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Babbage T, Sayegh ALC, Fan JL, Gant N, Paton JFR, Fisher JP. Influence of endurance versus resistance exercise training on central and peripheral chemoreflexes in young healthy individuals. J Physiol Sci 2025; 75:100027. [PMID: 40381469 PMCID: PMC12143778 DOI: 10.1016/j.jphyss.2025.100027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 05/10/2025] [Accepted: 05/15/2025] [Indexed: 05/20/2025]
Abstract
Heightened central and peripheral chemoreflex sensitivity are associated with poor outcomes, but therapeutic approaches to target them are lacking. Endurance and resistance exercise training improve a multitude of physiological outcomes, but their effects on ventilatory chemoreflex sensitivity are unclear. Accordingly, the cardiorespiratory responses to steady-state isocapnic hypoxia (10 % O2, 5-minutes) and hyperoxic hypercapnic rebreathing (5 % CO2-95 % O2) were compared in endurance, resistance, and untrained groups. Central chemoreflex sensitivity was taken as the slope of the relationship between minute ventilation (V̇E) and end-tidal partial pressure of CO2. Peripheral chemoreflex sensitivity was determined from the absolute increase in V̇E from baseline to peak V̇E expressed relative to the fall in oxygen saturation. Neither central (P = 0.093) nor peripheral (P = 0.847) ventilatory chemoreflex sensitivities were different between groups. Future investigations should seek to understand whether exercise training modality influences central and peripheral chemoreflex sensitivity in older and clinical populations.
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Affiliation(s)
- Thalia Babbage
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, New Zealand; Department of Anaesthesiology, Faculty of Medical & Health Sciences, University of Auckland, New Zealand
| | - Ana L C Sayegh
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, New Zealand
| | - Jui-Lin Fan
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, New Zealand
| | - Nicholas Gant
- Department of Exercise Sciences, Faculty of Science, University of Auckland, New Zealand
| | - Julian F R Paton
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, New Zealand
| | - James P Fisher
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, New Zealand.
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2
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Montuoro S, Gentile F, Giannoni A. Neuroimmune cross-talk in heart failure. Cardiovasc Res 2025; 121:550-567. [PMID: 39498795 DOI: 10.1093/cvr/cvae236] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 11/07/2024] Open
Abstract
Heart failure (HF) is characterized by autonomic nervous system (ANS) imbalance and low-grade chronic inflammation. The bidirectional relationship between the ANS and immune system (IS) is named 'neuroimmune cross-talk' (NICT) and is based on common signaling molecules, receptors, and pathways. NICT may be altered in HF, and neuroinflammation seems to be a main driver of HF progression. In HF, heightened sympathetic nerve activity triggers inflammatory cascades that lead to cardiomyocyte death and myocardial interstitial fibrosis. Concurrently, parasympathetic withdrawal may impair the cholinergic anti-inflammatory pathway, with a less effective immune response to infections or inflammatory events. Additionally, microglial activation and inflammatory molecules contribute to autonomic imbalance by acting on central nuclei and peripheral visceral feedbacks, which in turn promote adverse cardiac remodeling, HF decompensation, and potentially life-threatening arrhythmias. Therefore, neuroinflammation has been identified as a potential target for treatment. Pharmacological antagonism of the neurohormonal system remains the cornerstone of chronic HF therapy. While some drugs used in HF management may have additional benefits due to their anti-inflammatory properties, clinical trials targeting inflammation in patients with HF have so far produced inconclusive results. Nevertheless, considering the pathophysiological relevance of NICT, its modulation seems an appealing strategy to optimize HF management. Current research is therefore investigating novel pharmacological targets for anti-inflammatory drugs, and the immunomodulatory properties of denervation approaches and bioelectronic medicine devices targeting NICT and neuroinflammation in HF. A deeper understanding of the complex relationship between the ANS and IS, as outlined in this review, could therefore facilitate the design of future studies aimed at improving outcomes by targeting NICT in patients with HF.
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Affiliation(s)
- Sabrina Montuoro
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà, 33, 56127 Pisa, Italy
| | - Francesco Gentile
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà, 33, 56127 Pisa, Italy
- Cardiovascular Medicine Division, Fondazione Toscana G. Monasterio, Via Moruzzi 1, 56126 Pisa, Italy
| | - Alberto Giannoni
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà, 33, 56127 Pisa, Italy
- Cardiovascular Medicine Division, Fondazione Toscana G. Monasterio, Via Moruzzi 1, 56126 Pisa, Italy
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Żera T, Paleczny B, Siński M, Conde SV, Narkiewicz K, Ponikowski P, Paton JF, Niewiński P. Translating physiology of the arterial chemoreflex into novel therapeutic interventions targeting carotid bodies in cardiometabolic disorders. J Physiol 2025; 603:2487-2516. [PMID: 40186613 PMCID: PMC12072261 DOI: 10.1113/jp285081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/10/2025] [Indexed: 04/07/2025] Open
Abstract
This review resulted from a conference on the pathological role of arterial chemoreflex and carotid bodies in cardiometabolic diseases held at the 27th Congress of the Polish Cardiac Society in September 2023 in Poznan, Poland. It reflects the contribution of Polish researchers and their international collaborations, which have been fundamental in the development of the field. Aberrant activity of the carotid bodies leads to both high tonicity and increased sensitivity of the arterial chemoreflex with resultant sympathoexcitation in chronic heart failure, resistant hypertension and obstructive sleep apnoea. This observation has led to several successful attempts of removing or denervating the carotid bodies as a therapeutic option in humans. Regrettably, such interventions are accompanied by serious respiratory and acid-base balance side-effects. Rather than a single stereotyped reaction, arterial chemoreflex comprises an integrative multi-system response to a variety of stimulants and its specific reflex components may be individually conveyed at varying intensities. Recent research has revealed that carotid bodies express diverse receptors, synthesize a cocktail of mediators, and respond to a plethora of metabolic, hormonal and autonomic nervous stimuli. This state-of-the-art summary discusses exciting new discoveries regarding GLP-1 receptors, purinergic receptors, the glutamate-GABA system, efferent innervation and regulation of blood flow in the carotid body and how they open new avenues for novel pharmacological treatments selectively targeting specific receptors, mediators and neural pathways to correct distinct responses of the carotid body-evoked arterial chemoreflex in cardiometabolic diseases. The carotid body offers novel and advantageous therapeutic opportunities for future consideration by trialists.
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Affiliation(s)
- Tymoteusz Żera
- Department of Experimental and Clinical PhysiologyMedical University of WarsawWarsawPoland
| | - Bartłomiej Paleczny
- Department of Physiology and PathophysiologyWroclaw Medical UniversityWroclawPoland
| | - Maciej Siński
- Department of Internal Medicine, Hypertension and Vascular DiseasesMedical University of WarsawWarsawPoland
| | - Sílvia V. Conde
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências MédicasUniversidade NOVA de LisboaLisbonPortugal
| | - Krzysztof Narkiewicz
- Department of Hypertension and DiabetologyMedical University of GdańskGdańskPoland
| | - Piotr Ponikowski
- Institute of Heart DiseasesWroclaw Medical UniversityWroclawPoland
| | - Julian F.R. Paton
- Manaaki Manawa – The Centre for Heart Research, Department of Physiology, Faculty of Medical & Health SciencesUniversity of AucklandAucklandNew Zealand
| | - Piotr Niewiński
- Institute of Heart DiseasesWroclaw Medical UniversityWroclawPoland
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Siddiqi AK, Shahzad M, Kumar A, Ahmed M, Sridharan L, Abdou MH, Naeem M. The efficacy of inspiratory muscle training in improving clinical outcomes in heart failure patients: An updated systematic review and meta-analysis. J Cardiol 2025; 85:374-385. [PMID: 39909304 DOI: 10.1016/j.jjcc.2025.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/17/2025] [Accepted: 01/28/2025] [Indexed: 02/07/2025]
Abstract
BACKGROUND Inspiratory muscle training (IMT) has shown improvements in clinical variables for heart failure (HF) patients. We conducted a meta-analysis to investigate if IMT can enhance respiratory muscle strength, quality of life (QoL), and reduce cardiac biomarker levels in HF patients. METHODS PubMed, Cochrane Library, and Google Scholar databases were systematically searched up to July 8, 2024. Randomized controlled trials of IMT in HF patients were included. A random effects model was used to calculate weighted mean differences (WMDs) and 95 % confidence intervals. Outcomes analyzed included minute ventilation to carbon dioxide output slope (VE/VCO2), QoL, six-minute walk distance (6MWD), maximum expiratory pressure, maximum inspiratory pressure (MIP), N-terminal pro B-type natriuretic peptide (NT-pro-BNP), forced vital capacity, forced expiratory volume in one second, and metabolic equivalents. RESULTS Seventeen studies involving 510 patients (252 in IMT group, 258 in control) were included. IMT significantly improved 6MWD [WMD: 72.72; 95 % CI: (16.65 to 128.78); p = 0.01], QoL [WMD: -15.27; 95 % CI: (-21.01 to -9.53); p < 0.00001], VE/VCO2 [WMD: -5.09; 95 % CI: (-7.36 to -2.83); p < 0.0001], MIP [WMD: 13.77; 95 % CI: (7.51 to 20.03); p < 0.0001], and NT-pro-BNP levels [WMD: -659.66; 95 % CI: (-1212.87 to -106.46); p = 0.02]. CONCLUSION IMT significantly improved respiratory muscle strength, QoL, and reduced cardiac biomarker levels in patients with both heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. These findings suggest that IMT may be a promising exercise-based strategy for treating HF.
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Affiliation(s)
- Ahmed Kamal Siddiqi
- Division of Cardiothoracic Imaging, Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA.
| | - Maryam Shahzad
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Akash Kumar
- Department of Medicine, Bilawal Medical College, Jamshoro, Pakistan
| | - Manahil Ahmed
- Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Lakshmi Sridharan
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Mahmoud H Abdou
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Muhammad Naeem
- Division of Cardiothoracic Imaging, Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA
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Collins SÉ, Phillips DB, Stickland MK. Carotid chemoreceptor inhibition improves exercise tolerance in participants with elevated carotid chemosensitivity: A secondary analysis. Auton Neurosci 2025; 260:103278. [PMID: 40220511 DOI: 10.1016/j.autneu.2025.103278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/24/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025]
Abstract
RATIONALE Chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are characterized by exaggerated carotid chemoreceptor (CC) sensitivity and exercise intolerance. We tested the hypothesis that participants with elevated CC sensitivity would have the greatest improvement in exercise tolerance with CC inhibition, secondary to increased vascular conductance, and lower ventilatory requirements, dyspnea and leg discomfort. METHODS Data from healthy controls, and patients with CHF or COPD were included in this secondary analysis of results from 2 randomized placebo-controlled double-blind crossover trials. Assessments included pulmonary function, incremental cardiopulmonary exercise test, and basal CC sensitivity assessment. High CC sensitivity was defined as either a stepwise hypoxic ventilatory response (HVR) or transient HVR greater than one SD above the mean in healthy controls. Participants received 2 μg/kg/min dopamine or placebo infusions (randomized) during 2 separate constant work-rate exercise tests to examine exercise endurance time (EET) and cardiopulmonary responses. RESULTS Among 33 adults, 17 were categorized to normal HVR (11 controls/3 COPD/3 CHF), and 16 to high HVR (1 control/7 COPD/8 CHF). Participants with high HVR experienced significant dopamine-induced improvements in EET (pinteraction = 0.011), and reduced leg discomfort at the 4-min isotime (pinteraction = 0.024). Those with improved vascular conductance and leg discomfort had the greatest improvements in EET (p = 0.042 and p = 0.021, respectively). CONCLUSIONS CC inhibition with dopamine in participants with high HVR was associated with improvement in EET. These findings suggest that high HVR is related to exercise limitation, and that improvement in EET is associated with a CC-mediated increase in vascular conductance and leg discomfort.
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Affiliation(s)
- Sophie É Collins
- Research Institute of the McGill University Health Centre, McGill University, Montréal, Québec, Canada
| | - Devin B Phillips
- School of Kinesiology & Health Science, Faculty of Health, York University, Toronto, Ontario, Canada; Muscle Health Research Centre, Faculty of Health, York University, Toronto, Ontario, Canada
| | - Michael K Stickland
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; G.F. MacDonald Centre for Lung Health, Covenant Health, Edmonton, Alberta, Canada.
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Hinton T, Hope K, Adams Z, Simpson LL, Paton JFR, Kendrick A, Abdala AP, Blythe H, Nightingale AK, Hart EC. Carotid chemoreflex control of blood pressure at rest and during exercise in young-onset hypertension. J Physiol 2025; 603:2313-2332. [PMID: 40159372 DOI: 10.1113/jp287743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 02/07/2025] [Indexed: 04/02/2025] Open
Abstract
Despite reports of amplified carotid chemoreflex sensitivity to hypoxia in young adults with hypertension (<40 years), it is unclear whether this equates to a direct role of this reflex in maintaining high resting and exercise blood pressures (BP). The aim of this study was to examine whether tonic carotid chemoreflex activity contributes to high resting and exercise BP in young people with untreated hypertension compared to normotensives (NTN). In 14 NTN and 14 untreated hypertensives (HTN) (aged 27 ± 6 and 28 ± 5 years, respectively) the ventilatory and haemodynamic responses to hypoxia were measured using the transient hypoxic test at rest and during submaximal steady-state upright cycle exercise (40%-50%V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_2}{\mathrm{peak}}}}$ ). A double-blinded placebo-controlled systemic infusion of low-dose dopamine (2 mcg/kg/min) was used to inhibit the carotid chemoreflex and assess its tonic contribution to ventilation and BP at rest and submaximal exercise (mixed-model ANOVA). The hypoxic ventilatory response (HVR) at rest and submaximal cycle exercise were comparable between groups and were similarly blunted by dopamine infusion in both groups. However, at rest, there was a greater decrease in resting systolic BP (SBP) during carotid chemoreflex inhibition in the HTN group. Notably, during submaximal exercise, SBP was reduced during dopamine versus that during saline, but the decrease was similar between groups. The carotid chemoreflex appears to contribute to resting SBP in young people with untreated HTN but does not play a role in exaggerated exercise BP responses in this group. KEY POINTS: The role of the carotid chemoreflex in maintaining high resting and exercise blood pressures in young adults with untreated hypertension is unclear. Carotid chemoreflex sensitivity, assessed by the ventilatory response to hypoxia was similar between untreated young adults with hypertension (n = 14, age < 40 years) and age-matched normotensives (n = 14). During normoxic rest, there was a reduction in SBP during carotid chemoreflex inhibition with low-dose dopamine (2 mcg/kg/min; vs. saline) in people with hypertension which was not observed in the normotensive group. During submaximal cycle exercise, SBP was reduced during carotid chemoreflex inhibition, but this was similar between groups. These results suggest the carotid chemoreflex influences resting SBP in hypertensives but does not affect the exaggerated exercise BP response in this group.
