• carotid body
• diabetes mellitus
• heart failure
• hyperglycaemia
• hypertension
• hypoxia
• sleep apnoea
• sympathetic nervous system

• Humans
• Carotid Body/physiology
• Carotid Body/physiopathology
• Animals
• Reflex
• Arteries/physiology
• Cardiovascular Diseases/physiopathology
• Cardiovascular Diseases/therapy
• Chemoreceptor Cells/physiology
• Metabolic Diseases/physiopathology
• Metabolic Diseases/therapy

• 19/687 Manatu Hauora | Health Research Council of New Zealand (HRC)
• 2019 Sidney Taylor Trust

• Exercise
• Oxygen consumption
• Ventilatory efficiency
• Ventilatory threshold

• cardiopulmonary exercise testing
• central chemosensitivity
• chronic coronary syndrome
• inefficient ventilation
• resting ventilation

• VE/VCO2 ratio
• exercise oscillatory ventilation
• heart failure
• nasal breathing
• rapid shallow breathing index

• autonomic nervous system
• blood flow
• cardiovascular diseases
• carotid body
• heart failure
• hypertension
• sympathetic nervous system

• Animals
• Humans
• Carotid Body/physiology
• Hypertension
• Heart Failure
• Heart
• Metabolic Diseases

• P01 HL062222 NHLBI NIH HHS

• exercise
• hypertension
• minute ventilation/volume of expired CO2 slope
• ventilatory efficiency

• Humans
• Middle Aged
• Aged
• Oxygen Consumption/physiology
• Lung
• Prognosis
• Exercise Test/methods
• Heart Failure/diagnosis
• Hypertension/diagnosis
• Essential Hypertension
• Exercise Tolerance

• FS/18/18/33522 British Heart Foundation
• FS/17/49/32917 British Heart Foundation
• AA/18/7/34219 British Heart Foundation
• Department of Health
• British Heart Foundation
• the James Tudor Foundation
• Health Research Council of New Zealand

• Arrhythmias
• Baroreflex
• Chemoreflex
• Ergoreflex
• Heart failure
• Hypertension
• Sleep apnoea

• Humans
• Cardiovascular Diseases
• Heart Failure
• Chemoreceptor Cells/metabolism
• Heart
• Autonomic Nervous System
• Baroreflex/physiology
• Heart Rate/physiology

• R01 NS113764 NINDS NIH HHS
• R01 NS123155 NINDS NIH HHS
• U01 NS090414 NINDS NIH HHS

• cardiology
• heart failure
• pathophysiology
• peripheral chemoreceptors

• Anaemia
• Chemoreflex
• Exercise
• Heart failure
• Iron
• Sleep

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.

• Narodowe Centrum Nauki

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.

• Narodowe Centrum Nauki

Central apneas (CA) are a frequent comorbidity in patients with heart failure (HF) and are associated with worse prognosis. The clinical and prognostic relevance of CA in each sex is unknown.

Consecutive outpatients with HF with either reduced or mildly reduced left ventricular ejection fraction (n=550, age 65±12 years, left ventricular ejection fraction 32%±9%, 21% women) underwent a 24‐hour ambulatory polygraphy to evaluate CA burden and were followed up for the composite end point of cardiac death, appropriate implantable cardioverter‐defibrillator shock, or first HF hospitalization. Compared with men, women were younger, had higher left ventricular ejection fraction, had lower prevalence of ischemic etiology and of atrial fibrillation, and showed lower apnea‐hypopnea index (expressed as median [interquartile range]) at daytime (3 [0–9] versus 10 [3–20] events/hour) and nighttime (10 [3–21] versus 23 [11–36] events/hour) (all P<0.001), despite similar neurohormonal activation and HF therapy. Increased chemoreflex sensitivity to either hypoxia or hypercapnia (evaluated in 356 patients, 65%, by a rebreathing test) was less frequent in women (P<0.001), but chemoreflex sensitivity to hypercapnia was a predictor of apnea‐hypopnea index in both sexes. At adjusted survival analysis, daytime apnea‐hypopnea index ≥15 events/hour (hazard ratio [HR], 2.70; 95% CI, 1.06–7.34; P=0.037), nighttime apnea‐hypopnea index ≥15 events/hour (HR, 2.84; 95% CI, 1.28–6.32; P=0.010), and nighttime CA index ≥10 events/hour (HR, 5.01; 95% CI, 1.88–13.4; P=0.001) were independent predictors of the primary end point in women but not in men (all P>0.05), also after matching women and men for possible confounders.

