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OBJECTIVE: Supervised exercise therapy (SET) provides clinical benefit for patients suffering from intermittent claudication and has been widely recommended as first-line therapy before endovascular or surgical intervention. However, published rates of SET program completion range from 5% to 55%, with historic completion of 54% at our own institution. As such, we sought to identify if targeted patient-supportive interventions improve SET completion rates while still maintaining efficacious SET programming. METHODS: Patients who were diagnosed with intermittent claudication, as defined by ankle-brachial index (ABI) <0.9 without rest pain, were offered enrollment in a prospective quality improvement protocol for our 12-week SET for peripheral artery disease program. Program completion was defined as ≥24 of 36 offered sessions over 12 weeks. A three-pronged approach was utilized to improve completion during the study, including financial incentives up to $180, scheduled coaching with our advanced practitioner staff, and informational materials on the importance of SET programming and lifestyle modification. Patient-reported improvements in walking symptoms were tracked via regularly administered questionnaires. Functional measures of SET programming including total walking duration and distance, metabolic equivalent of task, and ABIs; vascular intervention within 12-months after enrollment was also collected and compared using univariate paired analysis. RESULTS: In total, seventy-three patients were enrolled in SET for peripheral artery disease programming over the study period. Utilizing our three-pronged coaching approach, 56 patients completed SET programming, increasing our SET completion rate to 76.7% over a 2-year study period. Compared with pre-SET baseline, patients who completed SET noted less pain, aching, cramps in calves when walking (P = .004), and less difficulty walking 1 block (P = .038). Additionally, patients significantly increased their metabolic equivalent of task (3.1 vs 2.6; P < .001), total walking duration (30 mins vs 13.5 mins; P < .001), and total walking distance (0.7 vs 0.3 miles; P < .001) from their pre-SET baseline. There were no changes in participant ABIs from enrollment to completion in participants. Patients who completed SET programming also delayed vascular intervention compared with those who did not complete SET or declined participation (213.5 vs 122.5 days from enrollment; P = .041). CONCLUSIONS: Targeted incentives, including cost-coverage vouchers and personalized coaching with instructional materials, successfully improved patient completion of a prescribed SET program. Patients who completed SET programming reported subjective improvement in walking symptoms and objective walking benefits. In addition, these patients had delayed time to vascular intervention, supporting current vascular guidelines advocating for effective SET therapy prior to offering vascular intervention for intermittent claudication.
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BACKGROUND: Supervised exercise therapy (SET) provides clinical benefit for patients suffering from intermittent claudication due to peripheral artery disease (PAD). However, enrollment in programs when offered remains low. We sought to identify patient-reported barriers to enrollment in SET as part of a prospective quality improvement program. METHODS: Patients who presented to clinic and were diagnosed with claudication were offered enrollment in a prospective quality improvement protocol, offered at 9 regional offices throughout our health system. Both patients who enrolled and declined enrollment were offered a 12-question questionnaire to identify potential barriers to enrollment. Additional data including gender, smoking status, ankle-brachial index (ABI), proximity to the nearest regional office, and disadvantage levels of neighborhoods (low: 1-3, medium: 4-7, and high: 8-10 area deprivation index [ADI]) was collected and compared by program participation using univariate analysis. RESULTS: Patients enrolled in the SET program (n = 66 patients) versus those who declined (n = 84 patients) were of similar age (medium age: 71.4 vs. 69.7 years, P = 0.694), baseline ABI (0.6 vs. 0.6, P = 0.944), smoking status (former 56.1% vs. 53.6%, P = 0.668), distance away from outpatient center (8.2 mi vs. 8.4 mi, P = 0.249), and had similar Connecticut state ADIs (2021 high-disadvantage: 35.4% vs. 33.3%, P = 0.549). Patients participating in the SET program were more likely to be male (78.8% vs. 56.0%, P = 0.003). Top self-reported barriers for patients who declined participation included transportation/distance (39.3%), preference for independent walking (56.0%), inability to commit to 3 sessions per week (52.4%), and lack of interest (20.2%). In addition, a higher proportion of patients who declined participation identified severe barriers of preference for independent walking (39.3% vs. 1.5%, P < 0.001), inability to commit to 3 sessions per week (26.2% vs. 3.0% P < 0.001), transportation/distance issues (23.8% vs. 7.6% P = 0.008), and cost (27.4% vs. 9.1%, P = 0.005) as significant barriers for participation in SET. CONCLUSIONS: Patients who declined participation in SET for PAD had similar disease status and access to care than participating counterparts. Top reported barriers to enrollment include a preference for independent walking, transportation/distance, commitment to 3x/week program, and cost, which highlight areas of focus for equitable access to these limb-saving services.
