Introduction The Impella 5.5® with SmartAssist System® has short term use (≤14 days) approval for cardiogenic shock. The largest diameter of the device is the 19 Fr pump motor (∼6.33 mm). We discuss a case of successful implantation, wean and explantation in a child with arterial vessels measuring smaller than the pump motor. Case Report A previously healthy 11 year old male presented with severe systolic dysfunction, ventricular arrhythmias and progression to cardiac arrest. Initial left ventricular ejection fraction (LVEF) was 27%. Femoral veno-arterial ECMO support was initiated. Endomyocardial biopsy was negative for myocarditis. He was transitioned to Impella 5.5® as a bridge to decision/recovery after 4 days of support. Pre-implant ultrasound showed the right subclavian artery measured 4.8 mm x 5.1 mm, smaller than the recommended 7 mm for adult implantation of Impella 5.5®. Despite this the 5.5 was implanted due to increased device longevity versus the smaller Impella CP®. A 10 mm diameter graft was anastomosed to the axillary artery and tunneled with an exit site lateral to the pectoralis major. Gentle pressure and external manipulation of the axillary artery allowed stepwise advancement and placement without complication, despite some resistance at the graft vessel junction. Device performed as expected at 4.5 liters on P8. The patient was extubated POD 4 and placed on oral cardiac remodeling and antiarrhythmic therapies with ongoing nutritional support and cardiac rehabilitation. Complications included access site bleeding, wound dehiscence requiring wound VAC and revised surgical closure. He improved over several weeks and tolerated weaning of support. The device developed low purge flow and high purge pressures, despite TPA per protocol, and was explanted POD 29. Post explant, he completed a 4 week antibiotic course for S. epidermidis bacteremia. He underwent subcutaneous ICD implant for gene-negative long QT syndrome and was discharged 2 months after presentation with an LVEF of 51%. Summary The Impella 5.5 can be used in a child with small arterial vessels and expected recoverable cardiac function, avoiding a sternotomy and ventriculotomy, and allowing for recovery and discharge to home.

Parasympathetic control of the heart via the vagus nerve is the primary mechanism that regulates beat-to-beat control of heart rate. Additionally, the vagus nerve exerts significant effects at the AV node, as well as effects on both atrial and ventricular myocardium. Vagal control is abnormal in heart failure, occurring at early stages of left ventricular dysfunction, and this reduced vagal function is associated with worse outcomes in patients following myocardial infarction and with heart failure. While central control mechanisms are abnormal, one of the primary sites of attenuated vagal control is at the level of the parasympathetic ganglion. It remains to be seen whether or not preventing or treating abnormal vagal control of the heart improves prognosis.

Background-Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). Although the therapeutic benefits of sympathetic inhibition with beta-blockers in HF are clear, the role of increased vagal tone in this setting has been less studied. We have investigated the impact of enhancing vagal tone (achieved through chronic cervical vagus nerve stimulation, [VNS]) on HF development in a canine high-rate ventricular pacing model.Methods and Results-Fifteen dogs were randomized into control (n = 7) and VNS (n = 8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 bpm for the first 4 weeks to develop HF and another 4 weeks at 180 bpm to maintain HF). Concomitant VNS, at an intensity reducing sinus rate approximate to 20 bpm, was delivered together with the ventricular pacing in the VNS group. At 4 and 8 weeks of ventricular pacing, both left ventricular end-diastolic and -systolic volumes were lower and left ventricular ejection fraction was higher in the VNS group than in the control group. Heart rate variability and baroreflex sensitivity improved in the VNS dogs. Rises in plasma norepinephrine, angiotensin II, and C-reactive protein levels, ordinarily expected in this model, were markedly attenuated with VNS treatment.Conclusions-Chronic VNS improves cardiac autonomic control and significantly attenuates HF development in the canine high-rate ventricular pacing model. The therapeutic benefit of VNS is associated with pronounced anti-inflammatory effects. VNS is a novel and potentially useful therapy for treating HF. (Circ Heart Fail. 2009; 2: 692-699.)