In chronic HF, CA are associated with a greater risk of adverse events in women than in men.

• Cheyne‐Stokes breathing
• central apneas
• chemoreflex
• chronic heart failure
• prognosis
• sex difference
• women

• Levosimendan
• cardiopulmonary exercise test
• heart failure

Changes in peak exercise oxygen uptake (VO₂) and cardiac output (CO) 6 months after successful percutaneous edge‐to‐edge mitral valve repair (pMVR) in severe primary (PMR) and functional mitral regurgitation (FMR) patients are unknown.

The aim of the study was to assess the efficacy of pMVR at rest by echocardiography, VO₂ and CO (inert gas rebreathing) measurement and during cardiopulmonary exercise test with CO measurement.

We evaluated 145 and 115 patients at rest and 98 and 66 during exercise before and after pMVR, respectively.

After successful pMVR, significant reductions in MR and NYHA class were observed in FMR and PMR patients. Cardiac ultrasound showed reverse remodelling (left ventricular end‐diastolic volume from 158 ± 63 mL to 147 ± 64, P < 0.001; ejection fraction from 51 ± 15 to 48 ± 14, P < 0.001; pulmonary artery systolic pressure (PASP) from 43 ± 13 to 38 ± 8 mmHg, P < 0.001) in the entire population. These changes were significant in PMR (n = 62) and a trend in FMR (n = 53), except for PASP, which decreased in both groups. At rest, CO and stroke volume (SV) increased in FMR with a concomitant reduction in arteriovenous O₂ content difference [ΔC(a‐v)O₂]. Peak exercise, CO and SV increased significantly in both groups (CO from 5.5 ± 1.4 L/min to 6.3 ± 1.5 and from 6.2 ± 2.4 to 6.7 ± 2.0, SV from 57 ± 19 mL to 66 ± 20 and from 62 ± 20 to 69 ± 20, in FMR and PMR, respectively), whereas peak VO₂ was unchanged and ΔC(a‐v)O₂ decreased.

These data confirm pMVR‐induced clinical improvement and reverse ventricular remodelling at a 6‐month analysis and show, in spite of an increase in CO, an unchanged exercise performance, which is achieved through a ‘more physiological’ blood flow distribution and O₂ extraction behaviour. Direct rest and exercise CO should be measured to assess pMVR efficacy.

• Cardiac output
• Exercise
• Oxygen uptake
• Percutaneous edge-to-edge mitral valve repair
• Transcatheter mitral valve repair

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.

• cardiorespiratory
• carotid body
• chemoreflex activation
• coronary blood flow
• heart failure
• sympathetic nerve activity

• enhanced ventilatory response
• exercise
• heart failure
• obstructive sleep apnea

• Hypoxemia
• Pulmonary hypertension
• Right heart failure
• Sleep-disordered breathing

• Benefit prediction
• Nocturnal respiratory rate
• Primary prophylactic ICD

• carotid body
• chemoreceptors
• hypercapnia
• hypoxia
• sympathetic nervous system
• ventilation

• Oscillatory ventilation
• cardiopulmonary stress test
• heart failure

• Area M
• Cardiopulmonary exercise testing
• Exercise ventilatory pattern
• O(2) uptake
• TV-RR slope

Chronic heart failure (CHF) is characterized by heightened sympathetic nervous activity, carotid chemoreceptor (CC) sensitivity, marked exercise intolerance and an exaggerated ventilatory response to exercise. The purpose of this study was to determine the effect of CC inhibition on exercise cardiovascular and ventilatory function, and exercise tolerance in health and CHF.

Twelve clinically stable, optimally treated patients with CHF (mean ejection fraction: 43 ± 2.5%) and 12 age- and sex-matched healthy controls were recruited. Participants completed two time-to-symptom-limitation (TLIM) constant load cycling exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 μg⋅kg^–1⋅min^–1; order randomized). Ventilation was measured using expired gas data and operating lung volume data were determined during exercise by inspiratory capacity maneuvers. Cardiac output was estimated using impedance cardiography, and vascular conductance was calculated as cardiac output/mean arterial pressure.

