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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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kowalski, Rebis, Wilk, Klusiewicz, Wiecha and Paleczny.)

The clinical significance of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients remains an area of evolving understanding, particularly regarding their utility in the presence or absence of pre-existing heart conditions. While clear cutoff values and established roles in heart failure are understood in adult patients, pediatric norms vary with age, complicating interpretation. Notably, the emergence of multi-system inflammatory syndrome in children (MIS-C) has highlighted the importance of these markers not only in the detection of acute heart failure but also as a marker of disease severity and even as a differential diagnosis tool. This review summarizes current knowledge on the utility of BNP and NT-proBNP in pediatric patients. Their unique physiology, including circulation and compensation mechanisms, likely influence BNP and NT-proBNP release, potentially even in non-heart failure states. Factors such as dynamic volemic changes accompanying inflammatory diseases in children may contribute. Thus, understanding the nuanced roles of BNP and NT-proBNP in pediatric populations is crucial for the accurate diagnosis, management, and differentiation of cardiac and non-cardiac conditions.

Introduction: The research examines the relationship between marathon performance and muscle stiffness changes from pre to marathon in recreational runners aged 50+ years., Methods: Thirty-one male long-distance runners aged 50-73 years participated in the experiment. The muscle stiffness of quadriceps and calves was measured in two independent sessions: the day before the marathon and 30 min after the completed marathon run using a Myoton device., Results and Discussion: The 42.195-km run was completed in 4.30,05 h ± 35.12 min, which indicates an intensity of 79.3% ± 7.1% of HRmax. The long-term, low-intensity running exercise (marathon) in older recreational runners and the low level of HRmax and VO2max showed no statistically significant changes in muscle stiffness (quadriceps and calves). There was reduced muscle stiffness ( p = 0.016), but only in the triceps of the calf in the dominant (left) leg. Moreover, to optimally evaluate the marathon and adequately prepare for the performance training program, we need to consider the direct and indirect analyses of the running economy, running technique, and HRmax and VO2max variables. These variables significantly affect marathon exercise., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mackala, Mroczek, Chmura, Konefał, Pawlik, Ochman, Chmura, Paleczny, Seredyński, Wyciszkiewicz, Nowicka-Czudak, Łopusiewicz, Adamiec, Wiecha, Ponikowski and Ponikowska.)

Background: The guidelines recommend intensive blood pressure control. Randomized trials have focused on the relevance of the systolic blood pressure (SBP) lowering, leaving the safety of the diastolic blood pressure (DBP) reduction unresolved. There are data available which show that low DBP should not stop clinicians from achieving SBP targets; however, registries and analyses of randomized trials present conflicting results. The purpose of the study was to apply machine learning (ML) algorithms to determine, whether DBP is an important risk factor to predict stroke, heart failure (HF), myocardial infarction (MI), and primary outcome in the SPRINT trial database. Methods: ML experiments were performed using decision tree, random forest, k-nearest neighbor, naive Bayesian, multi-layer perceptron, and logistic regression algorithms, including and excluding DBP as the risk factor in an unselected and selected (DBP < 70 mmHg) study population. Results: Including DBP as the risk factor did not change the performance of the machine learning models evaluated using accuracy, AUC, mean, and weighted F-measure, and was not required to make proper predictions of stroke, MI, HF, and primary outcome. Conclusions: Analyses of the SPRINT trial data using ML algorithms imply that DBP should not be treated as an independent risk factor when intensifying blood pressure control.

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.