The subunit composition of nicotinic acetylcholine receptors (nAChR) that mediate synaptic transmission in autonomic pathways remain incompletely elucidated. Conotoxin (ctx) MII blocks the majority (~70%) of cholinergic ganglionic transmission in vivo but acts on both α3/β2 and α6/β2 nAChR (only 5.6-fold higher affinity for α3/β2 vs. α6/β2). We used a more specific nAChR blocker to investigate the hypothesis that α6/β2 nAChR play a functional role in ganglionic transmission. Methods 4 dogs were anesthetized and underwent cervical vagal nerve stimulations (VSTIM). The artery supplying the sinus node was perfused with Tyrodes solution in vivo. Sinus cycle length (SCL) was measured after 3, 5, and 10 Hz VSTIM before and after perfusion with ctx MII-H9A;L15A (2020-fold higher affinity for α6/β2 vs. α3/β2). Results At baseline VSTIM prolonged SCL by 345±38, 476±43, 901±125 msec. Perfusion with ctx MII-H9A;L15A resulted in similar responses to VSTIM (300±29, 449±37, 866±125 msec, p>0.05, ANOVA) suggesting that blockade of α6/β2 did not alter responsiveness. Hexamethonium abolished responses to VSTIM confirming that the ganglion was perfused entirely by the cannulated sinus node artery. Conclusion The previously reported blockade in this ganglion by ctx MII is attributable specifically to α3/β2 nAChR and not α6 containing receptors.

We have shown previously that exposure to intermittent nicotinic acetylcholine receptor (nAChR) agonist (DMPP) in dogs during pacing induced heart failure (HF) development results in prevention of parasympathetic down-regulation. We hypothesized that treatment with DMPP during development of HF can result in improved physiologic parameters. Methods Dogs underwent rapid pacing at 250 bpm and were treated with 300mcg of DMPP IV weekly for 6 weeks. During HF development, we recorded RR responses to DMPP injection, LV volumes (echo), and standard deviation (SD) of RR interval in conscious dogs (n=4 treated and 4 untreated). Results Results shown are at 42 days of pacing. Maximal RR following DMPP was 2133 msec±155 vs. 626 msec±15 with vehicle. EDV was less dilated in the treated group vs. untreated (71±3.5 ml vs. 81±1.9 ml). SD of RR was higher in the treated group at 42 days (131±2.5 vs. 51±12 msec) reflecting preserved parasympathetic tone. Conclusions Treatment with a nicotinic receptor agonist during HF development preserved ganglionic sensitivity to agonist, increased resting parasympathetic tone and attenuated adverse cardiac remodeling. These data suggest that repeated exposure to a nicotinic agonist during the development of HF can prevent the loss of parasympathetic control in HF and helps to preserve myocardial function, possibly mediated by preventing loss of nAChR ganglionic function.

Background-We have previously demonstrated that selective atrioventricular nodal (AVN) vagal stimulation (AVN-VS) can be used to control ventricular rate during atrial fibrillation (AF) in acute experiments. However, it is not known whether this approach could provide a long-term treatment in conscious animals. Thus, this study reports the first observations on the long-term efficacy and safety of this novel approach to control ventricular rate during AF in chronically instrumented dogs.Methods and Results-In 18 dogs, custom-made bipolar patch electrodes were sutured to the epicardial AVN fat pad for ;delivery of selective AVN- VS by a subcutaneously implanted nerve stimulator ( pulse width 100 mu s or 1 ms, frequency 20 or 160 Hz, amplitude 6 to 10 V). Fast-rate right atrial pacing ( 600 bpm) was used to induce and maintain AF. ECG, blood pressure, and body temperature were monitored telemetrically. One week after the induction of AF, AVN- VS was delivered and maintained for at least 5 weeks. It was found that AVN- VS had a consistent effect on ventricular rate slowing ( on average 45 +/- 13 bpm) over the entire period of observation. Echocardiography showed improvement of cardiac indices with ventricular rate slowing. AVN- VS was well tolerated by the animals, causing no signs of distress or discomfort.Conclusions-Beneficial long-term ventricular rate slowing during AF can be achieved by implantation of a nerve stimulator attached to the epicardial AVN fat pad. This novel concept is an attractive alternative to other methods of rate control and may be applicable in a selected group of patients.