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Affiliation(s)
- Thomas Hinton
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Katrina Hope
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Zoe Adams
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Lydia L Simpson
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Julian F R Paton
- Manaaki Manawa, The Centre for Heart Research, University of Auckland, Auckland, New Zealand
| | - Adrian Kendrick
- School of Applied Sciences, University of Western England, Bristol, UK
| | - Ana P Abdala
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Hazel Blythe
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Angus K Nightingale
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
- Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Emma C Hart
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
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7
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Javaheri S, Giannoni A, Somers VK, Malhotra A, Emdin M, Costanzo MR. Central sleep apnea and cardiovascular disease state-of-the-art. Sleep 2025; 48:zsae307. [PMID: 39786443 DOI: 10.1093/sleep/zsae307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/15/2024] [Indexed: 01/12/2025] Open
Abstract
Central sleep apnea, a rare polysomnographic finding in the general population, is prevalent in certain cardiovascular conditions including systolic and diastolic left ventricular dysfunction, atrial fibrillation, coronary artery disease, carotid artery stenosis, stroke, and use of certain cardiac-related medications. Polysomnographic findings of central sleep apnea with adverse cardiovascular impacts include nocturnal hypoxemia and arousals, which can lead to increased sympathetic activity both at night and in the daytime. Among cardiovascular diseases, central sleep apnea is most prevalent in patients with left ventricular systolic dysfunction; a large study of more than 900 treated patients has shown a dose-dependent relationship between nocturnal desaturation and mortality. Multiple small randomized controlled trials have shown mitigation of sympathetic activity when central sleep apnea is treated with nocturnal oxygen, continuous positive airway pressure, and adaptive servoventilation. However, two early randomized controlled trials with positive airway pressure devices have shown either a neutral effect on survival or excess premature mortality in the active treatment arm, compared to untreated central sleep apnea. In contrast, the results of the most recent trial using an advanced adaptive servoventilation device showed improved quality of life and no signal for mortality suggesting that treatment of central sleep apnea was at least safe. In addition to positive airway pressure devices, multiple medications have been shown to improve central sleep apnea, but no long-term trials of pharmacologic therapy have been published. Currently, phrenic nerve stimulation is approved for the treatment of central sleep apnea, and the results of a randomized controlled trial showed significant improvement in sleep metrics and quality of life.
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Affiliation(s)
- Shahrokh Javaheri
- Pulmonary and Sleep Division, Bethesda North Hospital, Cincinnati, OH, USA
| | - Alberto Giannoni
- Health Science Interdisciplinary Center, Scuola Superiore Sant'anna, Pisa, Italy
- Cardiology and Cardiovascular Medicine Department, Fondazione Toscana G. Monasterio, Pisa, Italy
| | - Virend K Somers
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Atul Malhotra
- Division of Pulmonary Critical Care, Sleep Medicine and Physiology, UC, San Diego, CA, USA
| | - Michele Emdin
- Health Science Interdisciplinary Center, Scuola Superiore Sant'anna, Pisa, Italy
- Cardiology and Cardiovascular Medicine Department, Fondazione Toscana G. Monasterio, Pisa, Italy
| | - Maria R Costanzo
- Department of Advanced Heart Failure and Transplant Cardiology, Midwest Cardiovascular Institute, Naperville, IL, USA
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Jura M, Tubek S, Reczuch J, Seredyński R, Niewiński P, Protasiewicz M, Ponikowska B, Paleczny B. Hemodynamic Factors Driving Peripheral Chemoreceptor Hypersensitivity: Is Severe Aortic Stenosis Treated with Transcatheter Aortic Valve Implantation a Valuable Human Model? Biomedicines 2025; 13:611. [PMID: 40149588 PMCID: PMC11940327 DOI: 10.3390/biomedicines13030611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/17/2025] [Accepted: 02/22/2025] [Indexed: 03/29/2025] Open
Abstract
Background: A reduction in carotid artery blood flow (CABF) and ultimately in wall shear stress (WSS) is a major driver of heightened peripheral chemoreceptor (PCh) activity in animal models of heart failure. However, it is yet to be translated to humans. To provide more insight into this matter, we considered severe aortic stenosis (AS) before and after transcatheter aortic valve implantation (TAVI) as a human model of carotid and aortic body function under dramatically different hemodynamic conditions. Materials and Methods: A total of 26 severe AS patients (aged 77 ± 6 y, body mass index: 29.1 ± 5.1 kg/m2, left ventricular ejection fraction (LVEF): 50 ± 15%) were subjected to a transient hypoxia test twice: immediately before vs. 1-4 months after TAVI (median follow-up: 95 days). PCh function was analyzed in terms of ventilatory (HVR, L/min/SpO2%) and heart rate responses to hypoxia (HR slope, bpm/SpO2%). Standard ultrasound (inc. aortic valve area [AVA], mean aortic valve gradient, peak aortic jet velocity, LVEF, and CABF), respiratory, hemodynamic, and blood parameters were collected at both visits. Pre- vs. post-TAVI data regarding HVR and HR slopes were available for N = 26 and N = 10 patients, respectively. Results: HVR did not change following TAVI (pre- vs. post-TAVI: 0.42 ± 0.29 vs. 0.39 ± 0.33 L/min/SpO2%, p = 0.523). The HR slope increased after TAVI (pre- vs. post-TAVI: 0.26 ± 0.23 vs. 0.37 ± 0.30 bpm/SpO2%, p = 0.019), and the magnitude of the increase was strongly associated with an increase in AVA (Spearman's R = 0.80, p = 0.006). No other significant relations between pre- vs. post-TAVI changes in PCh activity measures vs. hemodynamic parameters were found (all p > 0.12). Conclusions: The ventilatory component of the PCh reflex (defined as HVR) in severe AS patients is not affected by TAVI, and pre-TAVI values in this group are fairly comparable to those reported previously for healthy subjects. On the contrary, HR responses to hypoxia are increased after TAVI, and pre-TAVI values appear to be lower compared to the healthy population. An extraordinarily strong correlation between post-TAVI increases in HR slope and AVA may suggest that hemodynamic repercussions of the surgery in the aortic body area (most likely reduced WSS) play a critical role in determining aortic body function with a negligible effect on the carotid bodies. However, caution is needed when interpreting the results of the HR response to hypoxia in our study due to the small sample size (N = 10).
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Affiliation(s)
- Maksym Jura
- Department of Physiology and Pathophysiology, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wroclaw, Poland; (M.J.); (R.S.); (B.P.)
| | - Stanisław Tubek
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (S.T.); (J.R.); (P.N.); (M.P.)
| | - Jędrzej Reczuch
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (S.T.); (J.R.); (P.N.); (M.P.)
| | - Rafał Seredyński
- Department of Physiology and Pathophysiology, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wroclaw, Poland; (M.J.); (R.S.); (B.P.)
| | - Piotr Niewiński
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (S.T.); (J.R.); (P.N.); (M.P.)
| | - Marcin Protasiewicz
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (S.T.); (J.R.); (P.N.); (M.P.)
| | - Beata Ponikowska
- Department of Physiology and Pathophysiology, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wroclaw, Poland; (M.J.); (R.S.); (B.P.)
| | - Bartłomiej Paleczny
- Department of Physiology and Pathophysiology, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wroclaw, Poland; (M.J.); (R.S.); (B.P.)
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9
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Herring N, Ajijola OA, Foreman RD, Gourine AV, Green AL, Osborn J, Paterson DJ, Paton JFR, Ripplinger CM, Smith C, Vrabec TL, Wang HJ, Zucker IH, Ardell JL. Neurocardiology: translational advancements and potential. J Physiol 2025; 603:1729-1779. [PMID: 39340173 PMCID: PMC11955874 DOI: 10.1113/jp284740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
In our original white paper published in the The Journal of Physiology in 2016, we set out our knowledge of the structural and functional organization of cardiac autonomic control, how it remodels during disease, and approaches to exploit such knowledge for autonomic regulation therapy. The aim of this update is to build on this original blueprint, highlighting the significant progress which has been made in the field since and major challenges and opportunities that exist with regard to translation. Imbalances in autonomic responses, while beneficial in the short term, ultimately contribute to the evolution of cardiac pathology. As our understanding emerges of where and how to target in terms of actuators (including the heart and intracardiac nervous system (ICNS), stellate ganglia, dorsal root ganglia (DRG), vagus nerve, brainstem, and even higher centres), there is also a need to develop sensor technology to respond to appropriate biomarkers (electrophysiological, mechanical, and molecular) such that closed-loop autonomic regulation therapies can evolve. The goal is to work with endogenous control systems, rather than in opposition to them, to improve outcomes.
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Affiliation(s)
- N. Herring
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - O. A. Ajijola
- UCLA Neurocardiology Research Center of ExcellenceDavid Geffen School of MedicineLos AngelesCAUSA
| | - R. D. Foreman
- Department of Biochemistry and PhysiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityOKUSA
| | - A. V. Gourine
- Centre for Cardiovascular and Metabolic NeuroscienceUniversity College LondonLondonUK
| | - A. L. Green
- Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
| | - J. Osborn
- Department of SurgeryUniversity of MinnesotaMinneapolisMNUSA
| | - D. J. Paterson
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - J. F. R. Paton
- Manaaki Manawa – The Centre for Heart Research, Department of Physiology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
| | - C. M. Ripplinger
- Department of PharmacologyUniversity of California DavisDavisCAUSA
| | - C. Smith
- Department of Physiology and BiophysicsCase Western Reserve UniversityClevelandOHUSA
| | - T. L. Vrabec
- Department of Physical Medicine and Rehabilitation, School of MedicineCase Western Reserve UniversityClevelandOHUSA
| | - H. J. Wang
- Department of AnesthesiologyUniversity of Nebraska Medical CenterOmahaNEUSA
| | - I. H. Zucker
- Department of Cellular and Integrative PhysiologyUniversity of Nebraska Medical CenterOmahaNEUSA
| | - J. L. Ardell
- UCLA Neurocardiology Research Center of ExcellenceDavid Geffen School of MedicineLos AngelesCAUSA
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10
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Eser P, Käesermann D, Calamai P, Kalberer A, Stütz L, Huber S, Duffin J, Wilhelm M. Excess ventilation and chemosensitivity in patients with inefficient ventilation and chronic coronary syndrome or heart failure: a case-control study. Front Physiol 2025; 15:1509421. [PMID: 39911179 PMCID: PMC11794504 DOI: 10.3389/fphys.2024.1509421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/31/2024] [Indexed: 02/07/2025] Open
Abstract
Background In patients with chronic coronary syndromes (CCS), increased ventilation/carbon dioxide production (V ˙ E/V ˙ CO2) slope has been found to predict disease progression and mortality, similarly to patients with heart failure (HF); however, increased chemosensitivity, a well-established predictor for mortality in patients with HF, has rarely been assessed in patients with CCS. Method Patients with CCS, HF with reduced ejection fraction (EF < 50%), healthy controls (45+ years), and young healthy adults (<35 years) were recruited. For patients, aV ˙ E/V ˙ CO2 slope ≥36 was an inclusion criterion. The Duffin rebreathing method was used to determine the resting end-expiratory partial pressure of carbon dioxide (PETCO2), ventilatory recruitment threshold (VRT), and slope (sensitivity) during a hyperoxic (150 mmHg O2) and hypoxic (50 mmHg O2) rebreathing test to determine the central and peripheral chemosensitivity. Results In patients with CCS, HF, controls, and young healthy adults, medianV ˙ E/V ˙ CO2 slopes were 40.2, 41.3, 30.5, and 28.0, respectively. Both patient groups had similarly reduced hyperoxic VRT (at PETCO2 42.1 and 43.2 mmHg) compared to 46.0 and 48.8 mmHg in the control and young healthy adults. Neither hypoxic VRT nor hyper- or hypoxic slopes were significantly different in patients compared to controls. Both patient groups had lower resting PETCO2 than controls, but only patients with HF had increased breathing frequency and rapid shallow breathing at rest. Conclusion In patients with HF and/or CCS and excess ventilation, central chemoreflex VRT was reduced independently of the presence of HF. Low VRTs were related to resting excess ventilation in patients with CCS or HF; however, rapid shallow breathing at peak exercise was present only in patients with HF. Clinical trial registration number NCT05057884.
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Affiliation(s)
- Prisca Eser
- Centre for Rehabilitation & Sports Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Dominic Käesermann
- Centre for Rehabilitation & Sports Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Pietro Calamai
- Centre for Rehabilitation & Sports Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Anja Kalberer
- Centre for Rehabilitation & Sports Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Laura Stütz
- Centre for Rehabilitation & Sports Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Sarina Huber
- Centre for Rehabilitation & Sports Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - James Duffin
- Department of Anesthesia and Pain Management, University of Toronto, Toronto, ON, Canada
| | - Matthias Wilhelm
- Centre for Rehabilitation & Sports Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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11
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Zhang K, Shi Y, Han Y, Cai TY, Gu FM, Gu ZX, Zhang T, Huang MX. J-Shaped Association Between Respiratory Rate and In-Hospital Mortality in Acute Myocardial Infarction Patients Complicated by Congestive Heart Failure in Intensive Care Unit. Dose Response 2024; 22:15593258241303040. [PMID: 39629219 PMCID: PMC11613282 DOI: 10.1177/15593258241303040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 10/18/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Background: While respiratory rate has proven to be a sensitive prognostic indicator in ICU settings, its relevance in the context of Acute Myocardial Infarction (AMI) patients complicated by Congestive Heart Failure (CHF) remains underexplored. Therefore, this study aims to investigate the relationship between respiratory rate and in-hospital mortality in this specific patient cohort. Methods: This retrospective cohort study utilized the Medical Information Mart for Intensive Care-IV database to analyze all AMI patients with concomitant CHF. The primary outcome, in-hospital mortality, was assessed through multivariate analysis. Logistic regression models, restricted cubic spline regression models, and subgroup analyses were employed to explore the association between respiratory rate and in-hospital mortality. Results: The study encompassed 5056 participants diagnosed with both CHF and AMI. After adjusting for confounding variables, each incremental unit rise in respiratory rate was associated with an 8% increase in the risk of patient mortality (OR = 1.08, 95% CI: 1.05∼1.11, P < 0.001). When comparing individuals with respiratory rates in the first tertile (≤17 breaths per minute) and the third tertile (>17-20 breaths per minute) to those in the second tertile (17-20 breaths per minute), the adjusted ORs for in-hospital mortality were 1.09 (95% CI: 0.82∼1.46, P = 0.546) and 1.62 (95% CI: 1.27∼2.06, P < 0.001), respectively. A dose-response relationship depicted a J-shaped curve between respiratory rate and the risk of in-hospital mortality, with an inflection point at approximately 19 breaths per minute. Stratified analyses confirmed the robustness of this correlation. Conclusions: This study reveals a J-shaped association between respiratory rate and in-hospital mortality in ICU patients suffering from both AMI and CHF.
