Expanded Use of the One-Step Technique for Simultaneous Landing Zone Stenting and Placement of the Melody Transcatheter Pulmonary Valve.

OBJECTIVES: We report a multicenter experience with simultaneous right ventricular outflow tract (RVOT) stenting and transcatheter pulmonary valve implantation using the Melody valve (Medtronic). BACKGROUND: Prestenting the RVOT before Melody valve implantation is now the standard of care. Prestenting is usually performed as a separate step. The "one-step" technique for simultaneous landing zone stenting and Melody delivery was previously reported using only Max LD stents (Medtronic). We report a multicenter experience of simultaneous stenting and Melody implantation using multiple stent types in combination. METHODS: This retrospective cohort study includes 33 patients from 3 centers who underwent simultaneous stenting and Melody valve implantation between 2017 and 2020. Key variables were compared with 31 patients from the same centers who underwent standard (non-simultaneous) prestenting followed by Melody implantation during the same time frame. RESULTS: The 2 groups were similar in terms of age, weight, sex, and total procedure time. The 2 groups had similar clinical results and safety profiles, with no difference between the postimplantation right ventricle (RV) to pulmonary artery systolic pressure gradient, RV to aortic pressure ratio, and complication rate. The simultaneous group had lower radiation exposure as measured by dose area product. Up to 3 stents were safely placed simultaneously with a Melody valve. CONCLUSIONS: Simultaneous RVOT stenting and Melody valve implantation can safely be used to place up to 3 stents outside a Melody valve. This approach can simplify the catheterization procedure and potentially reduce radiation dose.

Serial Dilation of Low-Profile Stents Delivered in the Aorta and Pulmonary Arteries in Pediatric Patients Leads to Spontaneous Fractures but Not to Adverse Events.

OBJECTIVES: Low-profile stents placed in pediatric patients with congenital heart disease must be expanded by balloon angioplasty to accommodate patient growth. During the process of serial dilation, some stents may spontaneously fracture. The incidence and safety profile of spontaneous fracture is unclear. We report the performance characteristics and safety profile of a cohort of low-profile, premounted stents placed in the pulmonary arteries and aorta and then serially dilated over time to accommodate patient growth, including incidence of fracture and any adverse events. METHODS: A retrospective chart review was conducted of 25 pediatric patients who underwent 27 stent placements with low-profile, premounted stents from January 2005 to September 2018. RESULTS: Nine stents (33%) sustained a spontaneous fracture. There was no statistically significant association between stent fracture and our variables of interest, ie, patient gender, patient weight at time of original stenting, stent location (aorta vs pulmonary artery), stent type, original diameter of stent, and weight at the time of stent implantation. There was no association between time to spontaneous fracture and the aforementioned variables of interest. The majority of the spontaneous fractures occurred within the first 4 years after stent implantation, and there was no difference in survival between the 3 stent types investigated in our cohort. CONCLUSION: One-third of stents undergoing serial dilation for patient growth fractured spontaneously. Patients with fractured stents were free from significant adverse events in this cohort.

Transient Receptor Potential Channels TRPM4 and TRPC3 Critically Contribute to Respiratory Motor Pattern Formation but not Rhythmogenesis in Rodent Brainstem Circuits.