There was no change in TLIM in either group with dopamine (CHF: saline 13.1 ± 2.4 vs. dopamine 13.5 ± 1.6 min, p = 0.78; Control: saline 10.3 ± 1.2 vs. dopamine 11.5 ± 1.3 min, p = 0.16). In CHF patients, dopamine increased cardiac output (p = 0.03), vascular conductance (p = 0.01) and oxygen delivery (p = 0.04) at TLIM, while ventilatory parameters were unaffected (p = 0.76). In controls, dopamine improved vascular conductance at TLIM (p = 0.03), but no other effects were observed.

Our findings suggest that the CC contributes to cardiovascular regulation during full-body exercise in patients with CHF, however, CC inhibition does not improve exercise tolerance.

• cardiovascular function
• carotid chemoreceptor
• chronic heart failure
• dopamine
• exercise tolerance

• Bisoprolol, CID: 2405
• Cardiopulmonary interaction
• Carvedilol, CID: 2585
• Heart failure
• Lung
• Metoprolol, CID: 441308
• Nebivolol, CID: 189562
• Prognosis
• Sotalol, CID: 66245
• β-blocker
• β-receptor

• Adrenergic beta-Antagonists/adverse effects
• Adrenergic beta-Antagonists/therapeutic use
• Aged
• Algorithms
• Chronic Disease
• Clinical Decision-Making
• Decision Support Techniques
• Female
• Heart Failure/drug therapy
• Heart Failure/metabolism
• Heart Failure/physiopathology
• Humans
• Lung/drug effects
• Lung/metabolism
• Male
• Middle Aged
• Myocardium/metabolism
• Receptors, Adrenergic, beta/drug effects
• Receptors, Adrenergic, beta/metabolism
• Signal Transduction
• Treatment Outcome

• Diagnosis
• Exercise ventilation
• Heart failure
• Parathyroid hormone
• Pulmonary circulation
• Right ventricular

Heart failure (HF) is a condition that carries a considerable burden of disability many now related to co-existing co-morbidities. The drive to find newer effective therapies targeting novel mechanisms has led to a recent emphasis on treating common co-morbidities that are clustered around contemporary HF patients. Here is renewed contemporary co-morbidities that until recently have received little attention but which are now subject of considerable interest and potential therapeutic advance. These include, diabetes, functional mitral regurgitation and sleep disordered breathing. These three contemporary co-morbidities that have recently been subject to major trial evaluation will be reviewed in this paper.

• Exercise testing
• cardiac patients
• respiratory compensation point

• cardiopulmonary exercise testing
• heart failure
• periodic breathing

The ability to reliably and safely communicate chronically with small diameter (100–300 µm) autonomic nerves could have a significant impact in fundamental biomedical research and clinical applications. However, this ability has remained elusive with existing neural interface technologies. Here we show a new chronic nerve interface using highly flexible materials with axon-like dimensions. The interface was implemented with carbon nanotube (CNT) yarn electrodes to chronically record neural activity from two separate autonomic nerves: the glossopharyngeal and vagus nerves. The recorded neural signals maintain a high signal-to-noise ratio (>10 dB) in chronic implant models. We further demonstrate the ability to process the neural activity to detect hypoxic and gastric extension events from the glossopharyngeal and vagus nerves, respectively. These results establish a novel, chronic platform neural interfacing technique with the autonomic nervous system and demonstrate the possibility of regulating internal organ function, leading to new bioelectronic therapies and patient health monitoring.

• Alveolar ventilation
• Breathing instability
• Control of ventilation
• Dead space
• Exercise
• Hypoxia
• Periodic breathing

It is not known whether determinants of ventilation (VE)/volume of exhaled carbon dioxide (VCO₂) slope during incremental exercise may differ at different stages of reduced ejection fraction chronic heart failure natural history.

VE/VCO₂ slope was fitted up to lowest VE/VCO₂ ratio, that is, a proxy of the VE/perfusion ratio devoid of nonmetabolic stimuli to ventilatory drive. VE/VCO₂ slope tertiles were generated from our database (<27.5 [tertile 1], ≥27.5 to <32.0 [tertile 2], and ≥32.0 [tertile 3]), and 147 chronic heart failure patients with repeated tests yielding VE/VCO₂ slopes in 2 different tertiles were selected. Determinants of VE/VCO₂ slope changes across tertile pairs 1 versus 2, 2 versus 3, and 1 versus 3 were assessed by exploring changes in VE and VCO₂ at lowest VE/VCO₂ and those in VE/work rate (W) and VCO₂/W slope. Resting and peak cardiac output (CO) were calculated as VO₂/estimated arteriovenous O₂ difference and the CO/W slope analyzed. Notwithstanding a progressively lower W with increasing tertile, VE at lowest VE/VCO₂ and VE/W slope were significantly higher in tertiles 2 and 3 versus tertile 1. Conversely, VCO₂ at lowest VE/VCO₂ and CO/W slope significantly decreased across tertiles, whereas VCO₂/W slope did not. Difference (Δ) in VE/W slope between tertiles accounted for 71% of ΔVE/VCO₂ slope variance, with ΔVCO₂/W slope explaining an additional 26% (model r=0.99; r²=0.97; P<0.0001). Similar results were obtained substituting ΔVCO₂/W slope with ΔCO/W slope.

