Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex.

Following sinoaortic denervation, which eliminates arterial baroreceptor input into the brain, there are slowly developing adaptations that abolish initial sympathetic activation and hypertension. In comparison, electrical stimulation of the carotid sinus for 1 wk produces sustained reductions in sympathetic activity and arterial pressure. However, whether compensations occur subsequently to diminish these responses is unclear. Therefore, we determined whether there are important central and/or peripheral adaptations that diminish the sympathoinhibitory and blood pressure-lowering effects of more sustained carotid sinus stimulation. To this end, we measured whole body plasma norepinephrine spillover and alpha(1)-adrenergic vascular reactivity in six dogs over a 3-wk period of baroreflex activation. During the first week of baroreflex activation, there was an approximately 45% decrease in plasma norepinephrine spillover, along with reductions in mean arterial pressure and heart rate of approximately 20 mmHg and 15 beats/min, respectively; additionally, plasma renin activity did not increase. Most importantly, these responses during week 1 were largely sustained throughout the 3 wk of baroreflex activation. Acute pressor responses to alpha-adrenergic stimulation during ganglionic blockade were similar throughout the study, indicating no compensatory increases in adrenergic vascular reactivity. These findings indicate that the sympathoinhibition and lowering of blood pressure and heart rate induced by chronic activation of the carotid baroreflex are not diminished by adaptations in the brain and peripheral circulation. Furthermore, by providing evidence that baroreflexes have long-term effects on sympathetic activity and arterial pressure, they present a perspective that is opposite from studies of sinoaortic denervation.

Implementation of a Low-Dose, High-Frequency Cardiac Resuscitation Quality Improvement Program in a Community Hospital.

BACKGROUND: In 2015 the American Heart Association launched the Resuscitation Quality ImprovementⓇ (RQIⓇ) Program to address the urgent need to improve in-hospital cardiac arrest survival through a novel competency-based model for health care provider (HCP) cardiopulmonary resuscitation (CPR) training. This innovation differs from the traditional Basic Life Support (BLS) training model by providing self-directed, low-dose, high-frequency CPR skill activities with the objectives of skills mastery and retention. A program implementation study was conducted at the first hospital in the state of Illinois to adopt RQI in 2016. METHODS: The study was designed to evaluate implementation of the RQI program, CPR performance during RQI simulation sessions, and participant impressions at a community hospital. Quantitative data were evaluated based on psychomotor compression and ventilation performance. Quantitative and qualitative data were evaluated based on a perceptual CPR confidence and program satisfaction survey. RESULTS: Statistical analysis demonstrates significant improvement in HCPs' quarterly psychomotor CPR skill performance over a one-year period in first compression score, and first and highest ventilation score per quarterly session. The number of attempts to pass the ventilation skill session decreased between the first and fourth quarter. Survey results of HCPs' program perceptions 30 months post-RQI implementation indicate satisfaction with the RQI program and an increase in CPR skill confidence. CONCLUSION: Findings demonstrate that the RQI program for ongoing verification of BLS skill and knowledge provides improvements in HCPs' CPR psychomotor competence and confidence/satisfaction using an efficient and sustainable method at a community hospital.

Non-clinical and Pre-clinical Testing to Demonstrate Safety of the Barostim Neo Electrode for Activation of Carotid Baroreceptors in Chronic Human Implants.

The Barostim neo™ electrode was developed by CVRx, Inc.to deliver baroreflex activation therapy (BAT)™ to treat hypertension and heart failure. The neo electrode concept was designed to deliver electrical stimulation to the baroreceptors within the carotid sinus bulb, while minimizing invasiveness of the implant procedure. This device is currently CE marked in Europe, and in a Pivotal (akin to Phase III) Trial in the United States. Here we present the in vitro and in vivo safety testing that was completed in order to obtain necessary regulatory approval prior to conducting human studies in Europe, as well as an FDA Investigational Device Exemption (IDE) to conduct a Pivotal Trial in the United States. Stimulated electrodes (10 mA, 500 µs, 100 Hz) were compared to unstimulated electrodes using optical microscopy and several electrochemical techniques over the course of 27 weeks. Electrode dissolution was evaluated by analyzing trace metal content of solutions in which electrodes were stimulated. Lastly, safety testing under Good Laboratory Practice guidelines was conducted in an ovine animal model over a 12 and 24 week time period, with results processed and evaluated by an independent histopathologist. Long-term stimulation testing indicated that the neo electrode with a sputtered iridium oxide coating can be stimulated at maximal levels for the lifetime of the implant without clinically significant dissolution of platinum or iridium, and without increasing the potential at the electrode interface to cause hydrolysis or significant tissue damage. Histological examination of tissue that was adjacent to the neo electrodes indicated no clinically significant signs of increased inflammation and no arterial stenosis as a result of 6 months of continuous stimulation. The work presented here involved rigorous characterization and evaluation testing of the neo electrode, which was used to support its safety for chronic implantation. The testing strategies discussed provide a starting point and proven framework for testing new neuromodulation electrode concepts to support regulatory approval for clinical studies.