Transient receptor potential channel, TRPM4, the putative molecular substrate for Ca2+-activated nonselective cation current (ICAN), is hypothesized to generate bursting activity of pre-Bötzinger complex (pre-BötC) inspiratory neurons and critically contribute to respiratory rhythmogenesis. Another TRP channel, TRPC3, which mediates Na+/Ca2+ fluxes, may be involved in regulating Ca2+-related signaling, including affecting TRPM4/ICAN in respiratory pre-BötC neurons. However, TRPM4 and TRPC3 expression in pre-BötC inspiratory neurons and functional roles of these channels remain to be determined. By single-cell multiplex RT-PCR, we show mRNA expression for these channels in pre-BötC inspiratory neurons in rhythmically active medullary in vitro slices from neonatal rats and mice. Functional contributions were analyzed with pharmacological inhibitors of TRPM4 or TRPC3 in vitro as well as in mature rodent arterially perfused in situ brainstem-spinal cord preparations. Perturbations of respiratory circuit activity were also compared with those by a blocker of ICAN. Pharmacologically attenuating endogenous activation of TRPM4, TRPC3, or ICANin vitro similarly reduced the amplitude of inspiratory motoneuronal activity without significant perturbations of inspiratory frequency or variability of the rhythm. Amplitude perturbations were correlated with reduced inspiratory glutamatergic pre-BötC neuronal activity, monitored by multicellular dynamic calcium imaging in vitro. In more intact circuits in situ, the reduction of pre-BötC and motoneuronal inspiratory activity amplitude was accompanied by reduced post-inspiratory motoneuronal activity, without disruption of rhythm generation. We conclude that endogenously activated TRPM4, which likely mediates ICAN, and TRPC3 channels in pre-BötC inspiratory neurons play fundamental roles in respiratory pattern formation but are not critically involved in respiratory rhythm generation.

Transcranial Doppler Microemboli Monitoring for Stroke Risk Stratification in Blunt Cerebrovascular Injury.

OBJECTIVES: To assess whether microemboli burden, assessed noninvasively by bedside transcranial Doppler ultrasonography, correlates with risk of subsequent stroke greater than 24 hours after hospital arrival among patients with blunt cerebrovascular injury. The greater than 24-hour time frame provides a window for transcranial Doppler examinations and therapeutic interventions to prevent stroke. DESIGN: Retrospective cohort study. SETTING: Level I trauma center. PATIENTS: One thousand one hundred forty-six blunt cerebrovascular injury patients over 10 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 1,146 blunt cerebrovascular injury patients; 54 (4.7%) experienced stroke detected greater than 24 hours after arrival. Among those with isolated internal carotid artery injuries, five of nine with delayed stroke had positive transcranial Dopplers (at least one microembolus detected with transcranial Dopplers) before stroke, compared with 46 of 248 without (risk ratio, 5.05; 95% CI, 1.41-18.13). Stroke risk increased with the number of microemboli (adjusted risk ratio, 1.03/microembolus/hr; 95% CI, 1.01-1.05) and with persistently positive transcranial Dopplers over multiple days (risk ratio, 16.0; 95% CI, 2.00-127.93). Among patients who sustained an internal carotid artery injury with or without additional vessel injuries, positive transcranial Dopplers predicted stroke after adjusting for ipsilateral and contralateral internal carotid artery injury grade (adjusted risk ratio, 2.91; 95% CI, 1.42-5.97). No patients with isolated vertebral artery injuries had positive transcranial Dopplers before stroke, and positive transcranial Dopplers were not associated with delayed stroke among patients who sustained a vertebral artery injury with or without additional vessel injuries (risk ratio, 0.90; 95% CI, 0.21-3.83). CONCLUSIONS: Microemboli burden is associated with higher risk of stroke due to internal carotid artery injuries, but monitoring was not useful for vertebral artery injuries.

Voltage-Dependent Rhythmogenic Property of Respiratory Pre-Bötzinger Complex Glutamatergic, Dbx1-Derived, and Somatostatin-Expressing Neuron Populations Revealed by Graded Optogenetic Inhibition.