The aim of this research was to examine the prevalence of hyperventilation (defined by pCO 2 value) among acute heart failure (AHF) patients and to link it with potential triggers and prognosis. All patients underwent dyspnea severity assessment and capillary blood examination on hospital admission and during hospitalization. Out of 241 AHF patients, 57(24%) were assigned to low pCO 2 group (pCO 2  ≤ 30 mmHg) and 184 (76%) to normal pCO 2 group (pCO 2  > 30 mmHg). Low pCO 2 group had significantly lower HCO 3 - (22.3 ± 3.4 vs 24.7 ± 2.9 mmol/L, p < 0.0001) and significantly higher lactate level (2.53 ± 1.6 vs 2.14 ± 0.97 mmol/L, p = 0.03). No differences between groups were observed in respect to the following potential triggers of hyperventilation: hypoxia (sO 2 92.5 ± 5.2 vs 92 ± 5.6% p = 0.57), infection (CRP 10.5[4.9-26.4]vs 7.15[3.45-17.35] mg/L, p = 0.47), dyspnea severity (7.8 ± 2.3vs 8.0 ± 2.3 points, p = 0.59) and pulmonary congestion (82.5 vs 89.1%, p = 0.19), respectively. Low pCO 2 value was related to an increased 4-year all-cause mortality hazard ratio (HR) (95% CI) 2.2 (1.3-3.6); p = 0.002 and risk of death and of rehospitalization for HF, HR (95% CI) 2.0 (1.3-3.0); p = 0.002. Hyperventilation is relatively frequent in AHF and is related to poor prognosis. Low pCO 2 was not contingent on expected potential triggers of dyspnea but rather on tissue hypoperfusion., (© 2022. The Author(s).)

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 SpO 2 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 SpO 2 which induced first cycle of PB was 88.9 ± 3.7%, while in sPB mean SpO 2 preceding first spontaneous cycle of PB was 96.0 ± 2.5%. There was a reverse relationship between HVR and the relative variation of SpO 2 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Niewinski, Tubek, Paleczny, Banasiak and Ponikowski.)

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 [ΔSBP PHASE&#95;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 ΔSBP PHASE&#95;IV identified patients at risk in the long term, as evidenced by a low vs high ΔSBP PHASE&#95;IV comparison (square-wave response patients assigned to low ΔSBP PHASE&#95;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, ΔSBP PHASE&#95;IV and PAR-might carry prognostic value in patients with HFrEF receiving neurohormonal blockade pharmacotherapy., Competing Interests: Conflict of interest None declared., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2021. The Author(s).)

Background and Objectives: Recently, novel noiseless device for the assessment of baroreceptor function with the neck suction (NS) has been presented. In this study, we present another in-house approach to the variable-pressure neck chamber method. Our device offers further critical improvements. First, it enables delivery of negative (NS) as well as positive pressure (neck pressurizing, NP) in a noiseless manner. Second, we used small, 3D-printed cups positioned over the carotid sinuses instead of cumbersome neck collar to improve subject comfort and to test feasibility of tracking the pressure-induced changes in carotid artery with ultrasonography. Methods: Five healthy, non-smoking, normal-weight subjects aged 29 ± 3 years (mean ± SD) volunteered for the study. Heart rate (HR, bpm) and mean arterial pressure (MAP, mmHg) responses to short, 7-s long episodes of NS and NP were recorded. Each trial consisted of 12 episodes of variable-pressure: six episodes of NS (suction ranging between -10 and -80 mmHg) and six episodes of NP (pressure ranging between + 10 and + 80 mmHg). Carotid artery sonography was performed during the NS and NP in four subjects, on another occasion. Results: The variable-pressure episodes resulted consistently in the expected pattern of hemodynamic alterations: HR and MAP increases or decreases following the NP and NS, respectively, as evidenced by the coefficient of determination (R 2 ) of ≥0.78 for the carotid-HR response curve (for all five participants) and the carotid-MAP response curve (for four out of five participants; the curve cannot be calculated for one subject). We found a linear, dose-dependent relation between the applied pressure and the systolic-diastolic difference in carotid artery diameter. Conclusion: The novel device enables noiseless stimulation and unloading of the carotid baroreceptors with the negative and positive pressure, respectively, applied on the subject's neck via small, asymmetric and one-side flattened, 3D-printed cups. The unique design of the cups enables concomitant visualizing of the carotid artery during the NS or NP administration, and thereby direct monitoring of the intensity of mechanical stimulus targeting the carotid baroreceptors., Competing Interests: PM was employed by IMER Systems, Wrocław, Poland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Seredyński, Okupnik, Musz, Tubek, Ponikowska and Paleczny.)