Assuntos
Terapia por Exercício , Claudicação Intermitente , Doença Arterial Periférica , Humanos , Doença Arterial Periférica/terapia , Doença Arterial Periférica/fisiopatologia , Doença Arterial Periférica/diagnóstico , Masculino , Feminino , Idoso , Claudicação Intermitente/terapia , Claudicação Intermitente/fisiopatologia , Claudicação Intermitente/diagnóstico , Pessoa de Meia-Idade , Resultado do Tratamento , Estudos Prospectivos , Acessibilidade aos Serviços de Saúde , Aceitação pelo Paciente de Cuidados de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Recuperação de Função Fisiológica , Idoso de 80 Anos ou maisRESUMO
Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO2/H+, however, it is not clear how these cells detect changes in CO2/H+. Considering Kir4.1/5.1 channels are CO2/H+-sensitive and important for several astrocyte-dependent processes, we consider Kir4.1/5.1 a leading candidate CO2/H+ sensor in RTN astrocytes. To address this, we show that RTN astrocytes express Kir4.1 and Kir5.1 transcripts. We also characterized respiratory function in astrocyte-specific inducible Kir4.1 knockout mice (Kir4.1 cKO); these mice breathe normally under room air conditions but show a blunted ventilatory response to high levels of CO2, which could be partly rescued by viral mediated re-expression of Kir4.1 in RTN astrocytes. At the cellular level, astrocytes in slices from astrocyte-specific inducible Kir4.1 knockout mice are less responsive to CO2/H+ and show a diminished capacity for paracrine modulation of respiratory neurons. These results suggest Kir4.1/5.1 channels in RTN astrocytes contribute to respiratory behavior.
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Astrócitos , Dióxido de Carbono , Camundongos , Animais , Astrócitos/fisiologia , Respiração , Neurônios/fisiologia , Camundongos KnockoutRESUMO
Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt-Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt-Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt-Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.
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Transtorno do Espectro Autista , Deficiência Intelectual , Humanos , Animais , Camundongos , Clemastina , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Preparações Farmacêuticas , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genéticaRESUMO
Aneurysmal pelvic arteriovenous malformations in male patients are exceptionally rare. Upon spontaneous or traumatic rupture, these aneurysms can cause severe hemorrhage and are often associated with high mortality. Given that most intact aneurysms are found after symptomatic presentation, other case reports have detailed an approach for elective endovascular treatment for concomitant arterial and venous embolization. We describe an incidental discovery of a 7-cm-high flow pelvic aneurysmal arteriovenous malformation and successful endovascular treatment strategy through staged arterial and venous embolization, reducing the risk of rupture owing to high flow collateralization.
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General anesthetics are a mainstay of modern medicine, and although much progress has been made towards identifying molecular targets of anesthetics and neural networks contributing to endpoints of general anesthesia, our understanding of how anesthetics work remains unclear. Reducing this knowledge gap is of fundamental importance to prevent unwanted and life-threatening side-effects associated with general anesthesia. General anesthetics are chemically diverse, yet they all have similar behavioral endpoints, and so for decades, research has sought to identify a single underlying mechanism to explain how anesthetics work. However, this effort has given way to the 'multiple target hypothesis' as it has become clear that anesthetics target many cellular proteins, including GABAA receptors, glutamate receptors, voltage-independent K+ channels, and voltagedependent K+, Ca2+ and Na+ channels, to name a few. Yet, despite evidence that astrocytes are capable of modulating multiple aspects of neural function and express many anesthetic target proteins, they have been largely ignored as potential targets of anesthesia. The purpose of this brief review is to highlight the effects of anesthetic on astrocyte processes and identify potential roles of astrocytes in behavioral endpoints of anesthesia (hypnosis, amnesia, analgesia, and immobilization).