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Affiliation(s)
- Kai Zhang
- The Second Hospital of Jilin University, Changchun, China
| | - Yu Shi
- The Second Hospital of Jilin University, Changchun, China
| | - Yu Han
- Department of Ophthalmology, First Hospital of Jilin University, Changchun, China
- Department of Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Tian Yi Cai
- Jilin University Second Clinical School of Medicine, Changchun, China
| | - Fang Ming Gu
- Jilin University Second Clinical School of Medicine, Changchun, China
| | - Zhao Xuan Gu
- Jilin University Second Clinical School of Medicine, Changchun, China
| | - Tianqi Zhang
- Jilin University Second Clinical School of Medicine, Changchun, China
| | - Mao Xun Huang
- The Second Hospital of Jilin University, Changchun, China
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12
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Limberg JK, Ott EP, Pipkins AM, Lis EC, Gonsalves AM, Harper JL, Manrique-Acevedo C. Role of the peripheral chemoreceptors in cardiovascular and metabolic control in type 2 diabetes. J Physiol 2024; 602:4849-4864. [PMID: 39197114 DOI: 10.1113/jp286975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/30/2024] [Indexed: 08/30/2024] Open
Abstract
Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes (T2D) and the contribution of the peripheral chemoreceptors to resting cardiovascular and metabolic control. We hypothesized that: (1) adults with T2D exhibit exaggerated peripheral chemoreflex sensitivity; (2) the peripheral chemoreceptors contribute to cardiovascular dysfunction in T2D; and (3) attenuation of peripheral chemoreceptor activity improves glucose tolerance in T2D. Seventeen adults with diagnosed T2D [six males/11 females; aged 54 ± 11 years; glycated haemoglobin (HbA1c) 7.6 ± 1.5%] and 20 controls without T2D (9 males/11 females; aged 49 ± 13 years, HbA1c 5.2 ± 0.4%) participated in the study. The hypoxic ventilatory response (HVR) was assessed as an index of peripheral chemosensitivity. Resting heart rate, blood pressure and minute ventilation were measured when breathing normoxic followed by hyperoxic air (1.0F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) to acutely attenuate peripheral chemoreceptor activity. A subset of participants (n = 9 per group) completed two additional visits [normoxia (0.21F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), hyperoxia (1.0F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ )] where glucose and insulin were measured for 2 h following an oral glucose challenge. HVR was augmented in adults with T2D (-0.84 ± 0.49 L min-1/%) vs. control (-0.48 ± 0.40 L min-1/%, P = 0.021). Attenuation of peripheral chemoreceptor activity decreased heart rate (P < 0.001), mean blood pressure (P = 0.009) and minute ventilation (P = 0.002); any effect of hyperoxia did not differ between groups. There was no effect of hyperoxia on the glucose (control, P = 0.864; T2D, P = 0.982), nor insulin (control, P = 0.763; T2D, P = 0.189) response to the oral glucose challenge. Peripheral chemoreflex sensitivity is elevated in adults with T2D; however, acute attenuation of peripheral chemoreflex activity with hyperoxia does not restore cardiometabolic function. KEY POINTS: Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes and the contribution of the peripheral chemoreceptors to resting cardiovascular control and glucose tolerance. We observed elevated peripheral chemoreflex sensitivity in adults with diabetes which was associated with glycaemic control (i.e. glycated haemoglobin). Notably, acute attenuation of peripheral chemoreflex activity with hyperoxia did not restore cardiometabolic function in the individuals studied.
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Affiliation(s)
- Jacqueline K Limberg
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
| | - Elizabeth P Ott
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA
| | - Aubrey M Pipkins
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA
| | - Eric C Lis
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA
| | - Anna M Gonsalves
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA
| | - Jennifer L Harper
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA
| | - Camila Manrique-Acevedo
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
- Department of Medicine, University of Missouri, Columbia, MO, USA
- Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA
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13
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Sayegh ALC, Plunkett MJ, Babbage T, Dawes M, Paton JFR, Fisher JP. Peripheral chemoreflex restrains skeletal muscle blood flow during exercise in participants with treated hypertension. J Physiol 2024. [PMID: 39276118 DOI: 10.1113/jp286998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 08/01/2024] [Indexed: 09/16/2024] Open
Abstract
We tested the hypothesis that in human hypertension, an increased tonicity/sensitivity of the peripheral chemoreflex causes a sympathetically mediated restraint of nutritive blood flow to the exercising muscles. Fourteen patients with treated hypertension (age 69 ± 11 years, 136 ± 12/80 ± 11 mmHg; mean ± SD) were studied under conditions of intravenous 0.9% saline (control) and low-dose dopamine (2 µg kg-1 min-1) to inhibit the peripheral chemoreflex, at baseline, during isocapnic hypoxic rebreathing and during rhythmic handgrip exercise (3 min, 50% maximum voluntary contraction). At baseline, dopamine did not change mean blood pressure (95 ± 10 vs. 98 ± 10 mmHg, P = 0.155) but increased brachial artery blood flow (59 ± 20 vs. 48 ± 16 ml min-1, P = 0.030) and vascular conductance (0.565 ± 0.246 vs. 0.483 ± 0.160 ml min-1 mmHg-1; P = 0.039). Dopamine attenuated the increase in mean blood pressure (∆3 ± 4 vs. ∆8 ± 6 mmHg, P = 0.007) to isocapnic hypoxic rebreathing and reduced peripheral chemoreflex sensitivity by 28 ± 37% (P = 0.044). Rhythmic handgrip exercise induced increases in brachial artery blood flow and vascular conductance (both P < 0.05 vs. rest after 45 s) that were greater with dopamine than saline (e.g. Δ76 ± 54 vs. Δ60 ± 43 ml min-1 and Δ0.730 ± 0.440 vs. Δ0.570 ± 0.424 ml min-1 mmHg-1, respectively, at 60 s; main effect of condition both P < 0.0001). Our results indicate that the peripheral chemoreflex is tonically active at rest and restrains the blood flow and vascular conductance increases to exercise in treated human hypertension. KEY POINTS: It was hypothesised that in human hypertension, an increased tonicity/sensitivity of the peripheral chemoreflex causes a sympathetically mediated restraint of nutritive blood flow to the exercising muscles. Treated patients with hypertension (n = 14) were studied under conditions of intravenous 0.9% saline (control) and low-dose dopamine (2 µg kg-1 min-1) to inhibit the peripheral chemoreflex. Low-dose dopamine reduced resting ventilation and peripheral chemoreflex sensitivity, and while mean blood pressure was unchanged, brachial artery blood flow and vascular conductance were increased. Low-dose dopamine augmented the brachial artery blood flow and vascular conductance responses to rhythmic handgrip. These findings indicate that the peripheral chemoreflex is tonically active at rest and restrains the blood flow, and vascular conductance increases to exercise in treated human hypertension.
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Affiliation(s)
- Ana Luiza C Sayegh
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand
| | - Michael J Plunkett
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand
| | - Thalia Babbage
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand
| | - Mathew Dawes
- Department of Medicine, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand
| | - Julian F R Paton
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand
| | - James P Fisher
- Department of Physiology, Manaaki Manawa - The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand
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14
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Kowalski T, Rebis K, Wilk A, Klusiewicz A, Wiecha S, Paleczny B. Body Oxygen Level Test (BOLT) is not associated with exercise performance in highly-trained individuals. Front Physiol 2024; 15:1430837. [PMID: 39290618 PMCID: PMC11406178 DOI: 10.3389/fphys.2024.1430837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/16/2024] [Indexed: 09/19/2024] Open
Abstract
Introduction The analysis of chemoreflex and baroreflex sensitivity may contribute to optimizing patient care and athletic performance. Breath-holding tests, such as the Body Oxygen Level Test (BOLT), have gained popularity as a feasible way to evaluate the reflex control over the cardiorespiratory system. According to its proponents, the BOLT score reflects the body's sensitivity to carbon dioxide and homeostasis disturbances, providing feedback on exercise tolerance. However, it has not yet been scientifically validated or linked with exercise performance in highly-trained individuals. Therefore, we investigated the association of BOLT scores with the results of standard performance tests in elite athletes. Methods A group of 49 speedskaters performed BOLT, Wingate Anaerobic Test (WAnT), and cardiopulmonary exercise test (CPET) on a cycle ergometer. Peak power, total work, and power drop were measured during WAnT. Time to exhaustion and maximum oxygen uptake were measured during CPET. Spearman's rank correlation and multiple linear regression were performed to analyze the association of BOLT scores with parameters obtained during the tests, age, somatic indices, and training experience. Results No significant correlations between BOLT scores and parameters obtained during WAnT and CPET were found, r(47) = -0.172-0.013, p = 0.248-0.984. The parameters obtained during the tests, age, somatic indices, and training experience were not significant in multiple linear regression (p = 0.38-0.85). The preliminary regression model showed an R 2 of 0.08 and RMSE of 9.78 sec. Conclusions Our findings did not demonstrate a significant relationship between BOLT scores and exercise performance. Age, somatic indices, and training experience were not significant in our analysis. It is recommended to interpret BOLT concerning exercise performance in highly-trained populations with a great degree of caution.
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Affiliation(s)
- Tomasz Kowalski
- Department of Physiology, Institute of Sport - National Research Institute, Warsaw, Poland
| | - Kinga Rebis
- Department of Physiology, Institute of Sport - National Research Institute, Warsaw, Poland
| | - Adrian Wilk
- Department of Physiology, Institute of Sport - National Research Institute, Warsaw, Poland
| | - Andrzej Klusiewicz
- Department of Physical Education and Health in Biala Podlaska, Józef Piłsudski University of Physical Education in Warsaw, Warsaw, Poland
| | - Szczepan Wiecha
- Department of Physical Education and Health in Biala Podlaska, Józef Piłsudski University of Physical Education in Warsaw, Warsaw, Poland
| | - Bartłomiej Paleczny
- Department of Physiology and Pathophysiology, Wroclaw Medical University, Wrocław, Poland
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15
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Alvarez-Araos P, Jiménez S, Salazar-Ardiles C, Núñez-Espinosa C, Paez V, Rodriguez-Fernandez M, Raberin A, Millet GP, Iturriaga R, Andrade DC. Baroreflex and chemoreflex interaction in high-altitude exposure: possible role on exercise performance. Front Physiol 2024; 15:1422927. [PMID: 38895516 PMCID: PMC11184637 DOI: 10.3389/fphys.2024.1422927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 05/15/2024] [Indexed: 06/21/2024] Open
Abstract
The hypoxic chemoreflex and the arterial baroreflex are implicated in the ventilatory response to exercise. It is well known that long-term exercise training increases parasympathetic and decreases sympathetic tone, both processes influenced by the arterial baroreflex and hypoxic chemoreflex function. Hypobaric hypoxia (i.e., high altitude [HA]) markedly reduces exercise capacity associated with autonomic reflexes. Indeed, a reduced exercise capacity has been found, paralleled by a baroreflex-related parasympathetic withdrawal and a pronounced chemoreflex potentiation. Additionally, it is well known that the baroreflex and chemoreflex interact, and during activation by hypoxia, the chemoreflex is predominant over the baroreflex. Thus, the baroreflex function impairment may likely facilitate the exercise deterioration through the reduction of parasympathetic tone following acute HA exposure, secondary to the chemoreflex activation. Therefore, the main goal of this review is to describe the main physiological mechanisms controlling baro- and chemoreflex function and their role in exercise capacity during HA exposure.
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Affiliation(s)
- Pablo Alvarez-Araos
- Exercise Applied Physiology Laboratory, Centro de Investigación en Fisiología y Medicina de Altura, Departamento Biomedico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
- Departamento de Kinesiología, Facultad de Ciencias de la Salud, Universidad de Atacama, Copiapó, Chile
| | - Sergio Jiménez
- Departamento de Kinesiología, Facultad de Ciencias de la Salud, Universidad de Atacama, Copiapó, Chile
| | - Camila Salazar-Ardiles
- Exercise Applied Physiology Laboratory, Centro de Investigación en Fisiología y Medicina de Altura, Departamento Biomedico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
| | - Cristian Núñez-Espinosa
- Escuela de Medicina de la Universidad de Magallanes, Punta Arenas, Chile
- Centro Asistencial de Docencia e Investigación (CADI-UMAG), Santiago, Chile
| | - Valeria Paez
- Exercise Applied Physiology Laboratory, Centro de Investigación en Fisiología y Medicina de Altura, Departamento Biomedico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Maria Rodriguez-Fernandez
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Antoine Raberin
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Gregoire P. Millet
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Rodrigo Iturriaga
- Exercise Applied Physiology Laboratory, Centro de Investigación en Fisiología y Medicina de Altura, Departamento Biomedico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - David C. Andrade
- Exercise Applied Physiology Laboratory, Centro de Investigación en Fisiología y Medicina de Altura, Departamento Biomedico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
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16
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Kataoka Y, Sales ARK, Rodrigues AG, Goes-Santos BR, Azevedo LF, Groehs RV, Silva EO, Santos LS, Oliveira PA, Jordão CP, Andrade ACM, Lobo DML, Rondon E, Toschi-Dias E, Alves MJNN, Almeida DR, Negrão CE. Abnormal neurovascular control during central and peripheral chemoreceptors stimulation in heart failure patients with preserved ejection fraction. Clin Auton Res 2024; 34:363-374. [PMID: 38878143 DOI: 10.1007/s10286-024-01041-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 05/20/2024] [Indexed: 07/19/2024]
Abstract
PURPOSE Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF. METHODS Patients aged 55-80 years with symptoms of heart failure, body mass index ≤ 35 kg/m2, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m2, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e' index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF, n = 9). Patients without heart failure with preserved ejection fraction (non-HFpEF, n = 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O2 and 90% N2, with CO2 titrated) and central chemoreceptors stimulation (7% CO2 and 93% O2) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography. RESULTS During hypoxia, MSNA responses were greater (p < 0.001) and FBF responses were lower in patients with HFpEF (p = 0.006). Likewise, MSNA responses during hypercapnia were higher (p < 0.001) and forearm vascular conductance (FVC) levels were lower (p = 0.030) in patients with HFpEF. CONCLUSIONS Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction.