The aim of this study was to test the utility of haemodynamic and autonomic variables (e.g. peripheral chemoreflex sensitivity [PCheS], blood pressure variability [BPV]) for the prediction of individual performance (marathon time and VO 2max ) in older men. The post-competition vasodilation and sympathetic vasomotor tone predict the marathon performance in younger men, but their prognostic relevance in older men remains unknown. The peripheral chemoreflex restrains exercise-induced vasodilation via sympathetically-mediated mechanism, what makes it a plausible candidate for the individual performance marker. 23 men aged ≥ 50 year competing in the Wroclaw Marathon underwent an evaluation of: resting haemodynamic parameters, PCheS with two methods: transient hypoxia and breath-holding test (BHT), cardiac barosensitivity, heart rate variability (HRV) and BPV, plasma renin and aldosterone, VO 2max in a cardiopulmonary exercise test (CPET). All tests were conducted twice: before and after the race, except for transient hypoxia and CPET which were performed once, before the race. Fast marathon performance and high VO 2max were correlated with: low ventilatory responsiveness to hypoxia (r =  - 0.53, r = 0.67, respectively) and pre-race BHT (r =  - 0.47, r = 0.51, respectively), (1) greater SD of beat-to-beat SBP (all p < 0.05). Fast performance was related with an enhanced pre-race vascular response to BHT (r =  - 0.59, p = 0.005). The variables found by other studies to predict the marathon performance in younger men: post-competition vasodilation, sympathetic vasomotor tone (LF-BPV) and HRV were not associated with the individual performance in our population. The results suggest that PCheS (ventilatory response) predicts individual performance (marathon time and VO 2max ) in men aged ≥ 50 yeat. Although cause-effect relationship including the role of peripheral chemoreceptors in restraining the post-competition vasodilation via the sympathetic vasoconstrictor outflow may be hypothesized to underline these findings, the lack of correlation between individual performance and both, the post-competition vasodilation and the sympathetic vasomotor tone argues against such explanation. Vascular responsiveness to breath-holding appears to be of certain value for predicting individual performance in this population, however.

Purpose: Transcutaneous auricular vagus nerve stimulation (taVNS) has been considered for the treatment of sympathetically mediated disorders. However, the optimal mode of stimulation is unknown. This study aimed to compare the cardiovascular effects of respiratory-gated taVNS in healthy subjects., Methods: The examination included expiratory-gated, inspiratory-gated, and non-respiratory-gated taVNS trials. Subjects were examined twice (the order of expiratory- and inspiratory-gated taVNS was changed). taVNS trials started with controlled breathing without stimulation (pre-stimulatory recording) followed by controlled breathing with taVNS (stimulatory recording). Synchronizing taVNS with the respiratory phase was computer-controlled. Heart rate (HR) was calculated from ECG. Systolic blood pressure (SBP) and systemic vascular resistance (SVR) were recorded continuously and noninvasively. Baroreflex sensitivity based on rising (BRS-UP) or falling SBP sequences (BRS-DOWN) or all sequences (BRS-ALL) and heart rate variability (HRV) were analyzed., Results: Seventy-two taVNS trials were obtained from 12 subjects (age 23 ± 3 years). Pre-stimulatory HR correlated with change in HR (r = - 0.25) and SVR (r = 0.24, both p < 0.05). There were no differences between three stimulatory conditions in (1) the changes of hemodynamic parameters, (2) BRS-UP and BRS-ALL, or (3) HRV indices (all p > 0.20). However, in the group of high pre-stimulatory HR trials, HR change differed between inspiratory-gated (0.11 ± 0.53%) and both expiratory-gated (- 1.30 ± 0.58%, p = 0.06) and non-respiratory-gated taVNS (- 1.69 ± 0.65, p = 0.02). BRS-DOWN was higher in inspiratory- vs. non-respiratory-gated taVNS (15.4 ± 1.3 vs. 14.1 ± 0.9 ms/mmHg, p = 0.03)., Conclusions: Expiratory-gated and non-respiratory-gated taVNS exert clear cardioinhibitory effects in healthy subjects with high pre-stimulatory HR, whereas inspiratory-gated taVNS does not affect HR. Cardiac and vascular effects of taVNS depend on pre-stimulatory HR.

