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.

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.

Acute effects of increased gut microbial fermentation on the hypoxic ventilatory response in humans.

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/ SpO2 ) and breathing rate (Hyp-BR; breaths/min/ SpO2 ) 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.

Inspiratory- and expiratory-gated transcutaneous vagus nerve stimulation have different effects on heart rate in healthy subjects: preliminary results.

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.

Passive bilateral leg cycling with concomitant regional circulatory occlusion for testing mechanoreflex-metaboreflex interactions in humans.

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.

Hypoxic tachycardia is not a result of increased respiratory activity in healthy subjects.

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 ( SpO2 )], tidal volume [Hyp-VT; in litres per SpO2 ], heart rate [Hyp-HR; in beats per minute per SpO2 ], systolic [Hyp-SBP; in millimetres of mercury per SpO2 ] and mean blood pressure [Hyp-MAP; in millimetres of mercury per SpO2 ] and systemic vascular resistance [Hyp-SVR; in dynes seconds (centimetres)-5 per SpO2 ] was calculated as the slope of the regression line relating the variable to SpO2 , 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.

Central Chemoreceptor Sensitivity Is Not Enhanced in Contemporary Patients With Chronic Systolic Heart Failure Receiving Optimal Treatment.

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.

Effects of selective carotid body stimulation with adenosine in conscious humans.

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.

Increased body fat is associated with potentiation of blood pressure response to hypoxia in healthy men: relations with insulin and leptin.

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.

Age-related reflex responses from peripheral and central chemoreceptors in healthy men.

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.

Clinical predictors and hemodynamic consequences of elevated peripheral chemosensitivity in optimally treated men with chronic systolic heart failure.

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.

Impact of marathon performance on muscles stiffness in runners over 50 years old.

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.

Induction of Day-Time Periodic Breathing is Associated With Augmented Reflex Response From Peripheral Chemoreceptors in Male Patients With Systolic Heart Failure.

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.

Answering Clinical Questions Using Machine Learning: Should We Look at Diastolic Blood Pressure When Tailoring Blood Pressure Control?

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.

Clinical determinants and prognostic significance of hypocapnia in acute heart failure.

The aim of this research was to examine the prevalence of hyperventilation (defined by pCO2 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 pCO2 group (pCO2 ≤ 30 mmHg) and 184 (76%) to normal pCO2 group (pCO2 > 30 mmHg). Low pCO2 group had significantly lower HCO3- (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 (sO2 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 pCO2 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 pCO2 was not contingent on expected potential triggers of dyspnea but rather on tissue hypoperfusion.

A Methodological Perspective on the Function and Assessment of Peripheral Chemoreceptors in Heart Failure: A Review of Data from Clinical Trials.

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.

Acute hyperoxia reveals tonic influence of peripheral chemoreceptors on systemic vascular resistance in heart failure patients.

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.

Neck Chamber Technique Revisited: Low-Noise Device Delivering Negative and Positive Pressure and Enabling Concomitant Carotid Artery Imaging With Ultrasonography.

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 (R2) 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.

Low ventilatory responsiveness to transient hypoxia or breath-holding predicts fast marathon performance in healthy middle-aged and older men.

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 VO2max) 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, VO2max 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 VO2max 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 VO2max) 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.

Assessment of baroreflex sensitivity has no prognostic value in contemporary, optimally managed patients with mild-to-moderate heart failure with reduced ejection fraction: a retrospective analysis of 5-year survival.

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: rS = 0.27, and peak oxygen consumption: rS = 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.