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Affiliation(s)
- Yufuko Kataoka
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Allan R K Sales
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
- D'Or Institute for Research and Education (IDOR), São Paulo, Brazil
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
| | - Amanda G Rodrigues
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
- Research and Education Institute, Hospital Sirio Libanes, São Paulo, Brazil
| | - Beatriz R Goes-Santos
- School of Physical Education, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Luciene F Azevedo
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Raphaela V Groehs
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Edna O Silva
- School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Luciana S Santos
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Patricia A Oliveira
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Camila P Jordão
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Ana C M Andrade
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Denise M L Lobo
- Physiotherapy Unit, Fametro University Center (Unifametro), Fortaleza, Ceará, Brazil
| | - Eduardo Rondon
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Edgar Toschi-Dias
- Psychology, Development and Public Policy Program, Catholic University of Santos, São Paulo, Brazil
| | - Maria Janieire N N Alves
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil
| | - Dirceu R Almeida
- Division of Cardiology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Carlos E Negrão
- Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, CEP 05403-904, Brazil.
- School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
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17
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Panza L, Piamonti D, Palange P. Pulmonary gas exchange and ventilatory efficiency during exercise in health and diseases. Expert Rev Respir Med 2024; 18:355-367. [PMID: 38912849 DOI: 10.1080/17476348.2024.2370447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 06/17/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION Cardiopulmonary exercise testing (CPET) is nowadays used to study the exercise response in healthy subjects and in disease. Ventilatory efficiency is one of the main determinants in exercise tolerance, and its main variables are a useful tool to guide pathophysiologists toward specific diagnostic pathways, providing prognostic information and improving disease management, treatment, and outcomes. AREAS COVERED This review will be based on today's available scientific evidence, describing the main physiological determinants of ventilatory efficiency at rest and during exercise, and focusing also on how CPET variables are modified in specific diseases, leading to the possibility of early diagnosis and management. EXPERT OPINION Growing knowledge on CPET interpretation and a wider use of this clinical tool is expected in order to offer more precise diagnostic and prognostic information to patients and clinicians, helping in the management of therapeutic decisions. Future research could be able to identify new and more simple markers of ventilatory efficiency, and to individuate new interventions for the improvement of symptoms, such as exertional dyspnea.
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Affiliation(s)
- Luigi Panza
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Daniel Piamonti
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Paolo Palange
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
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18
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Young DA, Jones PAT, Matenchuk BA, Sivak A, Davenport MH, Steinback CD. The effect of hyperoxia on muscle sympathetic nerve activity: a systematic review and meta-analysis. Clin Auton Res 2024; 34:233-252. [PMID: 38709357 DOI: 10.1007/s10286-024-01033-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 04/09/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE We conducted a meta-analysis to determine the effect of hyperoxia on muscle sympathetic nerve activity in healthy individuals and those with cardio-metabolic diseases. METHODS A comprehensive search of electronic databases was performed until August 2022. All study designs (except reviews) were included: population (humans; apparently healthy or with at least one chronic disease); exposures (muscle sympathetic nerve activity during hyperoxia or hyperbaria); comparators (hyperoxia or hyperbaria vs. normoxia); and outcomes (muscle sympathetic nerve activity, heart rate, blood pressure, minute ventilation). Forty-nine studies were ultimately included in the meta-analysis. RESULTS In healthy individuals, hyperoxia had no effect on sympathetic burst frequency (mean difference [MD] - 1.07 bursts/min; 95% confidence interval [CI] - 2.17, 0.04bursts/min; P = 0.06), burst incidence (MD 0.27 bursts/100 heartbeats [hb]; 95% CI - 2.10, 2.64 bursts/100 hb; P = 0.82), burst amplitude (P = 0.85), or total activity (P = 0.31). In those with chronic diseases, hyperoxia decreased burst frequency (MD - 5.57 bursts/min; 95% CI - 7.48, - 3.67 bursts/min; P < 0.001) and burst incidence (MD - 4.44 bursts/100 hb; 95% CI - 7.94, - 0.94 bursts/100 hb; P = 0.01), but had no effect on burst amplitude (P = 0.36) or total activity (P = 0.90). Our meta-regression analyses identified an inverse relationship between normoxic burst frequency and change in burst frequency with hyperoxia. In both groups, hyperoxia decreased heart rate but had no effect on any measure of blood pressure. CONCLUSION Hyperoxia does not change sympathetic activity in healthy humans. Conversely, in those with chronic diseases, hyperoxia decreases sympathetic activity. Regardless of disease status, resting sympathetic burst frequency predicts the degree of change in burst frequency, with larger decreases for those with higher resting activity.
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Affiliation(s)
- Desmond A Young
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
| | - Paris A T Jones
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
| | - Brittany A Matenchuk
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
- Program for Pregnancy and Postpartum Health, Faculty of Kinesiology, Sport, and Recreation, Women and Children's Health Research Institute, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Allison Sivak
- Geoffrey and Robyn Sperber Health Sciences Library, University of Alberta, Edmonton, AB, Canada
| | - Margie H Davenport
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
- Program for Pregnancy and Postpartum Health, Faculty of Kinesiology, Sport, and Recreation, Women and Children's Health Research Institute, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Craig D Steinback
- Neurovascular Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada.
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19
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El-Medany A, Adams ZH, Blythe HC, Hope KA, Kendrick AH, Abdala Sheikh AP, Paton JFR, Nightingale AK, Hart EC. Carotid body dysregulation contributes to Long COVID symptoms. COMMUNICATIONS MEDICINE 2024; 4:20. [PMID: 38374172 PMCID: PMC10876702 DOI: 10.1038/s43856-024-00447-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 01/31/2024] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID. METHODS Non-hositalised participants with long-COVID (n = 14) and controls (n = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student's unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason's correlation coefficient was used to examine relationships between variables. RESULTS During cardiopulmonary exercise testing the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (-0.44 ± 0.23 l/min/ SpO2%, R2 = 0.77 ± 0.20) compared to controls (-0.17 ± 0.13 l/min/SpO2%, R2 = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the VE/VCO2 slope (r = -0.53, P = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity. CONCLUSIONS The carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.
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Affiliation(s)
- Ahmed El-Medany
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
- Department of Cardiology, Southmead Hospital, North Bristol NHS Trust, Bristol, UK
- Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Zoe H Adams
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Hazel C Blythe
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Katrina A Hope
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
- Department of Anaesthetics, Southmead Hospital, North Bristol NHS Trust, Bristol, UK
| | - Adrian H Kendrick
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
- Department of Respiratory Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | | | - Julian F R Paton
- Manaaki Manawa, The Centre for Heart Research, University of Auckland, Auckland, New Zealand
| | - Angus K Nightingale
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
- Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Emma C Hart
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
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20
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Dai L, Guo J, Hui X, Wang X, Luo J, Huang R, Xiao Y. The potential interaction between chemosensitivity and the development of cardiovascular disease in obstructive sleep apnea. Sleep Med 2024; 114:266-271. [PMID: 38244464 DOI: 10.1016/j.sleep.2024.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/03/2024] [Accepted: 01/07/2024] [Indexed: 01/22/2024]
Abstract
OBJECTIVES Chemosensitivity is an essential part of the pathophysiological mechanisms of obstructive sleep apnea (OSA). Not only does OSA have a certain relationship with the comorbidity of cardiovascular disease (CVD) but also chemosensitivity plays a crucial role in the development of CVD. This study aims to investigate the potential interaction between chemosensitivity and the development of CVD in OSA. METHODS A total of 169 participants with suspected OSA were included. Data were gathered on the parameters of polysomnography and baseline clinical features. Peripheral chemosensitivity was evaluated by employing the rebreathing test. The lifetime CVD risk was computed using the China-PAR (Prediction for atherosclerotic CVD Risk in China) risk equation. RESULTS After controlling for covariates, participants with chemosensitivity levels in the second and fifth quantiles tended to hold an increased proportion of high lifetime CVD risk (OR 10.90, 95%CI [2.81-42.28]; OR 6.78, 95%CI [1.70-27.05], respectively). The diagnosis of OSA would significantly increase the 10-year and lifetime CVD risks in participants with low chemosensitivity, while no such differences were found in participants with high chemosensitivity. CONCLUSION Higher lifetime CVD risk was associated with participants who had greater peripheral chemosensitivity. In terms of the CVD outcomes, adult patients with a relatively low level of chemosensitivity may be primarily related to their diagnosis of OSA, whereas adult patients with a relatively high level of chemosensitivity may be more strongly associated with their elevated levels of chemosensitivity rather than OSA.
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Affiliation(s)
- Lu Dai
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Junwei Guo
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Xinjie Hui
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Xiaona Wang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Jinmei Luo
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Rong Huang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Yi Xiao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
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21
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Felippe ISA, Río RD, Schultz H, Machado BH, Paton JFR. Commonalities and differences in carotid body dysfunction in hypertension and heart failure. J Physiol 2023; 601:5527-5551. [PMID: 37747109 PMCID: PMC10873039 DOI: 10.1113/jp284114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 08/29/2023] [Indexed: 09/26/2023] Open
Abstract
Carotid body pathophysiology is associated with many cardiovascular-respiratory-metabolic diseases. This pathophysiology reflects both hyper-sensitivity and hyper-tonicity. From both animal models and human patients, evidence indicates that amelioration of this pathophysiological signalling improves disease states such as a lowering of blood pressure in hypertension, a reduction of breathing disturbances with improved cardiac function in heart failure (HF) and a re-balancing of autonomic activity with lowered sympathetic discharge. Given this, we have reviewed the mechanisms of carotid body hyper-sensitivity and hyper-tonicity across disease models asking whether there is uniqueness related to specific disease states. Our analysis indicates some commonalities and some potential differences, although not all mechanisms have been fully explored across all disease models. One potential commonality is that of hypoperfusion of the carotid body across hypertension and HF, where the excessive sympathetic drive may reduce blood flow in both models and, in addition, lowered cardiac output in HF may potentiate the hypoperfusion state of the carotid body. Other mechanisms are explored that focus on neurotransmitter and signalling pathways intrinsic to the carotid body (e.g. ATP, carbon monoxide) as well as extrinsic molecules carried in the blood (e.g. leptin); there are also transcription factors found in the carotid body endothelium that modulate its activity (Krüppel-like factor 2). The evidence to date fully supports that a better understanding of the mechanisms of carotid body pathophysiology is a fruitful strategy for informing potential new treatment strategies for many cardiovascular, respiratory and metabolic diseases, and this is highly relevant clinically.
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Affiliation(s)
- Igor S. A. Felippe
- Manaaki Manawa – The Centre for Heart Research, Department of Physiology, Faculty of Health & Medical Sciences, University of Auckland, Grafton, Auckland, 1023, New Zealand
| | - Rodrigo Del Río
- Department of Physiology, Laboratory of Cardiorespiratory Control, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile
- Mechanisms of Myelin Formation and Repair Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Harold Schultz
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Benedito H. Machado
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Julian F. R. Paton
- Manaaki Manawa – The Centre for Heart Research, Department of Physiology, Faculty of Health & Medical Sciences, University of Auckland, Grafton, Auckland, 1023, New Zealand
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22
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Burtscher M, Niebauer J. Concerning the Article Published by Ogura et al, Entitled "Determinants of Anaerobic Threshold at Each Stage of Renal Dysfunction in Patients With Heart Disease". Am J Cardiol 2023; 206:355-356. [PMID: 37690941 DOI: 10.1016/j.amjcard.2023.08.126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 08/20/2023] [Indexed: 09/12/2023]
Affiliation(s)
- Martin Burtscher
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria.
| | - Josef Niebauer
- University Institute of Prevention, Rehabilitation and Sports Medicine, Salzburg, Austria; Research Institute of Molecular Sports Medicine and Rehabilitation, Paracelsus Medical University Salzburg, Salzburg, Austria
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23
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Tubek S, Niewinski P, Langner-Hetmanczuk A, Jura M, Kuliczkowski W, Reczuch K, Ponikowski P. The effects of P2Y 12 adenosine receptors' inhibitors on central and peripheral chemoreflexes. Front Physiol 2023; 14:1214893. [PMID: 37538377 PMCID: PMC10394699 DOI: 10.3389/fphys.2023.1214893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 06/30/2023] [Indexed: 08/05/2023] Open
Abstract
Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors' sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved. Methods: We measured peripheral chemoreceptors' sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors' sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478. Results: Ticagrelor significantly increased both HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L min-1 %-1; p < 0.01) and HCVR (1.05 ± 0.64 vs. 1.75 ± 1.04 L min-1 mmHg-1; p < 0.01). The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR (0.63 ± 0.32 vs. 0.58 ± 0.33 L min-1%-1; p = 0.53) and HCVR (1.22 ± 0.67 vs. 1.2 ± 0.64 L min-1 mmHg-1; p = 0.79). Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation. Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated.