New Findings: What is the central question of this study? Is there a link between gut microbial fermentation and ventilatory responsiveness to hypoxia in humans? What is the main finding and its importance? Increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to transient hypoxia. These findings imply a capacity for gut microbiota to modulate the peripheral chemoreflex response to hypoxia in humans., Abstract: Recent animal data indicate the presence of a bidirectional link between gut microbial activity and respiratory control. Nevertheless, the presence of a similar association between gut microbiota and peripheral chemoreceptor responsiveness to hypoxia in humans has not been reported to date. Therefore, we performed a within subject, placebo-controlled study in a group of 16 healthy individuals (eight men; mean ± SD age 25.9 ± 5.2 years). Participants underwent two tests (in a random order), receiving lactulose, which stimulates gut fermentation, or placebo. Ventilatory and haemodynamic responses to transient hypoxia were evaluated before and 2 h after the test meal. The magnitude of these responses was related to the net hydrogen content in the exhaled air, reflecting gut fermentation intensity. A lactulose meal, compared to placebo, caused an increase in the minute ventilation (Hyp-VI; l/min/ S p O 2 ) and breathing rate (Hyp-BR; breaths/min/ S p O 2 ) responses to hypoxia (for Hyp-VI, mean ± SD -0.03 ± 0.059 in placebo test vs. 0.05 ± 0.116 in lactulose test, P = 0.03; for Hyp-BR, -0.015 ± 0.046 vs. 0.034 ± 0.054, P = 0.01). The magnitude of these responses was positively correlated with the lactulose-induced hydrogen excretion (for Hyp-VI, r = 0.62, P = 0.01; for Hyp-BR, r = 0.73, P = 0.001). Changes in the resting parameters during normoxia did not differ significantly between the tests. Our results demonstrate that the increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to the transient hypoxia, which implies a capacity for gut microbiota to modulate the peripheral chemoreflex in humans., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

Purpose: The exercise pressor reflex (EPR) plays a fundamental role in physiological reactions to exercise in humans and in the pathophysiology of cardiovascular disorders. There is no "gold standard" method for EPR assessment; therefore, we propose a new protocol for testing interactions between the muscle mechanoreflex and metaboreflex (major components of EPR)., Methods: Thirty-four healthy subjects (mean age [± standard deviation] 24 ± 4 years, 22 men) were enrolled in the study. During the study, the hemodynamic and ventilatory parameters of these subjects were continuously monitored using our proposed assessment method. This assessment method consists of an initial 5-min rest period (baseline) followed by 5 min of passive cycling (PC) on an automated cycle ergometer (mechanoreceptor stimulation), after which tourniquet cuffs located bilaterally on the upper thighs are inflated for 3 min to evoke venous and arterial regional circulatory occlusion (CO) during PC (metaboreceptor stimulation). Deflation of the tourniquet cuffs is followed by a second 5 min of PC and finally by a 5-min recovery time. The control test comprises a 5-min rest period, followed by 3 min of CO only and a final 5-min recovery., Results: Mean arterial pressure (MAP) and minute ventilation (MV) increased significantly during PC (MAP: from 90 ± 9.3 to 95 ± 9.7 mmHg; MV: from 11.5 ± 2.5 to 13.5 ± 2.9 L/min; both p < 0.05) and again when CO was applied (MAP: from 95 ± 9.7 to 101 ± 11.0 mmHg; MV: from 13.5 ± 2.9 to 14.8 ± 3.8 L/min; both p < 0.05). In the control test there was a slight increase in MAP during CO (from 92 ± 10.5 to 94 ± 10.0 mmHg; p < 0.05) and no changes in the ventilatory parameters., Conclusion: Bilateral leg passive cycling with concomitant circulatory occlusion is a new, simple and effective method for testing interactions between the mechanoreflex and metaboreflex in humans.