Chronic Interactions Between Carotid Baroreceptors and Chemoreceptors in Obesity Hypertension.

Carotid bodies play a critical role in protecting against hypoxemia, and their activation increases sympathetic activity, arterial pressure, and ventilation, responses opposed by acute stimulation of the baroreflex. Although chemoreceptor hypersensitivity is associated with sympathetically mediated hypertension, the mechanisms involved and their significance in the pathogenesis of hypertension remain unclear. We investigated the chronic interactions of these reflexes in dogs with sympathetically mediated, obesity-induced hypertension based on the hypothesis that hypoxemia and tonic activation of carotid chemoreceptors may be associated with obesity. After 5 weeks on a high-fat diet, the animals experienced a 35% to 40% weight gain and increases in arterial pressure from 106±3 to 123±3 mm Hg and respiratory rate from 8±1 to 12±1 breaths/min along with hypoxemia (arterial partial pressure of oxygen=81±3 mm Hg) but eucapnia. During 7 days of carotid baroreflex activation by electric stimulation of the carotid sinus, tachypnea was attenuated, and hypertension was abolished before these variables returned to prestimulation values during a recovery period. After subsequent denervation of the carotid sinus region, respiratory rate decreased transiently in association with further sustained reductions in arterial partial pressure of oxygen (to 65±2 mm Hg) and substantial hypercapnia. Moreover, the severity of hypertension was attenuated from 125±2 to 116±3 mm Hg (45%-50% reduction). These findings suggest that hypoxemia may account for sustained stimulation of peripheral chemoreceptors in obesity and that this activation leads to compensatory increases in ventilation and central sympathetic outflow that contributes to neurogenically mediated hypertension. Furthermore, the excitatory effects of chemoreceptor hyperactivity are abolished by chronic activation of the carotid baroreflex.

Long-term subthreshold electrical stimulation of the left stellate ganglion and a canine model of sudden cardiac death.

OBJECTIVES: We sought to develop a high-yield canine model of sudden cardiac death (SCD). BACKGROUND: Because electrical stimulation is a powerful means to elicit nerve sprouting, we hypothesize that subthreshold electrical stimulation is more effective than nerve growth factor (NGF) infusion in inducing nerve sprouting and SCD in dogs with myocardial infarction (MI) and complete atrioventricular block (CAVB). METHODS: We gave subthreshold electrical stimulation to the left stellate ganglion (LSG) in six normal dogs for 41 +/- 9 days (protocol 1) and to six dogs with MI and CAVB for 41 +/- 29 days, while continuously monitoring their cardiac rhythm (protocol 2). We also monitored the rhythm of two dogs with MI, CAVB, and NGF infusion to the LSG and determined the ventricular nerve density in six healthy control dogs. RESULTS: In protocol 1, the hearts from dogs with LSG electrical stimulation had a higher density of nerve fibers immunopositive to tyrosine hydroxylase, synaptophysin, and growth-associated protein-43 than those of normal control dogs (p < 0.01). In protocol 2, there was a high magnitude of cardiac nerve sprouting in all dogs studied. Ventricular tachycardia > or =8 beats and > or =20 beats was more frequent in dogs with electrical stimulation than in dogs with NGF infusion to the LSG (36 +/- 60 and 11 +/- 17 vs. 4.7 +/- 6.1 and 0.1 +/- 0.33 episodes per day, p < 0.05 and p < 0.03, respectively). Four of six dogs in protocol 2 had SCD. CONCLUSIONS: Subthreshold electrical stimulation of the LSG induces cardiac nerve sprouting and sympathetic hyperinnervation and facilitates the development of a high-yield canine model of ventricular arrhythmia and SCD.

Defibrillation energy requirements using a left anterior chest cutaneous to subcutaneous shocking vector: implications for a total subcutaneous implantable defibrillator.

BACKGROUND: Subcutaneous implantable defibrillators (ICDs) are being developed to facilitate ICD implantation. OBJECTIVE: The purpose of this study was to estimate the human defibrillation energy requirement (DER) using a left chest cutaneous (Q) to subcutaneous (SQ) shocking vector. METHODS: Twenty patients undergoing implantation of an indicated ICD were enrolled (15 males, age = 63 +/- 12 years; ejection fraction = 0.27 +/- 0.14). Defibrillation testing was performed using an investigational system consisting of an external defibrillator and a constructed connector to deliver a shock between a pectoral SQ can and a cardiac apical Q electrode. Two attempts at defibrillation using this configuration were allowed. Stage 1 testing started at 70 J with a step-down/step-up to 50 or 100 J, respectively. Stage 2 testing began at 50 J with a step-down/step-up to 30 or 70 J. RESULTS: During stage 1, a 70-J shock was successful in 7/9 (78%) patients. A second attempt was successful in 7/7 patients using a 50-J shock. In the two remaining patients, a second attempt using a 100-J shock was successful. During stage 2, a 50-J shock was successful in 10/11 (91%) patients. The protocol could not be completed in 2/11 patients. Of the remaining nine patients, a second defibrillation was successful in seven (78%) using a 30-J shock. CONCLUSIONS: The defibrillation energy requirement (DER) of this study vector was 50 J or less in most patients. This low DER supports further investigation of a totally SQ-ICD. However, the DER of 100 J in two patients indicates that further investigation is needed regarding DER variability and safety margins.