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Affiliation(s)
- Stanislaw Tubek
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Institute of Heart Diseases, University Hospital, Wroclaw, Poland
| | - Piotr Niewinski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Institute of Heart Diseases, University Hospital, Wroclaw, Poland
| | - Anna Langner-Hetmanczuk
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Institute of Heart Diseases, University Hospital, Wroclaw, Poland
| | - Maksym Jura
- Institute of Heart Diseases, University Hospital, Wroclaw, Poland
- Department of Physiology, Wroclaw Medical University, Wroclaw, Poland
| | - Wiktor Kuliczkowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Institute of Heart Diseases, University Hospital, Wroclaw, Poland
| | - Krzysztof Reczuch
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Institute of Heart Diseases, University Hospital, Wroclaw, Poland
| | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Institute of Heart Diseases, University Hospital, Wroclaw, Poland
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24
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Magrì D, Palermo P, Salvioni E, Mapelli M, Gallo G, Vignati C, Mattavelli I, Gugliandolo P, Maruotti A, Di Loro PA, Fiori E, Sciomer S, Agostoni P. Influence of exertional oscillatory breathing and its temporal behavior in patients with heart failure and reduced ejection fraction. Int J Cardiol 2023:S0167-5273(23)00659-9. [PMID: 37164295 DOI: 10.1016/j.ijcard.2023.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/12/2023] [Accepted: 05/05/2023] [Indexed: 05/12/2023]
Abstract
BACKGROUND Exertional oscillatory breathing (EOV) represents an emerging prognostic marker in heart failure (HF) patients, however little is known about EOV meaning with respect to its disappearance/persistence during cardiopulmonary exercise test (CPET). The present single-center study evaluated EOV clinical and prognostic impact in a large cohort of reduced ejection fraction HF patients (HFrEF) and, contextually, if a specific EOV temporal behavior might be an addictive risk predictor. METHODS AND RESULTS Data from 1.866 HFrEF patients on optimized medical therapy were analysed. The primary cardiovascular (CV) study end-point was cardiovascular death, heart transplantation or LV assistance device (LVAD) implantation at 5-years. For completeness a secondary end-point of total mortality at 5- years was also explored. EOV presence was identified in 251 patients (13%): 142 characterized by EOV early cessation (Group A) and 109 by EOV persistence during the whole CPET (Group B). The entire EOV Group showed worse clinical and functional status than NoEOV Group (n = 1.615) and, within the EOV Group, Group B was characterized by a more severe HF. At CV survival analysis, EOV patients showed a poorer outcome than the NoEOV Group (events 27.1% versus 13.1%, p < 0.001) both unpolished and after matching for main confounders. Instead, no significant differences were found between EOV Group A and B with respect to CV outcome. Conversely the analysis for total mortality failed to be significant. CONCLUSIONS Our analysis, albeit retrospective, supports the inclusion of EOV into a CPET-centered clinical and prognostic evaluation of the HFrEF patients. EOV characterizes per se a more advanced HFrEF stage with an unfavorable CV outcome. However, the EOV persistence, albeit suggestive of a more severe HF, does not emerge as a further prognostic marker.
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Affiliation(s)
- Damiano Magrì
- Department of Clinical and Molecular Medicine, Azienda Ospedaliera Sant'Andrea, "Sapienza" University, Rome, Italy
| | | | | | - Massimo Mapelli
- Centro Cardiologico Monzino, IRCCS, Milan, Italy.; Dept. of Clinical sciences and Community health, Cardiovascular Section, University of Milano, Milan, Italy
| | - Giovanna Gallo
- Department of Clinical and Molecular Medicine, Azienda Ospedaliera Sant'Andrea, "Sapienza" University, Rome, Italy
| | | | | | | | - Antonello Maruotti
- Dipartimento di Giurisprudenza, Economia, Politica e Lingue Moderne - Libera Università Maria Ss Assunta; Department of Mathematics, University of Bergen, Norway; School of Computing, University of Portsmouth, United Kingdom
| | | | - Emiliano Fiori
- Department of Clinical and Molecular Medicine, Azienda Ospedaliera Sant'Andrea, "Sapienza" University, Rome, Italy
| | - Susanna Sciomer
- Dipartimento di Scienze Cardiovascolari, Respiratorie, Nefrologiche, Anestesiologiche e Geriatriche, "Sapienza" University, Rome, Italy
| | - Piergiuseppe Agostoni
- Centro Cardiologico Monzino, IRCCS, Milan, Italy.; Dept. of Clinical sciences and Community health, Cardiovascular Section, University of Milano, Milan, Italy..
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25
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Giannoni A, Borrelli C, Gentile F, Sciarrone P, Spießhöfer J, Piepoli M, Richerson GB, Floras JS, Coats AJS, Javaheri S, Emdin M, Passino C. Autonomic and respiratory consequences of altered chemoreflex function: clinical and therapeutic implications in cardiovascular diseases. Eur J Heart Fail 2023; 25:642-656. [PMID: 36907827 PMCID: PMC10989193 DOI: 10.1002/ejhf.2819] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 02/10/2023] [Accepted: 02/26/2023] [Indexed: 03/14/2023] Open
Abstract
The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases.
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Affiliation(s)
- Alberto Giannoni
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Pisa, Italy
- Fondazione Toscana G. Monasterio, Pisa, Italy
| | | | - Francesco Gentile
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Pisa, Italy
| | | | - Jens Spießhöfer
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Pisa, Italy
- University of Aachen, Aachen, Germany
| | | | | | - John S Floras
- Division of Cardiology, Mount Sinai Hospital, University of Toronto, Ontario, Canada
| | | | - Shahrokh Javaheri
- Division of Pulmonary and Sleep Medicine, Bethesda North Hospital, Cincinnati, Ohio, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, and Division of Cardiology, The Ohio State University, Columbus, Ohio USA
| | - Michele Emdin
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Pisa, Italy
- Fondazione Toscana G. Monasterio, Pisa, Italy
| | - Claudio Passino
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Pisa, Italy
- Fondazione Toscana G. Monasterio, Pisa, Italy
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26
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Lataro RM, Moraes DJA, Gava FN, Omoto ACM, Silva CAA, Brognara F, Alflen L, Brazão V, Colato RP, do Prado JC, Ford AP, Salgado HC, Paton JFR. P2X3 receptor antagonism attenuates the progression of heart failure. Nat Commun 2023; 14:1725. [PMID: 36977675 PMCID: PMC10050083 DOI: 10.1038/s41467-023-37077-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/02/2023] [Indexed: 03/30/2023] Open
Abstract
Despite advances in the treatment of heart failure, prognosis is poor, mortality high and there remains no cure. Heart failure is associated with reduced cardiac pump function, autonomic dysregulation, systemic inflammation and sleep-disordered breathing; these morbidities are exacerbated by peripheral chemoreceptor dysfunction. We reveal that in heart failure the carotid body generates spontaneous, episodic burst discharges coincident with the onset of disordered breathing in male rats. Purinergic (P2X3) receptors were upregulated two-fold in peripheral chemosensory afferents in heart failure, and when antagonized abolished these episodic discharges, normalized both peripheral chemoreceptor sensitivity and the breathing pattern, reinstated autonomic balance, improved cardiac function, and reduced both inflammation and biomarkers of cardiac failure. Aberrant ATP transmission in the carotid body triggers episodic discharges that via P2X3 receptors play a crucial role in the progression of heart failure and as such offer a distinct therapeutic angle to reverse multiple components of its pathogenesis.
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Affiliation(s)
- Renata M Lataro
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Davi J A Moraes
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Fabio N Gava
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Department of Clinical Veterinary, Agrarian Sciences Center, Londrina State University, Londrina, Brazil
| | - Ana C M Omoto
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Carlos A A Silva
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Fernanda Brognara
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Lais Alflen
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Vânia Brazão
- College of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Rafaela Pravato Colato
- College of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - José Clóvis do Prado
- College of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Helio C Salgado
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Julian F R Paton
- Manaaki Manawa-The Centre for Heart Research, Department of Physiology, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand.
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27
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Javaheri S, Badr MS. Central sleep apnea: pathophysiologic classification. Sleep 2023; 46:zsac113. [PMID: 35551411 PMCID: PMC9995798 DOI: 10.1093/sleep/zsac113] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 05/05/2022] [Indexed: 11/14/2022] Open
Abstract
Central sleep apnea is not a single disorder; it can present as an isolated disorder or as a part of other clinical syndromes. In some conditions, such as heart failure, central apneic events are due to transient inhibition of ventilatory motor output during sleep, owing to the overlapping influences of sleep and hypocapnia. Specifically, the sleep state is associated with removal of wakefulness drive to breathe; thus, rendering ventilatory motor output dependent on the metabolic ventilatory control system, principally PaCO2. Accordingly, central apnea occurs when PaCO2 is reduced below the "apneic threshold". Our understanding of the pathophysiology of central sleep apnea has evolved appreciably over the past decade; accordingly, in disorders such as heart failure, central apnea is viewed as a form of breathing instability, manifesting as recurrent cycles of apnea/hypopnea, alternating with hyperpnea. In other words, ventilatory control operates as a negative-feedback closed-loop system to maintain homeostasis of blood gas tensions within a relatively narrow physiologic range, principally PaCO2. Therefore, many authors have adopted the engineering concept of "loop gain" (LG) as a measure of ventilatory instability and susceptibility to central apnea. Increased LG promotes breathing instabilities in a number of medical disorders. In some other conditions, such as with use of opioids, central apnea occurs due to inhibition of rhythm generation within the brainstem. This review will address the pathogenesis, pathophysiologic classification, and the multitude of clinical conditions that are associated with central apnea, and highlight areas of uncertainty.
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Affiliation(s)
- Shahrokh Javaheri
- Division of Pulmonary and Sleep Medicine, Bethesda North Hospital, Cincinnati, OH, USA
- Division of Pulmonary Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH, USA
- Division of Cardiology, Department of Medicine, Ohio State University, Columbus, OH, USA
| | - M Safwan Badr
- Department of Internal Medicine, Liborio Tranchida, MD, Endowed Professor of Medicine, Wayne State University School of Medicine, University Health Center, Detroit, MI, USA
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Galdino GAM, Rehder-Santos P, Linares SN, Beltrame T, Catai AM. Cerebral oxygenation during cardiopulmonary exercise testing in cardiorespiratory diseases: A systematic review. Heart Lung 2023; 59:23-32. [PMID: 36669443 DOI: 10.1016/j.hrtlng.2023.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 12/29/2022] [Accepted: 01/08/2023] [Indexed: 01/20/2023]
Abstract
BACKGROUND Cardiopulmonary exercise testing (CPET) is the gold standard for analyzing cardiorespiratory fitness and integrating physiological responses. However, the presence of chronic diseases may compromise cerebral hemodynamic responses during CPET. In addition, the acute response of cerebral oxygenation during incremental CPET may identify abnormal behavior and ensure greater safety for patients with cardiovascular, respiratory, and metabolic diseases. OBJECTIVE To summarize the cerebral oxygenation acute response during CPET of patients with cardiovascular, metabolic, or respiratory diseases. METHODS From inception to 23rd September 2022, five databases (PubMed, SCOPUS, Web of Science, Embase and CINAHAL) were searched for cross-sectional studies performing incremental CPET and measuring the cerebral oxygenation acute response in cardiovascular, metabolic, or respiratory diseases compared with healthy individuals. The Downs and Black tool assessed the risk of bias of the studies. RESULTS We included seven studies with 428 participants (305 men and 123 women), aged 43 to 70 years. Of these, 101 had heart failure NYHA II and III; 77 idiopathic dilated cardiomyopathy; 33 valvular disease; 25 coronary heart disease; 22 pulmonary arterial hypertension; 15 had severe obstructive sleep apnea (OSA) and 166 were apparently healthy. There was no eligible article with metabolic disease. There was a lower magnitude increase in cerebral oxygenation of cardiovascular patients compared with the healthy individuals during the CPET. Furthermore, pulmonary arterial hypertension patients presented increased cerebral oxygen extraction, differently to those with severe OSA. CONCLUSION Considering the heterogeneity of the included studies, patients with cardiovascular disease may suffer from reduced cerebral oxygen supply, and individuals with OSA presented lower brain oxygen extraction during the CPET. Future studies should aim for strategies to improve cerebral oxygenation to ensure greater safety at CPET of cardiovascular and OSA patients. An acute response pattern for metabolic and other respiratory diseases was not established.
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Affiliation(s)
- Gabriela Aguiar Mesquita Galdino
- Cardiovascular Physical Therapy Laboratory, Department of Physical Therapy, Federal University of São Carlos, São Carlos, SP, Brazil
| | - Patrícia Rehder-Santos
- Cardiovascular Physical Therapy Laboratory, Department of Physical Therapy, Federal University of São Carlos, São Carlos, SP, Brazil
| | - Stephanie Nogueira Linares
- Cardiovascular Physical Therapy Laboratory, Department of Physical Therapy, Federal University of São Carlos, São Carlos, SP, Brazil
| | - Thomas Beltrame
- Cardiovascular Physical Therapy Laboratory, Department of Physical Therapy, Federal University of São Carlos, São Carlos, SP, Brazil; Samsung R&D Institute Brazil - SRBR, Campinas, SP, Brazil
| | - Aparecida Maria Catai
- Cardiovascular Physical Therapy Laboratory, Department of Physical Therapy, Federal University of São Carlos, São Carlos, SP, Brazil.
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29
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Evans AM. Of Mice and Men and Plethysmography Systems: Does LKB1 Determine the Set Point of Carotid Body Chemosensitivity and the Hypoxic Ventilatory Response? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1427:163-173. [PMID: 37322347 DOI: 10.1007/978-3-031-32371-3_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Our recent studies suggest that the level of liver kinase B1 (LKB1) expression in some way determines carotid body afferent discharge during hypoxia and to a lesser extent during hypercapnia. In short, phosphorylation by LKB1 of an as yet unidentified target(s) determines a set point for carotid body chemosensitivity. LKB1 is the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses, but conditional deletion of AMPK in catecholaminergic cells, including therein carotid body type I cells, has little or no effect on carotid body responses to hypoxia or hypercapnia. With AMPK excluded, the most likely target of LKB1 is one or other of the 12 AMPK-related kinases, which are constitutively phosphorylated by LKB1 and, in general, regulate gene expression. By contrast, the hypoxic ventilatory response is attenuated by either LKB1 or AMPK deletion in catecholaminergic cells, precipitating hypoventilation and apnea during hypoxia rather than hyperventilation. Moreover, LKB1, but not AMPK, deficiency causes Cheyne-Stokes-like breathing. This chapter will explore further the possible mechanisms that determine these outcomes.
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Affiliation(s)
- A Mark Evans
- Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh, UK.
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30
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A Methodological Perspective on the Function and Assessment of Peripheral Chemoreceptors in Heart Failure: A Review of Data from Clinical Trials. Biomolecules 2022; 12:biom12121758. [PMID: 36551186 PMCID: PMC9775522 DOI: 10.3390/biom12121758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/22/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Augmented peripheral chemoreceptor sensitivity (PChS) is a common feature of many sympathetically mediated diseases, among others, and it is an important mechanism of the pathophysiology of heart failure (HF). It is related not only to the greater severity of symptoms, especially to dyspnea and lower exercise tolerance but also to a greater prevalence of complications and poor prognosis. The causes, mechanisms, and impact of the enhanced activity of peripheral chemoreceptors (PChR) in the HF population are subject to intense research. Several methodologies have been established and utilized to assess the PChR function. Each of them presents certain advantages and limitations. Furthermore, numerous factors could influence and modulate the response from PChR in studied subjects. Nevertheless, even with the impressive number of studies conducted in this field, there are still some gaps in knowledge that require further research. We performed a review of all clinical trials in HF human patients, in which the function of PChR was evaluated. This review provides an extensive synthesis of studies evaluating PChR function in the HF human population, including methods used, factors potentially influencing the results, and predictors of increased PChS.