New Findings: What is the central question of this research? Does increased ventilation contribute to the increase in heart rate during transient exposure to hypoxia in humans? What is the main finding and its importance? Voluntary suppression of the ventilatory response to transient hypoxia does not affect the magnitude of the heart rate response to the stimulus. This indicates that hypoxic tachycardia is not secondary to hyperpnoea in humans. Better understanding of the physiology underlying the cardiovascular response to hypoxia might help in identification of new markers of elevated chemoreceptor activity, which has been proposed as a target in treatment of sympathetically mediated diseases., Abstract: Animal data suggest that hypoxic tachycardia is secondary to hyperpnoea, and for years this observation has been extrapolated to humans, despite a lack of experimental evidence. We addressed this issue in 17 volunteers aged 29 ± 7 (SD) years. A transient hypoxia test, comprising several nitrogen-breathing episodes, was performed twice in each subject. In the first test, the subject breathed spontaneously (spontaneous breathing). In the second test, the subject was repeatedly asked to adjust his or her depth and rate of breathing according to visual (real-time inspiratory flow) and auditory (metronome sound) cues, respectively (controlled breathing), to maintain respiration at the resting level during nitrogen-breathing episodes. Hypoxic responsiveness, including minute ventilation [Hyp-VI; in liters per minute per percentage of blood oxygen saturation ( S p O 2 )], tidal volume [Hyp-VT; in litres per S p O 2 ], heart rate [Hyp-HR; in beats per minute per S p O 2 ], systolic [Hyp-SBP; in millimetres of mercury per S p O 2 ] and mean blood pressure [Hyp-MAP; in millimetres of mercury per S p O 2 ] and systemic vascular resistance [Hyp-SVR; in dynes seconds (centimetres) -5 per S p O 2 ] was calculated as the slope of the regression line relating the variable to S p O 2 , including pre- and post-hypoxic values. The Hyp-VI and Hyp-VT were reduced by 69 ± 25 and 75 ± 10%, respectively, in controlled versus spontaneous breathing (Hyp-VI, -0.30 ± 0.15 versus -0.11 ± 0.09; Hyp-VT, -0.030 ± 0.024 versus -0.007 ± 0.004; both P < 0.001). However, the cardiovascular responses did not differ between spontaneous and controlled breathing (Hyp-HR, -0.62 ± 0.24 versus -0.71 ± 0.33; Hyp-MAP, -0.43 ± 0.19 versus -0.47 ± 0.21; Hyp-SVR, 9.15 ± 5.22 versus 9.53 ± 5.57; all P ≥ 0.22), indicating that hypoxic tachycardia is not secondary to hyperpnoea. Hyp-HR was correlated with Hyp-SVR (r = -074 and -0.80 for spontaneous and controlled breathing, respectively; both P < 0.05) and resting barosensitivity assessed with the sequence technique (r = -0.60 for spontaneous breathing; P < 0.05). This might suggest that the baroreflex mechanism is involved., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Objectives: We evaluated the prognostic value of cardiac baroreflex sensitivity (BRS) in contemporary, optimally treated patients with mild-to-moderate heart failure with reduced ejection fraction (HFrEF)., Methods and Results: Data from 97 patients with HFrEF (left ventricular ejection fraction 32 ± 6%, all receiving angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker, 85% receiving aldosterone antagonist) were analysed retrospectively. All patients underwent standard clinical assessment, cardiopulmonary exercise testing and BRS evaluation with three methods: the phenylephrine (BRS-Phe), the sequence (BRS-Seq) and the controlled breathing (BRS-CtrBr) method. Data on 5-year all-cause mortality and appropriate and documented implantable cardioverter-defibrillator (ICD) discharges were collected. During a mean follow-up of 53 ± 15 months, the composite endpoint of all-cause death and appropriate and documented ICD discharge occurred in 31 (32%) patients. BRS measures assessed using all three methods were not related to survival in univariate Cox proportional hazards analyses (all P >0.25). There were also no differences in survival between low vs. preserved BRS groups, irrespective of the method used for BRS assessment (all P ≥0.15). BRS-Phe correlated with several clinically important variables (including left ventricular ejection fraction: r S  = 0.27, and peak oxygen consumption: r S  = 0.32, both P < 0.05), while clinical associations of BRS-Seq and BRS-CtrBr were sparse., Conclusions: Assessment of cardiac BRS provides no prognostic information in the contemporary mild-to-moderate HFrEF population receiving optimal management., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

From the physiological point of view, carotid bodies are mainly responsible for the ventilatory response to hypoxia; however, they also take part in the regulation of sympathetic tone. According to preclinical data, these structures likely contribute to the development and progression of sympathetically mediated diseases. Moreover, carotid body deactivation in animal models improved blood pressure control in hypertension and reduced mortality in heart failure, along with reducing sympathetic activity. On this basis, two first-in-man studies have been recently performed to investigate the safety and feasibility of such an approach in humans. In this review we summarise the current knowledge regarding the function of carotid bodies, the prevalence of their abnormalities, and the consequences of their excision in human hypertension and heart failure.