Global- and renal-specific sympathoinhibition in aldosterone hypertension.

Recent technology for chronic electric activation of the carotid baroreflex and renal nerve ablation provide global and renal-specific suppression of sympathetic activity, respectively, but the conditions for favorable antihypertensive responses in resistant hypertension are unclear. Because inappropriately high plasma levels of aldosterone are prevalent in these patients, we investigated the effects of baroreflex activation and surgical renal denervation in dogs with hypertension induced by chronic infusion of aldosterone (12 µg/kg per day). Under control conditions, basal values for mean arterial pressure and plasma norepinephrine concentration were 100±3 mm Hg and 134±26 pg/mL, respectively. By day 7 of baroreflex activation, plasma norepinephrine was reduced by ≈40% and arterial pressure by 16±2 mm Hg. All values returned to control levels during the recovery period. Arterial pressure increased to 122±5 mm Hg concomitant with a rise in plasma aldosterone concentration from 4.3±0.4 to 70.0±6.4 ng/dL after 14 days of aldosterone infusion, with no significant effect on plasma norepinephrine. After 7 days of baroreflex activation at control stimulation parameters, the reduction in plasma norepinephrine was similar but the fall in arterial pressure (7±1 mm Hg) was diminished (≈55%) during aldosterone hypertension when compared with control conditions. Despite sustained suppression of sympathetic activity, baroreflex activation did not have central actions to inhibit either the stimulation of vasopressin secretion or drinking induced by increased plasma osmolality during chronic aldosterone infusion. Finally, renal denervation did not attenuate aldosterone hypertension. These findings suggest that aldosterone excess may portend diminished blood pressure lowering to global and especially renal-specific sympathoinhibition during device-based therapy.

Regulation of renin secretion and arterial pressure during prolonged baroreflex activation: influence of salt intake.

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation (BA) has not yet been determined. As the sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes (5, 40, 450 mmol/d, respectively) under control conditions and during a 7-day constant level of BA. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mm Hg) sodium intakes, but pressure increased 9±2 mm Hg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng angiotensin I/mL/h) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1 ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mm Hg) and norepinephrine (20%-40%) were lower at all salt intakes during BA, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by BA lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during BA is independent of salt intake.

Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial.

BACKGROUND: Previous trials have demonstrated clinically significant and durable reductions in arterial pressure from baroreflex activation therapy (BAT), resulting from electrical stimulation of the carotid sinus using a novel implantable device. A second-generation system for delivering BAT, the Barostim neo™ system, has been designed to deliver BAT with a simpler device and implant procedure. METHODS: BAT, delivered with the advanced system, was evaluated in a single-arm, open-label study of patients with resistant hypertension, defined as resting systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 medications, including ≥1 diuretic. Stable medical therapy was required for ≥4 weeks before establishing pretreatment baseline by averaging two SBP readings taken ≥24 hours apart. RESULTS: Thirty patients enrolled from seven centers in Europe and Canada. From a baseline of 171.7 ± 20.2/99.5 ± 13.9 mm Hg, arterial pressure decreased by 26.0 ± 4.4/12.4 ± 2.5 mm Hg at 6 months. In a subset (n = 6) of patients with prior renal nerve ablation, arterial pressure decreased by 22.3 ± 9.8 mm Hg. Background medical therapy for hypertension was unchanged during follow-up. Three minor procedure-related complications occurred within 30 days of implant. All complications resolved without sequelae. CONCLUSION: BAT delivered with the second-generation system significantly lowers blood pressure in resistant hypertension with stable, intensive background medical therapy, consistent with studies of the first-generation system for electrical activation of the baroreflex, and provides a safety profile comparable to a pacemaker.

Effects of electrical stimulation of the carotid sinus baroreflex using the Rheos device on ventricular-vascular coupling and myocardial efficiency assessed by pressure-volume relations in non-vagotomized anesthetized dogs.