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31
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Neder JA, Phillips DB, O'Donnell DE, Dempsey JA. Excess ventilation and exertional dyspnoea in heart failure and pulmonary hypertension. Eur Respir J 2022; 60:13993003.00144-2022. [PMID: 35618273 DOI: 10.1183/13993003.00144-2022] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/05/2022] [Indexed: 01/11/2023]
Abstract
Increased ventilation relative to metabolic demands, indicating alveolar hyperventilation and/or increased physiological dead space (excess ventilation), is a key cause of exertional dyspnoea. Excess ventilation has assumed a prominent role in the functional assessment of patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). We herein provide the key pieces of information to the caring physician to 1) gain unique insights into the seeds of patients' shortness of breath and 2) develop a rationale for therapeutically lessening excess ventilation to mitigate this distressing symptom. Reduced bulk oxygen transfer induced by cardiac output limitation and/or right ventricle-pulmonary arterial uncoupling increase neurochemical afferent stimulation and (largely chemo-) receptor sensitivity, leading to alveolar hyperventilation in HFrEF, PAH and small-vessel, distal CTEPH. As such, interventions geared to improve central haemodynamics and/or reduce chemosensitivity have been particularly effective in lessening their excess ventilation. In contrast, 1) high filling pressures in HFpEF and 2) impaired lung perfusion leading to ventilation/perfusion mismatch in proximal CTEPH conspire to increase physiological dead space. Accordingly, 1) decreasing pulmonary capillary pressures and 2) mechanically unclogging larger pulmonary vessels (pulmonary endarterectomy and balloon pulmonary angioplasty) have been associated with larger decrements in excess ventilation. Exercise training has a strong beneficial effect across diseases. Addressing some major unanswered questions on the link of excess ventilation with exertional dyspnoea under the modulating influence of pharmacological and nonpharmacological interventions might prove instrumental to alleviate the devastating consequences of these prevalent diseases.
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Affiliation(s)
- J Alberto Neder
- Clinical Exercise Physiology and Respiratory Investigation Unit, Division of Respiratory and Critical Care Medicine, Dept of Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, ON, Canada
| | - Devin B Phillips
- Clinical Exercise Physiology and Respiratory Investigation Unit, Division of Respiratory and Critical Care Medicine, Dept of Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, ON, Canada
| | - Denis E O'Donnell
- Clinical Exercise Physiology and Respiratory Investigation Unit, Division of Respiratory and Critical Care Medicine, Dept of Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, ON, Canada
| | - Jerome A Dempsey
- John Rankin Laboratory of Pulmonary Medicine, Dept of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
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Huang J, McDonnell BJ, Lawley JS, Byrd J, Stöhr EJ, Cornwell WK. Impact of Mechanical Circulatory Support on Exercise Capacity in Patients With Advanced Heart Failure. Exerc Sport Sci Rev 2022; 50:222-229. [PMID: 36095073 PMCID: PMC9475848 DOI: 10.1249/jes.0000000000000303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Approximately 6 million individuals have heart failure in the United States alone and 15 million in Europe. Left ventricular assist devices (LVAD) improve survival in these patients, but functional capacity may not fully improve. This article examines the hypothesis that patients supported by LVAD experience persistent reductions in functional capacity and explores mechanisms accounting for abnormalities in exercise tolerance.
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Affiliation(s)
- Janice Huang
- Department of Medicine-Cardiology. University of Colorado Anschutz Medical Campus, Aurora CO
| | - Barry J. McDonnell
- School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff UK
| | - Justin S. Lawley
- Department of Sport Science, University of Innsbruck, Innsbruck Austria
| | - Jessica Byrd
- Department of Medicine-Cardiology. University of Colorado Anschutz Medical Campus, Aurora CO
| | - Eric J. Stöhr
- Faculty of Philosophical Sciences, Institute of Sport Science, Leibniz University Hannover, Hannover, Germany
- Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York City, NY, USA
| | - William K. Cornwell
- Department of Medicine-Cardiology. University of Colorado Anschutz Medical Campus, Aurora CO
- Clinical Translational Research Center, University of Colorado Anschutz Medical Campus, Aurora CO
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Kulej-Lyko K, Niewinski P, Tubek S, Krawczyk M, Kosmala W, Ponikowski P. Inhibition of peripheral chemoreceptors improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction − a role of tonic activity and acute reflex response. Front Physiol 2022; 13:911636. [PMID: 36111161 PMCID: PMC9470150 DOI: 10.3389/fphys.2022.911636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 07/19/2022] [Indexed: 11/22/2022] Open
Abstract
Peripheral chemoreceptors (PChRs) play a significant role in maintaining adequate oxygenation in the bloodstream. PChRs functionality comprises two components: tonic activity (PChT) which regulates ventilation during normoxia and acute reflex response (peripheral chemosensitivity, PChS), which increases ventilation following a specific stimulus. There is a clear link between augmented PChS and exercise intolerance in patients with heart failure with reduced ejection fraction. It has been also shown that inhibition of PChRs leads to the improvement in exercise capacity. However, it has not been established yet: 1) whether similar mechanisms take part in heart failure with preserved ejection fraction (HFpEF) and 2) which component of PChRs functionality (PChT vs. PChS) is responsible for the benefit seen after the acute experimental blockade. To answer those questions we enrolled 12 stable patients with HFpEF. All participants underwent an assessment of PChT (attenuation of minute ventilation in response to low-dose dopamine infusion), PChS (enhancement of minute ventilation in response to hypoxia) and a symptom-limited cardiopulmonary exercise test on cycle ergometer. All tests were placebo-controlled, double-blinded and performed in a randomized order. Under resting conditions and at normoxia dopamine attenuated minute ventilation and systemic vascular resistance (p = 0.03 for both). These changes were not seen with placebo. Dopamine also decreased ventilatory and mean arterial pressure responses to hypoxia (p < 0.05 for both). Inhibition of PChRs led to a decrease in V˙E/V˙CO2 comparing to placebo (36 ± 3.6 vs. 34.3 ± 3.7, p = 0.04), with no effect on peak oxygen consumption. We found a significant relationship between PChT and the relative decrement of V˙E/V˙CO2 on dopamine comparing to placebo (R = 0.76, p = 0.005). There was a trend for correlation between PChS (on placebo) and V˙E/V˙CO2 during placebo infusion (R = 0.56, p = 0.059), but the relative improvement in V˙E/V˙CO2 was not related to the change in PChS (dopamine vs. placebo). We did not find a significant relationship between PChT and PChS. In conclusion, inhibition of PChRs in HFpEF population improves ventilatory efficiency during exercise. Increased PChS is associated with worse (higher) V˙E/V˙CO2, whereas PChT predicts an improvement in V˙E/V˙CO2 after PChRs inhibition. This results may be meaningful for patient selection in further clinical trials involving PChRs modulation.
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Affiliation(s)
- Katarzyna Kulej-Lyko
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
- *Correspondence: Katarzyna Kulej-Lyko,
| | - Piotr Niewinski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
| | - Stanislaw Tubek
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
| | | | - Wojciech Kosmala
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
| | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
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Beaudry RI, Brotto AR, Varughese RA, de Waal S, Fuhr DP, Damant RW, Ferrara G, Lam GY, Smith MP, Stickland MK. Persistent dyspnea after COVID-19 is not related to cardiopulmonary impairment; a cross-sectional study of persistently dyspneic COVID-19, non-dyspneic COVID-19 and controls. Front Physiol 2022; 13:917886. [PMID: 35874528 PMCID: PMC9297912 DOI: 10.3389/fphys.2022.917886] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/16/2022] [Indexed: 11/21/2022] Open
Abstract
Background: Up to 53% of individuals who had mild COVID-19 experience symptoms for >3-month following infection (Long-CoV). Dyspnea is reported in 60% of Long-CoV cases and may be secondary to impaired exercise capacity (VO2peak) as a result of pulmonary, pulmonary vascular, or cardiac insult. This study examined whether cardiopulmonary mechanisms could explain exertional dyspnea in Long-CoV. Methods: A cross-sectional study of participants with Long-CoV (n = 28, age 40 ± 11 years, 214 ± 85 days post-infection) and age- sex- and body mass index-matched COVID-19 naïve controls (Con, n = 24, age 41 ± 12 years) and participants fully recovered from COVID-19 (ns-CoV, n = 14, age 37 ± 9 years, 198 ± 89 days post-infection) was conducted. Participants self-reported symptoms and baseline dyspnea (modified Medical Research Council, mMRC, dyspnea grade), then underwent a comprehensive pulmonary function test, cardiopulmonary exercise test, exercise pulmonary diffusing capacity measurement, and rest and exercise echocardiography. Results: VO2peak, pulmonary function and cardiac/pulmonary vascular parameters were not impaired in Long- or ns-CoV compared to normative values (VO2peak: 106 ± 25 and 107 ± 25%predicted, respectively) and cardiopulmonary responses to exercise were otherwise normal. When Long-CoV were stratified by clinical dyspnea severity (mMRC = 0 vs mMRC≥1), there were no between-group differences in VO2peak. During submaximal exercise, dyspnea and ventilation were increased in the mMRC≥1 group, despite normal operating lung volumes, arterial saturation, diffusing capacity and indicators of pulmonary vascular pressures. Interpretation: Persistent dyspnea after COVID-19 was not associated with overt cardiopulmonary impairment or exercise intolerance. Interventions focusing on dyspnea management may be appropriate for Long-CoV patients who report dyspnea without cardiopulmonary impairment.
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Affiliation(s)
- Rhys I. Beaudry
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Andrew R. Brotto
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Rhea A. Varughese
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Stephanie de Waal
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Desi P. Fuhr
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Ronald W. Damant
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Giovanni Ferrara
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Grace Y. Lam
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Maeve P. Smith
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Michael K. Stickland
- Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- G.F. MacDonald Centre for Lung Health, Covenant Health, Edmonton, AB, Canada
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Role of the angiotensin type 1 receptor in modulating the carotid chemoreflex in an ovine model of renovascular hypertension. J Hypertens 2022; 40:1421-1430. [PMID: 35762481 DOI: 10.1097/hjh.0000000000003173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The carotid body has been implicated as an important mediator and putative target for hypertension. Previous studies have indicated an important role for angiotensin II in mediating carotid body function via angiotensin type-1 receptors (AT1R); however, their role in modulating carotid body function during hypertension is unclear. METHODS Using a large preclinical ovine model of renovascular hypertension, we hypothesized that acute AT1R blockade would lower blood pressure and decrease carotid body-mediated increases in arterial pressure. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries. RESULTS In both hypertensive and sham animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure but a reduction in renal vascular conductance. These responses were not different between groups. Infusion of angiotensin II led to an increase in arterial pressure and reduction in renal blood flow. The sensitivity of the renal vasculature to angiotensin II was significantly attenuated in hypertension compared with the sham animals. Systemic inhibition of the AT1R did not alter blood pressure in either group. Interestingly carotid body-evoked arterial pressure responses were attenuated by AT1R blockade in renovascular hypertension but not in shams. CONCLUSION Taken together, our findings indicate a decrease in vascular reactivity of the non-clipped kidney to angiotensin II in hypertension. The CB-evoked increase in blood pressure in hypertension is mediated in part, by the AT1R. These findings indicate a differential role of the AT1R in the carotid body versus the renal vasculature.
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36
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LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response. Commun Biol 2022; 5:642. [PMID: 35768580 PMCID: PMC9243028 DOI: 10.1038/s42003-022-03583-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 06/14/2022] [Indexed: 11/08/2022] Open
Abstract
The hypoxic ventilatory response (HVR) is critical to breathing and thus oxygen supply to the body and is primarily mediated by the carotid bodies. Here we reveal that carotid body afferent discharge during hypoxia and hypercapnia is determined by the expression of Liver Kinase B1 (LKB1), the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses. Conversely, conditional deletion in catecholaminergic cells of AMPK had no effect on carotid body responses to hypoxia or hypercapnia. By contrast, the HVR was attenuated by LKB1 and AMPK deletion. However, in LKB1 knockouts hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, while only hypoventilation and apnoea were observed after AMPK deletion. We therefore identify LKB1 as an essential regulator of carotid body chemosensing and uncover a divergence in dependency on LKB1 and AMPK between the carotid body on one hand and the HVR on the other.
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da Silva MP, Spiller PF, Paton JFR, Moraes DJA. Peripheral chemoreflex activation induces expiratory but not inspiratory excitation of C1 pre-sympathetic neurones of rats. Acta Physiol (Oxf) 2022; 235:e13853. [PMID: 35722749 DOI: 10.1111/apha.13853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/10/2022] [Accepted: 06/16/2022] [Indexed: 11/30/2022]
Abstract
AIMS Stimulation of peripheral chemoreceptors, as during hypoxia, increases breathing and respiratory-related sympathetic bursting. Activation of catecholaminergic C1 neurones induces sympathoexcitation, while its ablation reduces the chemoreflex sympathoexcitatory response. However, no study has determined the respiratory phase(s) in which the pre-sympathetic C1 neurones are recruited by peripheral chemoreceptor and whether C1 neurone activation affects all phases of respiratory modulation of sympathetic activity. We addressed these unknowns by testing the hypothesis that peripheral chemoreceptor activation excites pre-sympathetic C1 neurones during inspiration and expiration. METHODS Using the in situ preparation of rat, we made intracellular recordings from baroreceptive pre-sympathetic C1 neurones during peripheral chemoreflex stimulation. We optogenetically activated C1 neurones selectively and compared any respiratory-phase-related increases in sympathetic activity with that which occurs following stimulation of the peripheral chemoreflex. RESULTS Activation of peripheral chemoreceptors using cytotoxic hypoxia (potassium cyanide) increased the firing frequency of C1 neurones and both the frequency and amplitude of their excitatory post-synaptic currents during the phase of expiration only. In contrast, optogenetic stimulation of C1 neurones activates inspiratory neurones, which secondarily inhibit expiratory neurones, but produced comparable increases in sympathetic activity across all phases of respiration. CONCLUSION Our data reveal that the peripheral chemoreceptor-mediated expiratory-related sympathoexcitation is mediated through excitation of expiratory neurones antecedent to C1 pre-sympathetic neurones; these may be found in the Kölliker-Fuse nucleus. Despite peripheral chemoreceptor excitation of inspiratory neurones, these do not trigger C1 neurone-mediated increases in sympathetic activity. These studies provide compelling novel insights into the functional organization of respiratory-sympathetic neural networks.