Background: Evaluation of sympathetic baroreflex (sBR) function in humans requires intra-neural recording of muscle sympathetic nerve activity (MSNA) by microneurography., Aims: We proposed noninvasive approach for the evaluation of sBR function by applying the threshold-analysis (traditionally, based on MSNA) to systemic vascular resistance (SVR) measurement by photoplethysmography., Methods & Results: In nine healthy subjects (5M; age: 25±5y), the threshold-analysis was calculated twice: using MSNA and SVR. Both methods yield comparable results in men (T 50 (burst-vs.-svr): CV=8.8%, r>0.9; Slope (burst-svr) : CV=30.1%; r>0.9), but not in women., Conclusions: SVR-based threshold-analysis is feasible in healthy young subjects and provides a promising alternative to the traditional MSNA-based approach., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Clinical and prognostic consequences of enhanced central chemosensitivity in the contemporary optimally treated patients with chronic heart failure (CHF) are unknown., Methods and Results: We studied central chemosensitivity (defined as hypercapnic ventilatory response [HCVR; L/min/mmHg]) in 161 CHF patients (mean left ventricular ejection fraction [LVEF] 31 ± 6%, all receiving a combination of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker) and 55 sex- and age-matched healthy controls. HCVR did not differ between CHF patients and controls (median 0.63 vs 0.57 L/min -1 /mmHg -1 , P = .76). When the CHF patients were divided into tertiles according to their HCVR values, there were no significant differences in clinical characteristics (except for ischemic etiology, which was more frequent in those with the highest HCVR), results of the cardiopulmonary exercise testing, and indices of heart rate variability. During the follow-up (median 28 months, range 1-48 months, ≥15 months in all survivors), 21 patients died. HCVR was not related to survival in the Cox proportional hazards analysis., Conclusions: Central chemosensitivity is not enhanced in contemporary, optimally treated CHF patients and its assessment does not provide significant clinical or prognostic information., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Key Points: In humans, excitation of peripheral chemoreceptors with systemic hypoxia causes hyperventilation, hypertension and tachycardia. However, the contribution of particular chemosensory areas (carotid vs. aortic bodies) to this response is unclear. We showed that selective stimulation of the carotid body by the injection of adenosine into the carotid artery causes a dose-dependent increase in minute ventilation and blood pressure with a concomitant decrease in heart rate in conscious humans. The ventilatory response was abolished and the haemodynamic response was diminished following carotid body ablation. We found that the magnitude of adenosine evoked responses in minute ventilation and blood pressure was analogous to the responses evoked by hypoxia. By contrast, opposing heart rate responses were evoked by adenosine (bradycardia) vs. hypoxia (tachycardia). Intra-carotid adenosine administration may provide a novel method for perioperative assessment of the effectiveness of carotid body ablation, which has been recently proposed as a treatment strategy for sympathetically-mediated diseases., Abstract: Stimulation of peripheral chemoreceptors by acute hypoxia causes an increase in minute ventilation (VI), heart rate (HR) and arterial blood pressure (BP). However, the contribution of particular chemosensory areas, such as carotid (CB) vs. aortic bodies, to this response in humans remains unknown. We performed a blinded, randomized and placebo-controlled study in 11 conscious patients (nine men, two women) undergoing common carotid artery angiography. Doses of adenosine ranging from 4 to 512 μg or placebo solution of a matching volume were administered in randomized order via a diagnostic catheter located in a common carotid artery. Separately, ventilatory and haemodynamic responses to systemic hypoxia were also assessed. Direct excitation of a CB with intra-arterial adenosine increased VI, systolic BP, mean BP and decreased HR. No responses in these variables were seen after injections of placebo. The magnitude of the ventilatory and haemodynamic responses depended on both the dose of adenosine used and on the level of chemosensitivity as determined by the ventilatory response to hypoxia. Percutaneous radiofrequency ablation of the CB abolished the adenosine evoked respiratory response and partially depressed the cardiovascular response in one participant. The results of the present study confirm the excitatory role of purines in CB physiology in humans and suggest that adenosine may be used for selective stimulation and assessment of CB activity. The trial is registered at ClinicalTrials.gov NCT01939912., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Background: Increased peripheral chemosensitivity (PChS) has been proposed as mechanism underlying obesity-related sympathoactivation, with insulin and/or leptin as possible mediators. However, human data on PChS in obesity are scarce. Therefore, we explored this issue in a sample of 41 healthy men aged 30-59 years, divided according to body fat percentage (fat %) into two groups: <25 and ≥25 %., Methods: PChS was assessed using transient hypoxia method [respiratory (PChS-MV), heart rate (PChS-HR), and blood pressure (PChS-SBP) responses were calculated]. Baroreflex sensitivity (BRS-Seq) was assessed using sequence method. Fasting plasma insulin and leptin levels were measured. Homeostatic model assessment (HOMA) was used to assess insulin sensitivity/resistance., Results: Individuals with ≥25 % body fat demonstrated increased PChS-SBP (p < 0.01), but unchanged PChS-MV and PChS-HR (both p > 0.4). PChS-SBP was related positively with anthropometric characteristics (e.g. waist circumference, fat %), plasma insulin and HOMA (all p < 0.05), and negatively with BRS-Seq (p = 0.001), but not with plasma leptin (p = 0.27)., Conclusions: In healthy men, overweight/obesity is accompanied by augmented blood pressure response from peripheral chemoreceptors, while respiratory and heart rate responses remain unaltered. Hyperinsulinaemia and insulin resistance (but not hyperleptinaemia) are associated with augmented pressure response from chemoreceptors.