Ventilatory overactivation is the predominant cause of VE/VCO₂ slope increase at initial stages of chronic heart failure, whereas hemodynamic impairment plays an additional role at more‐advanced pathophysiological stages.

• cardiac output
• chronic heart failure
• exercise
• exercise gas exchanges
• ventilatory efficiency

• cardiopulmonary exercise test
• diastolic pressure gradient
• oscillatory breathing
• pulmonary hypertension
• ventilation

• Adult
• Aged
• Exercise/physiology
• Female
• Humans
• Hypertension, Pulmonary/complications
• Hypertension, Pulmonary/physiopathology
• Hyperventilation/etiology
• Hyperventilation/physiopathology
• Male
• Microcirculation/physiology
• Middle Aged
• Pulmonary Circulation
• Retrospective Studies
• Vascular Resistance/physiology

• Central chemoreflex
• heart failure
• hypercapnic ventilatory response

• Bayes Theorem
• Carbon Dioxide/metabolism
• Exercise/physiology
• Exercise Test/methods
• Female
• Heart Failure/physiopathology
• Humans
• Hypercapnia/physiopathology
• Hypoxia/physiopathology
• Male
• Middle Aged
• Oxygen Consumption/physiology
• Reflex/physiology
• Respiration
• Ventilation/methods
• Ventricular Function, Left/physiology

Alteration in breathing patterns characterized by cyclic variation of ventilation during rest and during exercise has been recognized in patients with advanced heart failure (HF) for nearly two centuries. Periodic breathing (PB) during exercise is known as exercise oscillatory ventilation (EOV) and is characterized by the periods of hyperpnea and hypopnea without interposed apnea. EOV is a non-invasive parameter detected during submaximal cardiopulmonary exercise testing. Presence of EOV during exercise in HF patients indicates significant impairment in resting and exercise hemodynamic parameters. EOV is also an independent risk factor for poor prognosis in HF patients both with reduced and preserved ejection fraction irrespective of other gas exchange variables. Circulatory delay, increased chemosensitivity, pulmonary congestion and increased ergoreflex signaling have been proposed as the mechanisms underlying the generation of EOV in HF patients. There is no proven treatment of EOV but its reversal has been noted with phosphodiesterase inhibitors, exercise training and acetazolamide in relatively small studies. In this review, we discuss the mechanistic basis of PB during exercise and the clinical implications of recognizing PB patterns in patients with HF.

• Exercise
• Oscillatory ventilation
• Heart failure

• Exercise Test
• Heart Failure
• Respiratory Muscle

• arrhythmias, cardiac
• autonomic nervous system
• death, sudden cardiac
• physiopathology

• Afferent Pathways/physiopathology
• Animals
• Arrhythmias, Cardiac/physiopathology
• Autonomic Nervous System/physiopathology
• Autonomic Nervous System Diseases/complications
• Autonomic Nervous System Diseases/physiopathology
• Cell Transdifferentiation
• Death, Sudden, Cardiac/etiology
• Denervation
• Diabetic Neuropathies/physiopathology
• Disease Models, Animal
• Feedback, Physiological
• Heart/innervation
• Heart Conduction System/physiopathology
• Heart Diseases/complications
• Heart Diseases/physiopathology
• Hemodynamics
• Humans
• Hypertension, Renal/physiopathology
• Hypertension, Renal/surgery
• Kidney/innervation
• Mice
• Myocardial Contraction/physiology
• Nerve Growth Factor/physiology
• Nerve Regeneration
• Semaphorin-3A/physiology
• Translational Research, Biomedical

• R01 HL071830 NHLBI NIH HHS
• R01 HL084261 NHLBI NIH HHS
• R01HL084261 NHLBI NIH HHS

• cardiac function
• dopamine
• vascular function