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Affiliation(s)
- Melina P da Silva
- School of Medicine of Ribeirão Preto, Department of Physiology, University of São Paulo, Ribeirão Preto, SP, Brazil.,Department of Biophysics, Paulista School of Medicine, Federal University of São Paulo, São Paulo, SP, Brazil
| | - Pedro F Spiller
- School of Medicine of Ribeirão Preto, Department of Physiology, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Julian F R Paton
- Manaaki Manawa, The Centre for Heart Research, Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Davi J A Moraes
- School of Medicine of Ribeirão Preto, Department of Physiology, University of São Paulo, Ribeirão Preto, SP, Brazil
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38
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Niewinski P, Tubek S, Paleczny B, Banasiak W, Ponikowski P. Induction of Day-Time Periodic Breathing is Associated With Augmented Reflex Response From Peripheral Chemoreceptors in Male Patients With Systolic Heart Failure. Front Physiol 2022; 13:912056. [PMID: 35711301 PMCID: PMC9197443 DOI: 10.3389/fphys.2022.912056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/19/2022] [Indexed: 11/28/2022] Open
Abstract
Spontaneous day-time periodic breathing (sPB) constitutes a common phenomenon in systolic heart failure (HF). However, it is unclear whether PB during wakefulness could be easily induced and what are the physiological and clinical correlates of patients with HF in whom PB induction is possible. Fifty male HF patients (age 60.8 ± 9.8 years, left ventricle ejection fraction 28.0 ± 7.4%) were prospectively screened and 46 enrolled. After exclusion of patients with sPB the remaining underwent trial of PB induction using mild hypoxia (stepwise addition of nitrogen gas to breathing mixture) which resulted in identification of inducible (iPB) in 51%. All patients underwent assessment of hypoxic ventilatory response (HVR) using transient hypoxia and of hypercapnic ventilatory response (HCVR) employing Read’s rebreathing method. The induction trial did not result in any adverse events and minimal SpO2 during nitrogen administration was ∼85%. The iPB group (vs. non-inducible PB group, nPB) was characterized by greater HVR (0.90 ± 0.47 vs. 0.50 ± 0.26 L/min/%; p <0.05) but comparable HCVR (0.88 ± 0.54 vs. 0.67 ± 0.68 L/min/mmHg; p = NS) and by worse clinical and neurohormonal profile. Mean SpO2 which induced first cycle of PB was 88.9 ± 3.7%, while in sPB mean SpO2 preceding first spontaneous cycle of PB was 96.0 ± 2.5%. There was a reverse relationship between HVR and the relative variation of SpO2 during induced PB (r = −0.49, p = 0.04). In summary, PB induction is feasible and safe in HF population using simple and standardized protocol employing incremental, mild hypoxia. Pathophysiology of iPB differs from sPB, as it relies mostly on overactive peripheral chemoreceptors. At the same time enhanced HVR might play a protective role against profound hypoxia during iPB.
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Affiliation(s)
- Piotr Niewinski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Stanislaw Tubek
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Bartlomiej Paleczny
- Department of Physiology and Pathophysiology, Wroclaw Medical University, Wroclaw, Poland
| | | | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
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Giannoni A, Gentile F, Buoncristiani F, Borrelli C, Sciarrone P, Spiesshoefer J, Bramanti F, Iudice G, Javaheri S, Emdin M, Passino C. Chemoreflex and Baroreflex Sensitivity Hold a Strong Prognostic Value in Chronic Heart Failure. JACC: HEART FAILURE 2022; 10:662-676. [DOI: 10.1016/j.jchf.2022.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/07/2022] [Accepted: 02/11/2022] [Indexed: 02/07/2023]
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40
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Kulej-Lyko K, Niewinski P, Tubek S, Ponikowski P. Contribution of Peripheral Chemoreceptors to Exercise Intolerance in Heart Failure. Front Physiol 2022; 13:878363. [PMID: 35492596 PMCID: PMC9046845 DOI: 10.3389/fphys.2022.878363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/29/2022] [Indexed: 01/08/2023] Open
Abstract
Peripheral chemoreceptors (PChRs), because of their strategic localization at the bifurcation of the common carotid artery and along the aortic arch, play an important protective role against hypoxia. Stimulation of PChRs evokes hyperventilation and hypertension to maintain adequate oxygenation of critical organs. A relationship between increased sensitivity of PChRs (hyperreflexia) and exercise intolerance (ExIn) in patients with heart failure (HF) has been previously reported. Moreover, some studies employing an acute blockade of PChRs (e.g., using oxygen or opioids) demonstrated improvement in exercise capacity, suggesting that hypertonicity is also involved in the development of ExIn in HF. Nonetheless, the precise mechanisms linking dysfunctional PChRs to ExIn remain unclear. From the clinical perspective, there are two main factors limiting exercise capacity in HF patients: subjective perception of dyspnoea and muscle fatigue. Both have many determinants that might be influenced by abnormal signalling from PChRs, including: exertional hyperventilation, oscillatory ventilation, ergoreceptor oversensitivity, and augmented sympathetic tone. The latter results in reduced muscle perfusion and altered muscle structure. In this review, we intend to present the milieu of abnormalities tied to malfunctioning PChRs and discuss their role in the complex relationships leading, ultimately, to ExIn.
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Affiliation(s)
- Katarzyna Kulej-Lyko
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
- *Correspondence: Katarzyna Kulej-Lyko,
| | - Piotr Niewinski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
| | - Stanislaw Tubek
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
| | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Cardiology, University Clinical Hospital, Wroclaw, Poland
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41
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Deep Singh T. Abnormal Sleep-Related Breathing Related to Heart Failure. Sleep Med Clin 2022; 17:87-98. [PMID: 35216764 DOI: 10.1016/j.jsmc.2021.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure (HF). Untreated obstructive sleep apnea (OSA) and central sleep apnea (CSA) in patients with HF are associated with worse outcomes. Detailed sleep history along with polysomnography (PSG) should be conducted if SDB is suspected in patients with HF. First line of treatment is the optimization of medical therapy for HF and if symptoms persist despite optimization of the treatment, positive airway pressure (PAP) therapy will be started to treat SDB. At present, there is limited evidence to prescribe any drugs for treating CSA in patients with HF. There is limited evidence for the efficacy of continuous positive airway pressure (CPAP) or adaptive servo-ventilation (ASV) in improving mortality in patients with heart failure with reduced ejection fraction (HFrEF). There is a need to perform well-designed studies to identify different phenotypes of CSA/OSA in patients with HF and to determine which phenotype responds to which therapy. Results of ongoing trials, ADVENT-HF, and LOFT-HF are eagerly awaited to shed more light on the management of CSA in patients with HF. Until then the management of SDB in patients with HF is limited due to the lack of evidence and guidance for treating SDB in patients with HF.
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Affiliation(s)
- Tripat Deep Singh
- Academy of Sleep Wake Science, #32 St.no-9 Guru Nanak Nagar, near Gurbax Colony, Patiala, Punjab, India 147003.
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Prigent A, Pellen C, Texereau J, Bailly S, Coquerel N, Gervais R, Liegaux JM, Luraine R, Renaud JC, Serandour AL, Pépin JL. CPAP telemonitoring can track Cheyne-Stokes respiration and detect serious cardiac events: The AlertApnée Study. Respirology 2021; 27:161-169. [PMID: 34873795 DOI: 10.1111/resp.14192] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 09/13/2021] [Accepted: 11/15/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND OBJECTIVE Case reports have suggested that continuous positive airway pressure (CPAP) telemonitoring can detect the onset of acute cardiac events such as decompensated heart failure (HF) or atrial fibrillation through an increase in the apnoea-hypopnoea index (AHI) and onset of Cheyne-Stokes Respiration (CSR). This study addressed whether long-term remote CPAP treatment telemonitoring revealing CSR can help detect serious cardiac events (SCEs) in obstructive sleep apnoea (OSA) patients. METHODS This monocentric prospective cohort study included adults receiving CPAP therapy for OSA with daily telemonitoring. Any sudden increase in AHI generated an alert for the home healthcare provider to download CPAP data to identify CSR. A medical consultation was scheduled if CSR was detected. RESULTS We included 555 adults (412 men; 57% with known cardiovascular comorbidities). During the 1-year follow-up, 78 CSR episodes were detected in 74 patients (CSR+). The main conditions associated with incident CSR were HF (24 patients [30.8%]), ventilatory instability (21, 26.9%), leaks (13, 16.7%), medications inducing central apnoeas (baclofen, ticagrelor, opioids) (7, 9.0%), arrhythmias (6, 7.7%) and renal failure (2, 2.6%). Fifteen (20.3%) CSR+ patients had a confirmed SCE. In univariable analysis, a CSR episode increased the risk of an SCE by 13.8-fold (5.7-35.6) (p < 0.0001), with an adjusted OR of 5.7 (2.0-16.8) in multivariable analysis. CONCLUSION Long-term telemonitoring of patients on CPAP treatment can alert CSR episodes and allows early detection of SCEs in patients with or without known cardiac comorbidities.
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Affiliation(s)
- Arnaud Prigent
- Groupe Medical de Pneumologie, Polyclinique Saint-Laurent, Rennes, France.,Centre du sommeil, Polyclinique Saint-Laurent, Rennes, France
| | | | - Joëlle Texereau
- Respiratory Physiology Unit, Department of Respiratory Medicine, Cochin Hospital, AP-HP/Université de Paris, Paris, France.,Air Liquide Health Care, VitalAire France, Gentilly, France
| | - Sébastien Bailly
- HP2 Laboratory, Inserm U1300, Univ. Grenoble Alpes, Grenoble, France
| | - Nicolas Coquerel
- Service de cardiologie, Polyclinique Saint Laurent, Rennes, France
| | - Renaud Gervais
- Service de cardiologie, Polyclinique Saint Laurent, Rennes, France
| | - Jean-Marc Liegaux
- Groupe Medical de Pneumologie, Polyclinique Saint-Laurent, Rennes, France.,Centre du sommeil, Polyclinique Saint-Laurent, Rennes, France
| | - Régis Luraine
- Groupe Medical de Pneumologie, Polyclinique Saint-Laurent, Rennes, France.,Centre du sommeil, Polyclinique Saint-Laurent, Rennes, France
| | - Jean-Christophe Renaud
- Groupe Medical de Pneumologie, Polyclinique Saint-Laurent, Rennes, France.,Centre du sommeil, Polyclinique Saint-Laurent, Rennes, France
| | | | - Jean Louis Pépin
- HP2 Laboratory, Inserm U1300, Univ. Grenoble Alpes, Grenoble, France
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Podsiadły A, Paleczny B, Olesińska-Mader M, Nowak K, Okupnik T, Wyciszkiewicz M, Łopusiewicz W, Ponikowski P, Ponikowska B. Valsalva-derived Measures and Phenylephrine Test in Patients With Heart Failure With Reduced Ejection Fraction Receiving Comprehensive Neurohormonal Blockade Drug Therapy: A 5-year Event-free Survival Analysis. J Card Fail 2021; 28:744-755. [PMID: 34758387 DOI: 10.1016/j.cardfail.2021.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 10/18/2021] [Accepted: 10/20/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND To assess the relationships between Valsalva- and phenylephrine test-derived measures and outcome in patients with heart failure with reduced ejection fraction (HFrEF) receiving comprehensive neurohormonal blockade pharmacotherapy. METHODS AND RESULTS Data from 56 patients with HFrEF (mean left ventricle ejection fraction of 32 ± 6%) subjected to Valsalva and phenylephrine tests were analyzed retrospectively. Baroreflex-related (Valsalva-ratio and blood pressure-RR interval slope from phase IV) and non-baroreflex-related measures (systolic blood pressure rise in phase IV [ΔSBPPHASE_IV], and pulse amplitude ratio [PAR]) were calculated from Valsalva. Short-term outcomes (HF-related hospitalization, implantable cardioverter-defibrillator shock or all-cause death within 24 months from examination) and long-term outcomes (implantable cardioverter-defibrillator shock or all-cause death within 60 months) were analyzed. The end point occurred in 16 and 18 patients, for the short- and long-term outcomes, respectively. A low ΔSBPPHASE_IV identified patients at risk in the long term, as evidenced by a low vs high ΔSBPPHASE_IV comparison (square-wave response patients assigned to low ΔSBPPHASE_IV group, P = .002), and Cox model (hazard ratio 0.91, 95% confidence interval 0.86-0.96, P < .001), and tended to identify patients at risk in the short term outcome (hazard ratio 0.95, 95% confidence interval 0.91-1.00, P = .055). There was a tendency toward a higher event-free survival in the low PAR group (low vs high PAR; hazard ratio 0.44, 95% CI 0.17-1.18, P = .104). CONCLUSIONS Non-baroreflex-related measures obtained from Valsalva-namely, ΔSBPPHASE_IV and PAR-might carry prognostic value in patients with HFrEF receiving neurohormonal blockade pharmacotherapy.