Objective: The study aimed: (i) to characterize reflex responses from peripheral and central chemoreceptors in different age groups of healthy men (<50 years old vs ≥50 years old) and, (ii) to assess, within these groups, whether there is any relationship between ventilatory and hemodynamic responses from chemoreceptors and indices of autonomic nervous system (ANS)., Methods: Peripheral chemoreflex sensitivity was assessed by the transient hypoxia method and respiratory, heart rate (HR) and blood pressure responses were calculated. Central chemoreflex sensitivity was assessed by the rebreathing method and respiratory response was calculated. ANS was assessed using heart rate variability indices and baroreflex sensitivity (BRS)., Results: Sixty-seven healthy men were divided into 2 groups: <50 years (n = 38, mean age: 32 ± 10 years) and ≥50 years (n = 29, mean age: 61 ± 8 years). There were no differences in respiratory response from central and peripheral chemoreceptors between the older and younger groups of healthy males. We found a significantly different pattern of hemodynamic responses from peripheral chemoreceptors between the older and the younger groups. The former expressed attenuated HR acceleration and exaggerated blood pressure increase in response to transient hypoxia. Blunted HR response was related to reduced BRS and sympathovagal imbalance characterized by reduced vagal tone. Blood pressure responses seemed to be independent of sympathovagal balance and BRS., Interpretation: Ageing impacts hemodynamic rather than respiratory response from chemoreceptors. Impaired arterial baroreflex and sympathovagal imbalance related to ageing may contribute to decreased heart rate response, but not to increased blood pressure response from peripheral chemoreceptors.

