibrillators (ICDs) are expensive and our health systems cannot afford them. In recent years there is a general consensus between guidelines from Europe (European Society of Cardiology and European Heart Rhythm Association) and the USA (American Heart Association, American College of Cardiology and Heart Rhythm) for device implantation.1 The indications for ICDs have appropriately expanded, based on excellent clinical data, to include wider indications for device implantation. This has made implementation of guidelines even less achievable for some countries, exacerbating the geographical variation in use. Sudden cardiac death is one of the most prevalent causes of death in the USA, with 180 000–400 000 deaths per year,2 with a higher incidence than death from stroke, lung cancer, and breast … [1]: #fn-2

Autonomic Control of the Heart

Abstract The cardiac autonomic nervous system (ANS) is a multilevel distributed neural network that extends from intrathoracic ganglia to the spinal cord, brainstem, and above. This interdependent network of central and peripheral reflexes control chronotropy, lusitropy, dromotropy, and inotropy on a beat-to-beat basis. Cardiac afferent input is projected to each of these processing centers with the ultimate outcome of modulating sympathetic and parasympathetic efferent inputs to all regions of the heart. Within peripheral autonomic ganglia, reflex processing of afferent input with descending projections from higher centers is dependent upon local circuit neurons. Herein, we outline the structural and functional organization of the hierarchy for cardiac control and how this neural network remodels in response to cardiac pathology. The fundamental premise is that the evolution of cardiac disease is dependent on dynamic interactions between the cardiac substrate and the neural networks that control it.

Predictors of left ventricular dysfunction with right ventricular pacing: Is paced QRS duration the answer?

Right ventricular (RV) pacing has been demonstrated to have detrimental effects on cardiac hemodynamics and is associated with a reduction in left ventricular function [1]. It is thought that about 25% of patients receiving right ventricular pacing for sick sinus syndrome and complete heart block experience ‘pacemaker syndrome’ with symptoms of shortness of breath, dizziness, palpitations, abnormal pulsations or chest pain [2]. Minimizing right ventricular pacing with optimization of pacemaker settings such as rate responsiveness, atrioventricular (AV) delay management and mode switching should all be adopted [3]. Allowing spontaneous sinus rate where possible, with preservation of spontaneous AV conduction, and restricting pacing to only when absolutely necessary is paramount. Many studies have been performed to try and identify predictors of progression of left ventricular (LV) dysfunction with RV pacing. To extrapolate conclusions from these studies there must be detailed information provided. For example, if the reported indication of pacing is complete heart block or sick sinus syndrome, knowing whether this is intermittent or permanent is important. This helps us understand the mode of pacing adopted such as single or dual chamber pacing. Knowing that RV pacing should be systematically avoided, more details would allow us understand whether long AV delays were implemented or was this not possible due to prolonged intrinsic AV conduction which may prevent this due to the development of diastolic mitral regurgitation or atrial fibrillation [4,5]. Complete heart block can be intermittent in the setting of tachycardia/bradycardia dependent heart block or initiated by a premature ventricular complex. Intrinsic AV block can result in an escape rhythm dependent on subsidiary pacemaker sites which can be unreliable and have a slow rate. The percentage of pacing should be reassessed at each pacemaker visit, or tele-monitoring transmission in order tominimize the amount of pacing if possible. Also the rate that RV pacing is set