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Anestésicos Gerais , Astrócitos , Anestesia Geral , Anestésicos Gerais/efeitos adversos , Humanos , Receptores de GABA-ARESUMO
Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et al., 2019). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)-, and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity.
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Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/metabolismo , Epilepsias Mioclônicas/metabolismo , Hidrogênio/metabolismo , Núcleos Intralaminares do Tálamo/metabolismo , Pulmão/inervação , Respiração , Somatostatina/metabolismo , Animais , Modelos Animais de Doenças , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Feminino , Ácido Glutâmico/metabolismo , Núcleos Intralaminares do Tálamo/fisiopatologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Inibição Neural , Somatostatina/genética , Transmissão SinápticaRESUMO
Respiratory chemoreceptors regulate breathing in response to changes in tissue CO2/H+. Blood flow is a fundamental determinant of tissue CO2/H+, yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO2/H+-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al., 2017). Here, we show in mice that CO2/H+ dilates arterioles in other chemoreceptor regions, thus demonstrating CO2/H+ vascular reactivity in the RTN is unique. We also identify P2Y2 receptors in RTN smooth muscle cells as the substrate responsible for this response. Specifically, pharmacological blockade or genetic deletion of P2Y2 from smooth muscle cells blunted the ventilatory response to CO2, and re-expression of P2Y2 receptors only in RTN smooth muscle cells fully rescued the CO2/H+ chemoreflex. These results identify P2Y2 receptors in RTN smooth muscle cells as requisite determinants of respiratory chemoreception.
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Dióxido de Carbono/metabolismo , Músculo Liso Vascular , Respiração , Animais , Células Quimiorreceptoras/metabolismo , Hidrogênio/metabolismo , Bulbo/fisiologia , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Receptores Purinérgicos P2Y2/genética , Receptores Purinérgicos P2Y2/metabolismo , Receptores Purinérgicos P2Y2/fisiologiaRESUMO
Dravet syndrome (DS) is a form of epilepsy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Respiratory failure is a leading cause of SUDEP, and DS patients' frequently exhibit disordered breathing. Despite this, mechanisms underlying respiratory dysfunction in DS are unknown. We found that mice expressing a DS-associated Scn1a missense mutation (A1783V) conditionally in inhibitory neurons (Slc32a1cre/+::Scn1aA1783V fl/+; defined as Scn1aΔE26) exhibit spontaneous seizures, die prematurely and present a respiratory phenotype including hypoventilation, apnea, and a diminished ventilatory response to CO2. At the cellular level in the retrotrapezoid nucleus (RTN), we found inhibitory neurons expressing the Scn1a A1783V variant are less excitable, whereas glutamatergic chemosensitive RTN neurons, which are a key source of the CO2/H+-dependent drive to breathe, are hyper-excitable in slices from Scn1aΔE26 mice. These results show loss of Scn1a function can disrupt respiratory control at the cellular and whole animal levels.
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Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Respiração/genética , Convulsões/genética , Potenciais de Ação/genética , Animais , Dióxido de Carbono/toxicidade , Modelos Animais de Doenças , Epilepsias Mioclônicas/fisiopatologia , Humanos , Camundongos , Mutação de Sentido Incorreto/genética , Neurônios/metabolismo , Neurônios/patologia , Convulsões/fisiopatologia , Morte Súbita Inesperada na Epilepsia/patologiaRESUMO
Cerebral blood flow is highly sensitive to changes in CO2/H+ where an increase in CO2/H+ causes vasodilation and increased blood flow. Tissue CO2/H+ also functions as the main stimulus for breathing by activating chemosensitive neurons that control respiratory output. Considering that CO2/H+-induced vasodilation would accelerate removal of CO2/H+ and potentially counteract the drive to breathe, we hypothesize that chemosensitive brain regions have adapted a means of preventing vascular CO2/H+-reactivity. Here, we show in rat that purinergic signaling, possibly through P2Y2/4 receptors, in the retrotrapezoid nucleus (RTN) maintains arteriole tone during high CO2/H+ and disruption of this mechanism decreases the CO2ventilatory response. Our discovery that CO2/H+-dependent regulation of vascular tone in the RTN is the opposite to the rest of the cerebral vascular tree is novel and fundamentally important for understanding how regulation of vascular tone is tailored to support neural function and behavior, in this case the drive to breathe.