Objective: To investigate the impact of iron status on survival in patients with type 2 diabetes and coronary artery disease (CAD)., Research Design and Methods: Serum ferritin, transferrin saturation (Tsat), and soluble transferrin receptor (sTfR) were measured in 287 patients with type 2 diabetes and stable CAD (65 ± 9 years of age, 78% men)., Results: During a mean follow-up of 45 ± 19 months, there were 59 (21%) deaths and 60 (21%) cardiovascular hospitalizations. Both serum ferritin and sTfR strongly predicted 5-year all-cause mortality rates, independently of other variables (including hemoglobin, measures of renal function, inflammation, and neurohormonal activation). There was an exponential relationship between sTfR and mortality (adjusted hazard ratio [HR] per 1 log mg/L: 4.24 [95% CI 1.43-12.58], P = 0.01), whereas the relationship between ferritin and mortality was U-shaped (for the lowest and the highest quintiles vs. the middle quintile [reference group], respectively: adjusted HR 7.18 [95% CI 2.03-25.46], P = 0.002, and adjusted HR 5.12 [1.48-17.73], P = 0.01). Similar patterns were observed for the composite outcome of all-cause mortality or cardiovascular hospitalization, and in these multivariable models, low Tsat was related to unfavorable outcome., Conclusions: Both low and high serum ferritin (possibly reflecting depleted and excessive iron stores, respectively) along with high serum sTfR (reflecting reduced metabolically available iron) identify patients with type 2 diabetes and CAD who have a poor prognosis.

Aims: Augmented peripheral chemoreflex response is an important mechanism in the pathophysiology of chronic heart failure (CHF). This study characterizes prevalence and clinical predictors of this phenomenon in optimally managed male CHF patients, and seeks to describe the hemodynamic consequences of chemoreceptor hypersensitivity., Methods and Results: Thirty-four optimally managed CHF patients and 16 control subjects were prospectively studied. Hypoxic ventilatory response (HVR)-a measure of peripheral chemosensitivity-was calculated with the use of short nitrogen gas administrations. Systolic blood pressure (SBP) and heart rate (HR) following transient hypoxic challenges were recorded with a Nexfin monitor. Hemodynamic responses to hypoxia were expressed by the linear slopes between oxygen saturation (%) and SBP (mm Hg) or HR (beats/min). Elevated HVR was present in 15 (44%) of the CHF patients. Patients with elevated HVR exhibited higher levels of N-terminal pro-B-type natriuretic peptide, lower left ventricular ejection fraction, and higher prevalence of atrial fibrillation. CHF patients with elevated HVR had significantly greater SBP and HR responses to hypoxia than CHF patients with normal HVR., Conclusions: Despite comprehensive pharmacotherapy, elevated HVR is prevalent in CHF patients, related to severity of the disease and associated with augmented hemodynamic responses to hypoxia. CHF patients with elevated HVR may be prone to unfavorable hemodynamic changes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: There is evidence that various stimuli affect the balance in the autonomic nervous system (ANS) and the functioning of cardiovascular system., Objective: The aim of the study was to assess whether the sounds of crying baby and the sounds of violence affected haemodynamic parameters and ANS in young, healthy adults and to measure differences in these reactions between the genders and these 2 stimuli., Methods: Haemodynamic parameters (measured non-invasively by the NEXFIN device), heart rate and blood pressure variability (HRV and BPV, respectively) and baroreflex sensitivity (BRS) were analyzed in 65 adults (21 women, mean age: 23years) during a 15-minute rest followed by the emission of two 5-minute acoustic stimuli: sounds of crying baby and sounds of violence emitted randomly and separated by a 4-minute pause., Results: Resting systolic blood pressure was lower, whereas indices of HRV (RMSSD, NN50, pNN50, high frequency component of HRV - HRV HF) and BPV (high frequency component - BPV HF) as well as BRS were higher in women as compared to men. During the emission of the sounds of crying baby, a decrease in diastolic blood pressure (DBP), systemic vascular resistance index, HRV HF and BPV LF (low frequency component of BPV) and an increase in stroke volume index were observed in the whole examined group, whereas during the emission of the sounds of violence subjects presented a decrease in DBP, mean blood pressure, HRV HF and BPV LF. The reaction to the sounds of crying baby (expressed as a decrease in HRV HF) was greater in women as compared to men (-0.28±0.49 versus -0.04±0.38ms(2), p=0.04). The comparison of the reaction between 2 stimuli revealed no differences., Conclusions: The stronger decrease in parasympathetic drive in women exposed to the sounds of crying baby may be related to a particular role of this stimulus, which signals the baby's distress and compels the caregivers to react., (Copyright © 2012 Elsevier B.V. All rights reserved.)