Nicotinic acetylcholine receptors ( nAChR) are assembled from a pool of nine alpha-subunits and three beta-subunits into functional pentamers in peripheral autonomic neurons. The contribution of different subunits to native, physiologically important nAChR for synaptic transmission in autonomic ganglia is unclear. Here, we examined the importance of the alpha(7)-subunit for parasympathetic innervation of the heart. Normal (C57BL/6J), (alpha 7)-deficient (Chrna7), and wild-type littermate mice were implanted with telemetry devices, and, under conscious, unsedated conditions, ECG recordings were obtained at baseline and after atropine, propranolol, and hexamethonium bromide administration. Spectral analysis of heart rate variability [power spectral analysis (PSA)] was performed for the evaluation of resting autonomic tone to the heart. At the completion of conscious studies, animals were anesthetized and underwent electrical stimulation of the vagus nerve (VS) while R-R intervals were recorded. Heart rate at baseline and after atropine, propranolol, or hexamethonium was similar in all three groups of animals. PSA curves were similar between normal, wildtype, and Chrna7 mice. VS showed no difference between control and Chrna7 mice throughout the range of stimulation (5 - 20 Hz). Mice deficient in the (alpha 7)-nAChR subunit do not display differences in resting autonomic tone to the heart at baseline or under conditions of single and combined autonomic blockade. VS showed no difference in heart rate responses between normal and (alpha 7)-deficient mice. These data support previous findings in vitro and highlight the important differences in function between nicotinic receptor subtypes because (alpha 3)-deficient mice display major autonomic dysfunction. We conclude that the (alpha 7)-subunit does not contribute critically to resting parasympathetic control of the heart.

Decreased synaptic transmission in parasympathetic ganglia contributes to abnormal parasympathetic function in heart failure (HF). Because nicotinic ACh receptors (nAChR) mediate synaptic transmission at the ganglion and upregulate in response to chronic exposure to agonist in vitro, we tested the hypothesis that repeated exposures of ganglionic neurons to a nAChR agonist can prevent a loss of parasympathetic control in HF. Two sets of experiments were performed. In set 1, unpaced control dogs and dogs undergoing pacing-induced HF were treated with a repeated intravenous nicotinic agonist during the development of HF. Under conditions of sympathetic blockade, R-R responses to a bolus injection of 200 microg 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP; nicotinic agonist) were found to be increased five times over the untreated group after 6 wk. In experimental set 2, dogs treated with weekly DMPP injections and in HF were anesthetized and underwent electrical stimulation of the right vagus nerve, which showed sinus cycle length responses >10 times that of controls (P < 0.05). Complete ganglionic blockade with hexamethonium abolished all responses, confirming that synaptic transmission was mediated entirely by nAChRs in both controls and HF. Despite decreased ganglionic function leading to reduced parasympathetic control of the heart in HF, repeated exposure with a nicotinic agonist during the development of HF results in not only preserved but also supranormal effects of parasympathetic stimulation on the sinus node.

Parasympathetic control of the heart is attenuated in heart failure (HF). We investigated possible mechanisms and sites of altered vagal control in dogs with HF induced by rapid pacing. Muscarinic blockade reduced the R-R interval by 308 ms in controls but only by 32 ms in HF, indicating low levels of resting vagal tone. Vagomimetic doses of atropine sulfate prolonged the R-R interval by 109 ms in controls and increased standard deviation of the R-R interval by 66 ms but only by 46 and 16 ms, respectively, in HF. Bradycardia elicited by electrical stimulation of the vagus nerve was also attenuated in the HF group. Conversely, muscarinic receptor activation by bethanechol, and indirectly by neostigmine, elicited exaggerated R-R interval responses in HF. To investigate possible mechanisms, we measured muscarinic receptor density (Bmax) and acetylcholinesterase activity in different areas of the heart. In sinoatrial nodes, Bmax was increased (230 +/- 75% of control) and acetylcholinesterase decreased (80 +/- 6% of control) in HF. We conclude that muscarinic receptors are upregulated and acetylcholinesterase is reduced in the sinus node in HF. Therefore, reduced vagal control in HF is most likely due to changes of presynaptic function (ganglionic), because postsynaptic mechanisms augment vagal control in HF.