The rhythm of breathing in mammals, originating within the brainstem pre-Bötzinger complex (pre-BötC), is presumed to be generated by glutamatergic neurons, but this has not been directly demonstrated. Additionally, developmental expression of the transcription factor Dbx1 or expression of the neuropeptide somatostatin (Sst), has been proposed as a marker for the rhythmogenic pre-BötC glutamatergic neurons, but it is unknown whether these other two phenotypically defined neuronal populations are functionally equivalent to glutamatergic neurons with regard to rhythm generation. To address these problems, we comparatively investigated, by optogenetic approaches, the roles of pre-BötC glutamatergic, Dbx1-derived, and Sst-expressing neurons in respiratory rhythm generation in neonatal transgenic mouse medullary slices in vitro and also more intact adult perfused brainstem-spinal cord preparations in situ. We established three different triple-transgenic mouse lines with Cre-driven Archaerhodopsin-3 (Arch) expression selectively in glutamatergic, Dbx1-derived, or Sst-expressing neurons for targeted photoinhibition. In each line, we identified subpopulations of rhythmically active, Arch-expressing pre-BötC inspiratory neurons by whole-cell recordings in medullary slice preparations in vitro, and established that Arch-mediated hyperpolarization of these inspiratory neurons was laser power dependent with equal efficacy. By site- and population-specific graded photoinhibition, we then demonstrated that inspiratory frequency was reduced by each population with the same neuronal voltage-dependent frequency control mechanism in each state of the respiratory network examined. We infer that enough of the rhythmogenic pre-BötC glutamatergic neurons also have the Dbx1 and Sst expression phenotypes, and thus all three phenotypes share the same voltage-dependent frequency control property.

Perturbations of Respiratory Rhythm and Pattern by Disrupting Synaptic Inhibition within Pre-Bötzinger and Bötzinger Complexes.

The pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes are the brainstem compartments containing interneurons considered to be critically involved in generating respiratory rhythm and motor pattern in mammals. Current models postulate that both generation of the rhythm and coordination of the inspiratory-expiratory pattern involve inhibitory synaptic interactions within and between these regions. Both regions contain glycinergic and GABAergic neurons, and rhythmically active neurons in these regions receive appropriately coordinated phasic inhibition necessary for generation of the normal three-phase respiratory pattern. However, recent experiments attempting to disrupt glycinergic and GABAergic postsynaptic inhibition in the pre-BötC and BötC in adult rats in vivo have questioned the critical role of synaptic inhibition in these regions, as well as the importance of the BötC, which contradicts previous physiological and pharmacological studies. To further evaluate the roles of synaptic inhibition and the BötC, we bilaterally microinjected the GABAA receptor antagonist gabazine and glycinergic receptor antagonist strychnine into the pre-BötC or BötC in anesthetized adult rats in vivo and in perfused in situ brainstem-spinal cord preparations from juvenile rats. Muscimol was microinjected to suppress neuronal activity in the pre-BötC or BötC. In both preparations, disrupting inhibition within pre-BötC or BötC caused major site-specific perturbations of the rhythm and disrupted the three-phase motor pattern, in some experiments terminating rhythmic motor output. Suppressing BötC activity also potently disturbed the rhythm and motor pattern. We conclude that inhibitory circuit interactions within and between the pre-BötC and BötC critically regulate rhythmogenesis and are required for normal respiratory motor pattern generation.

Intermittent hypercapnia enhances CO2 responsiveness and overcomes serotonergic dysfunction.

Serotonergic dysfunction compromises ventilatory chemosensitivity and may enhance vulnerability to pathologies such as the Sudden Infant Death Syndrome (SIDS). We have shown raphé contributions to central chemosensitivity involving serotonin (5-HT)-and γ-aminobutyric acid (GABA)-mediated mechanisms. We tested the hypothesis that mild intermittent hypercapnia (IHc) induces respiratory plasticity, due in part to strengthening of GABA mechanisms. Rat pups were IHc-pretreated (eight consecutive cycles; 5 min 5% CO2 - air, 10 min air) or constant normocapnia-pretreated as a control, each day for 5 consecutive days beginning at P12. We subsequently assessed CO2 responsiveness using the in situ perfused brainstem preparation. Hypercapnic responses were determined with and without pharmacological manipulation. Results show IHc-pretreatment induces plasticity sufficient for responsiveness despite removal of otherwise critical ketanserin-sensitive mechanisms. Responsiveness following IHc-pretreatment was absent if ketanserin was combined with GABAergic antagonism, indicating that plasticity depends on GABAergic mechanisms. We propose that IHc-induced plasticity could reduce the severity of reflex dysfunctions underlying pathologies such as SIDS.