We investigated the effects of the carotid sinus baroreflex on coupling of the left ventricle (LV) and the arterial system in twelve anesthetized dogs, with all nerves and carotid sinus circulation intact and instrumented to measure LV pressure and volume. The Rheos(R) device was used to directly electrically stimulate the carotid sinus baroreceptors. Stimulation resulted in a significant reduction in systolic blood pressure (SBP), 95.6+/-8.1 to 77.3+/-5.3 mmHg (p<0.0001) and heart rate (HR), 85+/-13.2 to 67.2+/-18.8 (p<.001). Cardiac output was unchanged. Ventricular-vascular coupling was determined by the ratio of arterial and ventricular elastance (Ea/Ees). At baseline, Ea/Ees was 1.26+/-0.27 and after stimulation decreased to 0.51+/-0.16 (p<0.001), favoring optimization of metabolic efficiency. This decrease was entirely due to a reduction in Ea while Ees was unchanged. The maintenance of end-diastolic volume (EDV) during stimulation allowed stroke work (SW) to remain unchanged as arterial pressure decreased. Thus mechanical efficiency, described as the ratio of stroke work to pressure-volume area (SW/PVA) increased from baseline of 0.51+/-0.05 to 0.69+/-0.04 (p<0.0001) during baroreceptor stimulation. We conclude that electrical activation of the carotid sinus baroreceptors results in optimization of both energetic and mechanical efficiency and has no acute effect on LV Ees. These novel findings await confirmation in chronically instrumented animals.

Prolonged activation of the baroreflex decreases arterial pressure even during chronic adrenergic blockade.

Previous studies suggest that prolonged electric activation of the baroreflex may reduce arterial pressure more than chronic blockade of alpha(1)- and beta(1,2)-adrenergic receptors. To determine whether central inhibition of sympathetic outflow has appreciable effects to chronically reduce arterial pressure by actions distinct from well-established mechanisms, we hypothesized that chronic baroreflex activation would lower arterial pressure substantially even during complete alpha(1)- and beta(1,2)-adrenergic receptor blockade. This hypothesis was tested in 6 dogs during adrenergic blockade (AB; 18 days) with and without electric activation of the carotid baroreflex (7 days). During chronic AB alone, there was a sustained decrease in the mean arterial pressure of 21+/-2 mm Hg (control: 95+/-4 mm Hg) and an approximately 3-fold increase in plasma norepinephrine concentration (control: 138+/-6 pg/mL), likely attributed to baroreceptor unloading. In comparison, during AB plus prolonged baroreflex activation, plasma norepinephrine concentration decreased to control levels, and mean arterial pressure fell an additional 10+/-1 mm Hg. Because of differences in plasma norepinephrine concentration, we also tested the acute blood pressure-lowering effects of MK-467, a peripherally acting alpha(2)-antagonist. After administration of MK-467, there was a significantly greater fall in arterial pressure during AB (15+/-3 mm Hg) than during AB plus prolonged baroreflex activation (7+/-3 mm Hg). These findings suggest that reflex-induced increases in sympathetic activity attenuate reductions in arterial pressure during chronic AB and that inhibition of central sympathetic outflow by prolonged baroreflex activation lowers arterial pressure further by previously undefined mechanisms, possibly by diminishing attendant activation of postjunctional alpha(2)-adrenergic receptors.

T wave alternans as a predictor of spontaneous ventricular tachycardia in a canine model of sudden cardiac death.

INTRODUCTION: We recently developed an ambulatory canine model of spontaneous ventricular tachycardia (VT) and sudden cardiac death by creating myocardial infarction, complete AV block, and infusion of nerve growth factor to the left stellate ganglion. Whether or not T wave alternans is associated with the spontaneously occurring episodes of VT in our model was unclear. METHODS AND RESULTS: Through intracardiac electrograms obtained from an implantable cardioverter defibrillator, we manually measured T wave amplitudes prior to VT and while the dogs were at rest (baseline, no VT). Of the 79 VT episodes analyzed, 28 (35.4%) exhibited repolarization alternans. In contrast, only 3 (4.7%) of 64 baseline data cases displayed alternans (P < 0.0001). The magnitude of T wave alternans for dogs that died of sudden cardiac death, dogs that did not die suddenly, and for the total 28 episodes that exhibited repolarization alternans were 4.8 +/- 2.8 mm, 4.9 +/- 3.5 mm, and 4.9 +/- 3.3 mm, respectively (P = NS). We also found the sensitivity, specificity, positive predictive value, negative predictive value, and relative risk of repolarization alternans in predicting VT to be 35.4%, 95.3%, 90.3%, 54.5%, and 1.98, respectively. The ventricular rate prior to VT (65 +/- 11 beats/min) was significantly higher than that at rest (49 +/- 12 beats/min; P < 0.0001). CONCLUSION: T wave alternans often occurred immediately before the onset of VT in dogs with myocardial infarction, complete AV block, and nerve growth factor infusion to the left stellate ganglion. Increased sympathetic activity might be responsible for the occurrence of the T wave alternans.