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Autonomic function and the carotid body in the clinical perspective
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
Methods: CB denervation (CBD) was performed on CHF rats. Resting breathing patterns, including apnea/hypopnea (AHI) index, were measured by plethysmography. Heart rate variability (LF/HF) was calculated as index of autonomic function. Activation of pre-sympathetic neurons was assessed in the RVLM using Fra-1 immunostaining. Cardiac function and renal blood flow (RBF) were determined by transthoracic echocardiography and pulsed-wave Doppler imaging respectively (VEVO 770, Visualsonics). Cardiac and renal fibrosis, arrhythmia incidence, and survival rates were also estimated in CHFrats that underwent CBD. Results: CHF-rats compared to sham exhibited elevated AHI and increased LF/HF and reduced RBF. RVLM Fra-1 expression was significantly elevated relative to sham levels. CBD in CHF rats decreased (pre- vs. post-CBD, P b 0.05) LF/HF (2.1 ± 0.3 vs. 0.9 ±0.2), AHI (16.8 ± 1.8 vs. 10.6 ± 0.6 events/h), and RVLM Fra-1 expression (1.5 ± 0.1 vs. 0.9 ± 0.1 a.u.), and normalized RBF (19.6 ± 1.6 vs. 32.3 ± 3.6 ml/min/kg). CHF-CBD rats displayed reduced collagen deposition in the heart and kidneys and the incidence of cardiac arrhythmias and delayed the reduction in cardiac ejection fraction by 40%. Notably, CBD reduced the mortality rate in CHF rats by 40%. Conclusions: Our results show that CBD reduces hyper-activation of the RVLM and improves cardiorespiratory control and kidney perfusion, delays cardiac function deterioration and improves survival in CHF. Supported by NIH (PO1-HL62222), NIH (5F32HL108592) and FONDECYT 1140275. doi:10.1016/j.autneu.2015.07.299
10.4 Autonomic function and the carotid body in the clinical perspective P. Niewinski Cardiology Department, 4th Military Hospital, Wroclaw, Poland Excessive augmentation of peripheral chemoreceptors`(PChR) activity is a well described and common phenomenon in congestive heart failure syndrome. It is related to exercise intolerance, arrhythmic events, periodic breathing and increased mortality. Recent studies also suggest its role in pathophysiology of resistant hypertension. Elevated sympathetic tone resulting from the excitation of brainstem nuclei by hyperactive PChR is believed to be responsible for the above ominous clinical consequences. Therefore, strategies targeting PChR (e.g. carotid bodies) seem particularly interesting especially in such high-risk populations. However, several issues require particular attention regarding potential interventions on PChR in heart failure and/or hypertensive patients. These caveats include: excessive lowering of sympathetic tone, problems with surgical / endovascular approach and decreased ventilatory drive. Moreover, the clinical predictors of favourable response to the therapeutic modulation of PChR are currently unknown. Additionally, it must be acknowledged that different types of PChR (i.e. carotid vs. aortic bodies) exert various hemodynamic and ventilatory responses. For example blood pressure response seems to be controlled mostly by carotid bodies, while heart rate response is believed to be mediated through aortic bodies. Another important clinical aspect of PChR physiology is the effect of dopamine – inotropic and vasoactive drug commonly used in critically ill patients. By blocking the release of neurotransmitters from PChR dopamine may lead to dangerous hypoxia and complicate the process of weaning from the ventilatory support. All the above issues will be discussed in detail in the context of most recent publications and speaker`s personal experience. doi:10.1016/j.autneu.2015.07.300
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ABSTRACTS SELECTED FOR PRESENTATION 10.5 Reduced Carotid Body KLF2 Expression Contributes to Autonomic and Respiratory Dysfunction in Chronic Heart Failure N.J. Marcusa, Y. Dingb, R. Del Rioc, H.D. Schultza a Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA b Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA c Center of Biomedical Research, Universidad Autónoma de Chile, Santiago, Chile Background: Breathing instability and increased sympathetic nerve activity (SNA) are associated with increased arrhythmia incidence and contribute to mortality in chronic heart failure (CHF). Increased carotid chemoreflex (CC) sensitivity