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Affiliation(s)
- Anna Podsiadły
- Department of Physiology and Pathophysiology, Wroclaw Medical Physiology, Wroclaw, Poland
| | - Bartłomiej Paleczny
- Department of Physiology and Pathophysiology, Wroclaw Medical Physiology, Wroclaw, Poland.
| | | | - Krzysztof Nowak
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland; Centre for Heart Diseases, University Hospital in Wroclaw, Wroclaw, Poland
| | - Tymoteusz Okupnik
- Department of Physiology and Pathophysiology, Wroclaw Medical Physiology, Wroclaw, Poland
| | | | - Wojciech Łopusiewicz
- Department of Physiology and Pathophysiology, Wroclaw Medical Physiology, Wroclaw, Poland
| | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland; Centre for Heart Diseases, University Hospital in Wroclaw, Wroclaw, Poland
| | - Beata Ponikowska
- Department of Physiology and Pathophysiology, Wroclaw Medical Physiology, Wroclaw, Poland
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Tubek S, Niewinski P, Paleczny B, Langner-Hetmanczuk A, Banasiak W, Ponikowski P. Acute hyperoxia reveals tonic influence of peripheral chemoreceptors on systemic vascular resistance in heart failure patients. Sci Rep 2021; 11:20823. [PMID: 34675332 PMCID: PMC8531381 DOI: 10.1038/s41598-021-99159-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 09/09/2021] [Indexed: 01/08/2023] Open
Abstract
Peripheral chemoreceptors’ (PCh) hyperactivity increases sympathetic tone. An augmented acute ventilatory response to hypoxia, being a marker of PCh oversensitivity, was also identified as a marker of poor prognosis in HF. However, not much is known about the tonic (chronic) influence of PCh on cardio-respiratory parameters. In our study 30 HF patients and 30 healthy individuals were exposed to 100% oxygen for 1 min during which minute ventilation and hemodynamic parameters were non-invasively recorded. Systemic vascular resistance (SVR) and mean arterial pressure (MAP) responses to acute hyperoxia differed substantially between HF and control. In HF hyperoxia caused a significant drop in SVR in early stages with subsequent normalization, while increase in SVR was observed in controls. MAP increased in controls, but remained unchanged in HF. Bilateral carotid bodies excision performed in two HF subjects changed the response to hyperoxia towards the course seen in healthy individuals. These differences may be explained by the domination of early vascular reaction to hyperoxia in HF by vasodilation due to the inhibition of augmented tonic activity of PCh. Otherwise, in healthy subjects the vasoconstrictive action of oxygen remains unopposed. The magnitude of SVR change during acute hyperoxia may be used as a novel method for tonic PCh activity assessment.
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Affiliation(s)
- Stanislaw Tubek
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556, Wrocław, Poland. .,Institute of Heart Diseases, University Hospital, Wrocław, Poland.
| | - Piotr Niewinski
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556, Wrocław, Poland.,Institute of Heart Diseases, University Hospital, Wrocław, Poland
| | | | - Anna Langner-Hetmanczuk
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556, Wrocław, Poland.,Institute of Heart Diseases, University Hospital, Wrocław, Poland
| | - Waldemar Banasiak
- Department of Cardiology, Centre for Heart Diseases, 4th Military Hospital, Wrocław, Poland
| | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Borowska 213, 50-556, Wrocław, Poland.,Institute of Heart Diseases, University Hospital, Wrocław, Poland
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Biegus J, Niewinski P, Josiak K, Kulej K, Ponikowska B, Nowak K, Zymlinski R, Ponikowski P. Pathophysiology of Advanced Heart Failure: What Knowledge Is Needed for Clinical Management? Heart Fail Clin 2021; 17:519-531. [PMID: 34511202 DOI: 10.1016/j.hfc.2021.06.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Understanding of heart failure (HF) has evolved from a simple hemodynamic problem through a neurohormonally and proinflammatory-driven syndrome to a complex multiorgan dysfunction accompanied by inadequate energy handling. This article discusses the most important clinical aspects of advanced HF pathophysiology. It presents the concept of neurohormonal activation and its deleterious effect on cardiovascular system and reflex control. The current theories regarding the role of inflammation, cytokine activation, and myocardial remodeling in HF progression are presented. Advanced HF is a multiorgan syndrome with interplay between cardiovascular system and other organs. The role of iron deficiency is also discussed.
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Affiliation(s)
- Jan Biegus
- Department of Heart Diseases, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland; Centre for Heart Diseases, Wrocław University Hospital, ul. Borowska 213, 50-556 Wrocław, Poland
| | - Piotr Niewinski
- Department of Heart Diseases, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland; Centre for Heart Diseases, Wrocław University Hospital, ul. Borowska 213, 50-556 Wrocław, Poland
| | - Krystian Josiak
- Department of Heart Diseases, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland; Centre for Heart Diseases, Wrocław University Hospital, ul. Borowska 213, 50-556 Wrocław, Poland
| | - Katarzyna Kulej
- Department of Heart Diseases, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland; Centre for Heart Diseases, Wrocław University Hospital, ul. Borowska 213, 50-556 Wrocław, Poland
| | - Barbara Ponikowska
- Student Scientific Organization, Department of Heart Diseases, Wroclaw Medical University, ul. Borowska 213, 50-556 Wrocław, Poland
| | - Krzysztof Nowak
- Department of Heart Diseases, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland; Centre for Heart Diseases, Wrocław University Hospital, ul. Borowska 213, 50-556 Wrocław, Poland
| | - Robert Zymlinski
- Department of Heart Diseases, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland; Centre for Heart Diseases, Wrocław University Hospital, ul. Borowska 213, 50-556 Wrocław, Poland
| | - Piotr Ponikowski
- Department of Heart Diseases, Wrocław Medical University, ul. Borowska 213, 50-556 Wrocław, Poland; Centre for Heart Diseases, Wrocław University Hospital, ul. Borowska 213, 50-556 Wrocław, Poland.
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Cauzzo S, Callara AL, Morelli MS, Hartwig V, Esposito F, Montanaro D, Passino C, Emdin M, Giannoni A, Vanello N. Mapping dependencies of BOLD signal change to end-tidal CO 2: linear and nonlinear modeling, and effect of physiological noise correction. J Neurosci Methods 2021; 362:109317. [PMID: 34380051 DOI: 10.1016/j.jneumeth.2021.109317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 07/28/2021] [Accepted: 08/06/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Disentangling physiological noise and signal of interest is a major issue when evaluating BOLD-signal changes in response to breath holding. Currently-adopted approaches for retrospective noise correction are general-purpose, and have non-negligible effects in studies on hypercapnic challenges. NEW METHOD We provide a novel approach to the analysis of specific and non-specific BOLD-signal changes related to end-tidal CO2 (PETCO2) in breath-hold fMRI studies. Multiple-order nonlinear predictors for PETCO2 model a region-dependent nonlinear input-output relationship hypothesized in literature and possibly playing a crucial role in disentangling noise. We explore Retrospective Image-based Correction (RETROICOR) effects on the estimated BOLD response, applying our analysis both with and without RETROICOR and analyzing the linear and non-linear correlation between PETCO2 and RETROICOR regressors. RESULTS The RETROICOR model of noise related to respiratory activity correlated with PETCO2 both linearly and non-linearly. The correction affected the shape of the estimated BOLD response to hypercapnia but allowed to discard spurious activity in ventricles and white matter. Activation clusters were best detected using non-linear components in the BOLD response model. COMPARISON WITH EXISTING METHOD We evaluated the side-effects of standard physiological noise correction procedure, tailoring our analysis on challenging understudied brainstem and subcortical regions. Our novel approach allowed to characterize delays and non-linearities in BOLD response. CONCLUSIONS RETROICOR successfully avoided false positives, still broadly affecting the estimated non-linear BOLD responses. Non-linearities in the model better explained CO2-related BOLD signal fluctuations. The necessity to modify the standard procedure for physiological-noise correction in breath-hold studies was addressed, stating its crucial importance.
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Affiliation(s)
- Simone Cauzzo
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy.
| | | | - Maria Sole Morelli
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Valentina Hartwig
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Fabrizio Esposito
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | | | - Claudio Passino
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Michele Emdin
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Alberto Giannoni
- Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy; Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Nicola Vanello
- Dipartimento di Ingegneria dell'Informazione, University of Pisa, Pisa, Italy
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Paula-Ribeiro M, Ribeiro IC, Aranda LC, Silva TM, Costa CM, Ramos RP, Ota-Arakaki J, Cravo SL, Nery LE, Stickland MK, Silva BM. Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: role of the peripheral chemoreflex. J Appl Physiol (1985) 2021; 131:794-807. [PMID: 34197227 DOI: 10.1152/japplphysiol.00152.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in nonhypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity [i.e., peak oxygen consumption (V̇o2peak)]; and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptor inhibition) or 21% O2 (control session) while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEI for all sequences (cBEIALL) at rest [means ± SD: PAH = 0.5 ± 0.2 vs. HA = 0.7 ± 0.1 arbitrary units (a.u.), P = 0.02] and lower cBRSALL (PAH = 6.8 ± 7.0 vs. HA = 9.7 ± 5.0 ms·mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs. HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to V̇o2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in nonhypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower V̇o2peak, suggesting that it could be functionally relevant.NEW & NOTEWORTHY Does the peripheral chemoreflex play a role in cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension (PAH)? Here we provide new evidence of cardiac baroreflex dysfunction under spontaneous and, most notably, provoked blood pressure fluctuations in patients with nonhypoxemic PAH. Importantly, impaired cardiac baroreflex effectiveness during provoked blood pressure fluctuations was independently associated with poorer functional capacity. Finally, our results indicated that the peripheral chemoreflex did not mediate cardiac baroreflex dysfunction among those patients.
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Affiliation(s)
- Marcelle Paula-Ribeiro
- Postgraduate Program in Translational Medicine, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.,Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Indyanara C Ribeiro
- Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.,Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Liliane C Aranda
- Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.,Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Talita M Silva
- Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.,Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Camila M Costa
- Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Roberta P Ramos
- Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Jaquelina Ota-Arakaki
- Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Sergio L Cravo
- Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Luiz E Nery
- Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Michael K Stickland
- Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Bruno M Silva
- Postgraduate Program in Translational Medicine, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.,Postgraduate Program in Pulmonary Medicine and Pulmonary Vascular Group, Division of Respiratory Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.,Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
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Collins SÉ, Phillips DB, Brotto AR, Rampuri ZH, Stickland MK. Ventilatory efficiency in athletes, asthma and obesity. Eur Respir Rev 2021; 30:30/161/200206. [PMID: 34289980 DOI: 10.1183/16000617.0206-2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/16/2020] [Indexed: 11/05/2022] Open
Abstract
During submaximal exercise, minute ventilation (V' E) increases in proportion to metabolic rate (i.e. carbon dioxide production (V' CO2 )) to maintain arterial blood gas homeostasis. The ratio V' E/V' CO2 , commonly termed ventilatory efficiency, is a useful tool to evaluate exercise responses in healthy individuals and patients with chronic disease. Emerging research has shown abnormal ventilatory responses to exercise (either elevated or blunted V' E/V' CO2 ) in some chronic respiratory and cardiovascular conditions. This review will briefly provide an overview of the physiology of ventilatory efficiency, before describing the ventilatory responses to exercise in healthy trained endurance athletes, patients with asthma, and patients with obesity. During submaximal exercise, the V' E/V' CO2 response is generally normal in endurance-trained individuals, patients with asthma and patients with obesity. However, in endurance-trained individuals, asthmatics who demonstrate exercise induced-bronchoconstriction, and morbidly obese individuals, the V' E/V' CO2 can be blunted at maximal exercise, likely because of mechanical ventilatory constraint.
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Affiliation(s)
- Sophie É Collins
- Division of Pulmonary Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.,Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada
| | - Devin B Phillips
- Respiratory Investigation Unit, Department of Medicine, Queen's University, Kingston, Canada
| | - Andrew R Brotto
- Division of Pulmonary Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Zahrah H Rampuri
- Division of Pulmonary Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.,Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada
| | - Michael K Stickland
- Division of Pulmonary Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.,G.F. MacDonald Centre for Lung Health, Covenant Health, Edmonton, Canada
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Grassi G, Mancia G, Esler M. CENTRAL AND PERIPHERAL SYMPATHETIC ACTIVATION IN HEART FAILURE. Cardiovasc Res 2021; 118:1857-1871. [PMID: 34240147 DOI: 10.1093/cvr/cvab222] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/02/2021] [Indexed: 11/12/2022] Open
Abstract
The sympathetic nervous system overdrive occurring in heart failure has been reported since more than half a century. Refinements in the methodological approaches to assess human sympathetic neural function have allowed during recent years to better define various aspects related to the neuroadrenergic alteration. These include 1) the different participation of the individual regional sympathetic cardiovascular districts at the process, 2) the role of the central nervous system in determining the neuroadrenergic overdrive, 3) the involvement of baroreflex, cardiopulmonary reflex and chemoreflex mechanisms in the phoenomenon, which is also closely linked to inflammation and the immune reaction, 4) the relationships with the severity of the disease, its ischaemic or idiopathic nature and the preserved or reduced left ventricular ejection fraction and 5) the adverse functional and structural impact of the sympathetic activation on cardiovascular organs, such as the brain, the heart and the kidneys. Information have been also gained on the active role exerted by the sympathetic activation on the disease outcome and its potential relevance as target of the therapeutic interventions based on non-pharmacological, pharmacological and invasive approaches, including the renal denervation, the splanchnic sympathetic nerve ablation and the carotid baroreflex stimulation. The still undefined aspects of the neurogenic alterations and the unmet goals of the therapeutic approach having the sympathetic activation as a target of the intervention will be finally mentioned.
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Affiliation(s)
- Guido Grassi
- Clinica Medica, Department of Medicine and Surgery, University of Milano-Bicocca
| | - Giuseppe Mancia
- Policlinico di Monza and University Milano-Bicocca, Milan, Italy
| | - Murray Esler
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia
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Iturriaga R, Alcayaga J, Chapleau MW, Somers VK. Carotid body chemoreceptors: physiology, pathology, and implications for health and disease. Physiol Rev 2021; 101:1177-1235. [PMID: 33570461 PMCID: PMC8526340 DOI: 10.1152/physrev.00039.2019] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O2 and CO2 and pH, eliciting reflex ventilatory, cardiovascular, and humoral responses to maintain homeostasis. This review examines the fundamental biology underlying CB chemoreceptor function, its contribution to integrated physiological responses, and its role in maintaining health and potentiating disease. Emphasis is placed on 1) transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O2-dependent K+ channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ion channels; 2) synaptic mechanisms linking type I cells and petrosal nerve terminals, focusing on the role played by the main proposed transmitters and modulatory gases, and the participation of glial cells in regulation of the chemosensory process; 3) integrated reflex responses to CB activation, emphasizing that the responses differ dramatically depending on the nature of the physiological, pathological, or environmental challenges, and the interactions of the chemoreceptor reflex with other reflexes in optimizing oxygen delivery to the tissues; and 4) the contribution of enhanced CB chemosensory discharge to autonomic and cardiorespiratory pathophysiology in obstructive sleep apnea, congestive heart failure, resistant hypertension, and metabolic diseases and how modulation of enhanced CB reactivity in disease conditions may attenuate pathophysiology.
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Affiliation(s)
- Rodrigo Iturriaga
- Laboratorio de Neurobiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile, and Centro de Excelencia en Biomedicina de Magallanes, Universidad de Magallanes, Punta Arenas, Chile
| | - Julio Alcayaga
- Laboratorio de Fisiología Celular, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Mark W Chapleau
- Department of Internal Medicine, University of Iowa and Department of Veterans Affairs Medical Center, Iowa City, Iowa
| | - Virend K Somers
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
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