Nicotinic acetylcholine receptors (nAChRs) mediate ganglionic transmission in the peripheral autonomic nervous system in mammals. Functional neuronal nAChRs have been shown to assemble from a combination of α and β subunits, including α3, α5, α7, β2, and β4 in RNA-injected oocytes, but the subunit composition of functional neuronal nAChRsin vivoin mammals remains unknown. We examined the subunit composition of functional nAChRs in the intracardiac parasympathetic ganglion in a physiologically intact systemin vivo. We report here that localized perfusion of the canine intracardiac ganglionin situwith an antagonist specific for nAChRs containing an α3/β2 subunit interface (α-conotoxin MII 100–200 nm) resulted in reversible attenuation of the sinus cycle length (SCL) response by ∼70% to electrical stimulation of the preganglionic vagus nerve. Perfusion with antagonist specific for receptors containing an α3/β4 subunit interface (α-conotoxin AuIB 1 μm) resulted in attenuation in SCL responses (∼20%) compared with baseline when applied by itself, but not in animals pretreated with α-conotoxin MII. Perfusion of the ganglion with α-bungarotoxin (1 μm, which blocks α7 receptors) caused a reduction in SCL response by ∼30% compared with baseline when perfused on its own and when added after blockade with MII and AuIB. Perfusion with hexamethonium bromide resulted in complete blockade of ganglionic transmission, confirming total perfusion of the ganglion and the nicotinic nature of ganglionic transmission at this synapse. Immunohistochemistry using monoclonal antibodies against specific nicotinic subunits confirmed the presence of α3, α7, β2, and β4 subunits. We conclude that functional ganglionic transmission in the canine intracardiac ganglion is mediated primarily by receptors containing an α3/β2 subunit interface, with a smaller contribution by receptors containing α7 nAChRs. Despite the presence of β4 subunits in functional channels, a contribution of a distinct α3/β4 receptor population that does not include an α3/β2 subunit interface was less clear.

BACKGROUND Previous work has shown that spontaneous and stimulated vagal activity is diminished in heart failure (HF) despite upregulation of functional postsynaptic cholinergic mechanisms. We therefore examined function of the postganglionic neuron in the paced canine model of HF as a possible site for diminished control. METHODS AND RESULTS We measured sinus cycle length changes in response to electrical stimulation of preganglionic and postganglionic parasympathetic neurons innervating the sinoatrial node in control and HF dogs (both, n=8). Cervical vagus stimulation (preganglionic) demonstrated attenuated responses in the HF group at all levels of stimulation (P<0.05). Stimulation of the right atrial fat pad, containing both postganglionic nerves and terminals of preganglionic neurons, showed no such difference between control and HF (200+/-25 versus 192+/-18 ms). To ensure that preganglionic input and different levels of baseline sympathetic activity did not contribute to the group difference, similar stimulations were done in the presence of ganglionic and beta-adrenergic blockade. Under these conditions, postganglionic stimulation showed smaller changes in sinus cycle length, but the HF group response remained significantly higher than in controls (76+/-10 versus 20+/-2 ms; P<0. 01), indicating that the difference was independent of preganglionic input and sympathetic activity. CONCLUSIONS A component of attenuated parasympathetic control in HF is located within the peripheral efferent limb. This defect is located within the parasympathetic ganglion. Future work should be focused on determining mechanisms of attenuated ganglionic transmission so that means targeted at restoring vagal activity can be developed.