contributes to this sympatho-respiratory dysregulation. A chronic reduction in blood flow to the carotid body (CB) region may mediate enhanced CC sensitivity in CHF. Aim: We hypothesized that downregulation of the endothelial shear stresssensitive transcription factor Krüppel-like Factor 2 (KLF2) in the CB mediates increased CC sensitivity in CHF and contributes to sympathorespiratory dysfunction and arrhythmia incidence. Methods and Results: Minute ventilation (VE), renal SNA (RSNA), and ECG were measured at rest and in response to CC activation with isocapnic hypoxia (IsoH) in sham operated and CHF rabbits. Compared with shams, CHF rabbits (EF ~ 40%) exhibited increased apnea-hypopnea index (AHI: 6 ± 1 vs. 35 ± 5/h), resting RSNA (22 ± 2 vs. 43 ± 5% max), arrhythmia incidence (50 ± 10 vs.300 ± 100/h) and VE and RSNA responses to IsoH (all p b 0.05). Protein expression of KLF2 in the CB was decreased 50% in CHF compared to sham (0.50 ± 0.07 vs. 0.25 ± 0.07 n.u., p b 0.05). Adenoviral transfection of KLF2 to the CB in CHF restored KLF2 expression (0.55 ± 0.07 n.u.) and attenuated AHI (7 ± 2/h), RSNA (18 ± 2% max), arrhythmia incidence (46 ± 13/h), and the reflex responses to IsoH (all p b 0.05 vs. CHF). Conversely, KLF2 knockdown (lentiviral KLF2 siRNA) in sham CB decreased CB KLF2 expression (0.35 ± 0.04 n.u.) and increased AHI (14 ± 3/h) and RSNA (32 ± 4% max). Conclusions: Down-regulation of KLF2 in the CB increases CC sensitivity causing breathing instability and sympathetic activation with adverse cardiac consequences in CHF. Supported by NIH (PO1-HL62222), NIH (5F32HL108592) and FONDECYT 1140275.
doi:10.1016/j.autneu.2015.07.301
SYMPOSIUM 11: SYNAPTIC TRANSMISSION IN THE NTS AUTONOMIC PATHWAYS 11.1 Neuro-glial communication in NTS after hypoxia D. Accorsi-Mendonça, C.E.L. Almado, L.G.H. Bonagamba, J.A. Castania, D.J.A. Moraes, B.H. Machado Department of Physiology, School of Medicine of Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil Humans ascending to high altitudes are submitted to sustained hypoxia (SH), which activates the peripheral chemoreflex with several autonomic and respiratory responses. In this study we analyzed initially the effect of short-term SH (24 hours, FIO210%) on the processing of cardiovascular and respiratory reflexes using an in situ preparation
Methods: CB denervation (CBD) was performed on CHF rats. Resting breathing patterns, including apnea/hypopnea (AHI) index, were measured by plethysmography. Heart rate variability (LF/HF) was calculated as index of autonomic function. Activation of pre-sympathetic neurons was assessed in the RVLM using Fra-1 immunostaining. Cardiac function and renal blood flow (RBF) were determined by transthoracic echocardiography and pulsed-wave Doppler imaging respectively (VEVO 770, Visualsonics). Cardiac and renal fibrosis, arrhythmia incidence, and survival rates were also estimated in CHFrats that underwent CBD. Results: CHF-rats compared to sham exhibited elevated AHI and increased LF/HF and reduced RBF. RVLM Fra-1 expression was significantly elevated relative to sham levels. CBD in CHF rats decreased (pre- vs. post-CBD, P b 0.05) LF/HF (2.1 ± 0.3 vs. 0.9 ±0.2), AHI (16.8 ± 1.8 vs. 10.6 ± 0.6 events/h), and RVLM Fra-1 expression (1.5 ± 0.1 vs. 0.9 ± 0.1 a.u.), and normalized RBF (19.6 ± 1.6 vs. 32.3 ± 3.6 ml/min/kg). CHF-CBD rats displayed reduced collagen deposition in the heart and kidneys and the incidence of cardiac arrhythmias and delayed the reduction in cardiac ejection fraction by 40%. Notably, CBD reduced the mortality rate in CHF rats by 40%. Conclusions: Our results show that CBD reduces hyper-activation of the RVLM and improves cardiorespiratory control and kidney perfusion, delays cardiac function deterioration and improves survival in CHF. Supported by NIH (PO1-HL62222), NIH (5F32HL108592) and FONDECYT 1140275. doi:10.1016/j.autneu.2015.07.299
10.4 Autonomic function and the carotid body in the clinical perspective P. Niewinski Cardiology Department, 4th Military Hospital, Wroclaw, Poland Excessive augmentation of peripheral chemoreceptors`(PChR) activity is a well described and common phenomenon in congestive heart failure syndrome. It is related to exercise intolerance, arrhythmic events, periodic breathing and increased mortality. Recent studies also suggest its role in pathophysiology of resistant hypertension. Elevated sympathetic tone resulting from the excitation of brainstem nuclei by hyperactive PChR is believed to be responsible for the above ominous clinical consequences. Therefore, strategies targeting PChR (e.g. carotid bodies) seem particularly interesting especially in such high-risk populations. However, several issues require particular attention regarding potential interventions on PChR in heart failure and/or hypertensive patients. These caveats include: excessive lowering of sympathetic tone, problems with surgical / endovascular approach and decreased ventilatory drive. Moreover, the clinical predictors of favourable response to the therapeutic modulation of PChR are currently unknown. Additionally, it must be acknowledged that different types of PChR (i.e. carotid vs. aortic bodies) exert various hemodynamic and ventilatory responses. For example blood pressure response seems to be controlled mostly by carotid bodies, while heart rate response is believed to be mediated through aortic bodies. Another important clinical aspect of PChR physiology is the effect of dopamine – inotropic and vasoactive drug commonly used in critically ill patients. By blocking the release of neurotransmitters from PChR dopamine may lead to dangerous hypoxia and complicate the process of weaning from the ventilatory support. All the above issues will be discussed in detail in the context of most recent publications and speaker`s personal experience. doi:10.1016/j.autneu.2015.07.300
17
ABSTRACTS SELECTED FOR PRESENTATION 10.5 Reduced Carotid Body KLF2 Expression Contributes to Autonomic and Respiratory Dysfunction in Chronic Heart Failure N.J. Marcusa, Y. Dingb, R. Del Rioc, H.D. Schultza a Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA b Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA c Center of Biomedical Research, Universidad Autónoma de Chile, Santiago, Chile Background: Breathing instability and increased sympathetic nerve activity (SNA) are associated with increased arrhythmia incidence and contribute to mortality in chronic heart failure (CHF). Increased carotid chemoreflex (CC) sensitivity contributes to this sympatho-respiratory dysregulation. A chronic reduction in blood flow to the carotid body (CB) region may mediate enhanced CC sensitivity in CHF. Aim: We hypothesized that downregulation of the endothelial shear stresssensitive transcription factor Krüppel-like Factor 2 (KLF2) in the CB mediates increased CC sensitivity in CHF and contributes to sympathorespiratory dysfunction and arrhythmia incidence. Methods and Results: Minute ventilation (VE), renal SNA (RSNA), and ECG were measured at rest and in response to CC activation with isocapnic hypoxia (IsoH) in sham operated and CHF rabbits. Compared with shams, CHF rabbits (EF ~ 40%) exhibited increased apnea-hypopnea index (AHI: 6 ± 1 vs. 35 ± 5/h), resting RSNA (22 ± 2 vs. 43 ± 5% max), arrhythmia incidence (50 ± 10 vs.300 ± 100/h) and VE and RSNA responses to IsoH (all p b 0.05). Protein expression of KLF2 in the CB was decreased 50% in CHF compared to sham (0.50 ± 0.07 vs. 0.25 ± 0.07 n.u., p b 0.05). Adenoviral transfection of KLF2 to the CB in CHF restored KLF2 expression (0.55 ± 0.07 n.u.) and attenuated AHI (7 ± 2/h), RSNA (18 ± 2% max), arrhythmia incidence (46 ± 13/h), and the reflex responses to IsoH (all p b 0.05 vs. CHF). Conversely, KLF2 knockdown (lentiviral KLF2 siRNA) in sham CB decreased CB KLF2 expression (0.35 ± 0.04 n.u.) and increased AHI (14 ± 3/h) and RSNA (32 ± 4% max). Conclusions: Down-regulation of KLF2 in the CB increases CC sensitivity causing breathing instability and sympathetic activation with adverse cardiac consequences in CHF. Supported by NIH (PO1-HL62222), NIH (5F32HL108592) and FONDECYT 1140275.
doi:10.1016/j.autneu.2015.07.301
SYMPOSIUM 11: SYNAPTIC TRANSMISSION IN THE NTS AUTONOMIC PATHWAYS 11.1 Neuro-glial communication in NTS after hypoxia D. Accorsi-Mendonça, C.E.L. Almado, L.G.H. Bonagamba, J.A. Castania, D.J.A. Moraes, B.H. Machado Department of Physiology, School of Medicine of Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil Humans ascending to high altitudes are submitted to sustained hypoxia (SH), which activates the peripheral chemoreflex with several autonomic and respiratory responses. In this study we analyzed initially the effect of short-term SH (24 hours, FIO210%) on the processing of cardiovascular and respiratory reflexes using an in situ preparation