Baroreflex activation therapy in patients with heart failure with reduced ejection fraction: a single-centre experience.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is associated with excessive sympathetic and impaired parasympathetic activity. The Barostim Neo™ device is used for electronical baroreflex activation therapy (BAT) to counteract autonomic nervous system dysbalance. Randomized trials have shown that BAT improves walking distance and reduces N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels at least in patients with only moderate elevation at baseline. Its impact on the risk of heart failure hospitalization (HFH) and death is not yet established, and experience in clinical routine is limited. METHODS AND RESULTS: We report on patient characteristics and clinical outcome in a retrospective, non-randomized single-centre registry of BAT in HFrEF. Patients in the New York Heart Association (NYHA) Classes III and IV with a left ventricular ejection fraction (LVEF) <35% despite guideline-directed medical therapy were eligible. Symptom burden, echocardiography, and laboratory testing were assessed at baseline and after 12 months. Clinical events of HFH and death were recorded at routine clinical follow-up. Data are shown as number (%) or median (inter-quartile range). Between 2014 and 2020, 30 patients were treated with BAT. Median age was 67 (63-77) years, and 27 patients (90%) were male. Most patients (83%) had previous HFH. Device implantation was successful in all patients. At 12 months, six patients had died and three were alive but did not attend follow-up. NYHA class was III/IV in 26 (87%)/4 (13%) patients at baseline, improved in 19 patients, and remained unchanged in 5 patients (P < 0.001). LVEF improved from 25.5 (20.0-30.5) % at baseline to 30.0 (25.0-36.0) % at 12 months (P = 0.014). Left ventricular end-diastolic diameter remained unchanged. A numerical decrease in NT-proBNP [3165 (880-8085) vs. 1001 (599-3820) pg/mL] was not significant (P = 0.526). Median follow-up for clinical events was 16 (10-33) months. Mortality at 1 (n = 6, 20%) and 3 years (n = 10, 33%) was as expected by the Meta-Analysis Global Group in Chronic Heart Failure risk score. Despite BAT, event rate was high in patients with NYHA Class IV, NT-proBNP levels >1600 pg/mL, or estimated glomerular filtration rate (eGFR) <30 mL/min at baseline. NYHA class and eGFR were independent predictors of mortality. CONCLUSIONS: Patients with HFrEF who are selected for BAT are in a stage of worsening or even advanced heart failure. BAT appears to be safe and improves clinical symptoms and-to a modest degree-left ventricular function. The risk of death remains high in advanced disease stages. Patient selection seems to be crucial, and the impact of BAT in earlier disease stages needs to be established.

Immediate effect of caffeine on sympathetic nerve activity: why coffee is safe? A single-centre crossover study.

PURPOSES: Habitual coffee drinking is ubiquitous and generally considered to be safe despite its transient hypertensive effect. Our purpose was to determine the role of the sympathetic nervous system in the hypertensive response. METHODS: In a single-centre crossover study, medical caregivers were studied after consumption of standard coffee (espresso), water and decaffeinated coffee (decaff) given in random order at least 1 month apart. Plasma caffeine levels, mean arterial pressure, heart rate, total peripheral resistance and muscle sympathetic activity were recorded. Baroreflex activity was assessed using burst incidence and RR interval changes to spontaneous blood pressure fluctuations. RESULTS: A total of 16 subjects (mean [± standard error] age 34.4 ± 2 years; 44% female) were recruited to the study. Three agents were studied in ten subjects, and two agents were studied in six subjects. Over a 120-min period following the consumption of standard coffee, mean (± SE) plasma caffeine levels increased from 2.4 ± 0.8 to 21.0 ± 4 µmol/L and arterial pressure increased to 103 ± 1 mmHg compared to water (101 ± 1 mmHg; p = 0.066) and decaff (100 ± 1 mmHg; p = 0.016). Peripheral resistance in the same period following coffee increased to 120 ± 4% of the baseline level compared to water (107 ± 4; p = 0.01) and decaff (109 ± 4; p = 0.02). Heart rate was lower after both coffee and decaff consumption: 62 ± 1 bpm compared to water (64 bpm; p = 0.01 and p = 0.02, respectively). Cardio-vagal baroreflex activity remained stable after coffee, but sympathetic activity decreased, with burst frequency of 96 ± 3% versus water (106 ± 3%; p = 0.04) and decaff (112 ± 3%; p = 0.001) despite a fall in baroreflex activity from - 2.2 ± 0.1 to - 1.8 ± 0.1 bursts/100 beats/mmHg, compared to water (p = 0.009) and decaff (p = 0.004). CONCLUSION: The hypertensive response to coffee is secondary to peripheral vasoconstriction but this is not mediated by increased sympathetic nerve activity. These results may explain why habitual coffee drinking is safe.

[New Technologies and Devices of Heart Failure with Reduced Ejection Fraction].

Heart failure is the terminal stage of many heart diseases, most of which are patients with reduced ejection fraction. The efficacy of drug therapy for these patients is still limited. However, heart transplantation has not been widely carried out in clinic due to its high price, limited donors and postoperative rejection. In recent years, the development of instrumentation therapy has brought about a breakthrough in the treatment of such patients with heart failure. In this review, we introduce the principle, design, clinical trial results and recent progress of two new implantable devices for the treatment of HFrEF patients, cardiac contractility modulation (CCM) and baroreflex activation therapy (BAT), and discuss their research directions and challenges.

Effect of Yoga Based Cardiac Rehabilitation on Blood Pressure Variability and Baroreflex Sensitivity: RCT in Patients Post MI.

To assess the effects of 12 weeks Yoga based Cardiac Rehabilitation program on Blood Pressure Variability and Baroreflex Sensitivity in Eighty patients post myocardial infarction. Randomized controlled trial with two parallel groups. A tertiary care institution in India. The Yoga group received 13 hospital-based structured yoga sessions in adjunct to the standard care. Control Group participants received enhanced standard care involving three brief educational sessions on importance of diet and physical activity. Beat to beat arterial pressure variability and baroreflex sensitivity was determined non-invasively. Baseline measurement was done at 3 weeks post Myocardial Infarction. The measurements were repeated at 13th week and at 26th week post MI. There was no significant difference between the groups in time domain indices of SBP variability. At 26th week post MI, after normalization the Low Frequency power increased in the yoga group as compared to the decrease in the standard care group (p = 0.02). Though the High Frequency power increased in both the groups, the magnitude of increase was higher in the standard care group (p = 0.005). However, the total power increased significantly in yoga group with a concurrent decrease in standard care group (p = < 0.001). The SBP All BRS was significantly different between the groups with an increase in the yoga group and a decline in standard care group (p = 0.003) at 13th week. A short-term Yoga based cardiac rehabilitation has additive effects in improving baroreflex sensitivity and dampening blood pressure variability post myocardial infarction in patients under optimal medication.The main trial is registered in Clinical Trials Registry-India (CTRI) (Ref. No: CTRI/2012/02/002408). In addition, CTRI has also been registered for the sub-study. (Ref. No: CTRI/2017/09/009925).

Cardiovascular autonomic modulation during passive heating protocols: a systematic review.

Objective.To conduct a systematic review of the possible effects of passive heating protocols on cardiovascular autonomic control in healthy individuals.Approach.The studies were obtained from MEDLINE (PubMed), LILACS (BVS), EUROPE PMC (PMC), and SCOPUS databases, simultaneously. Studies were considered eligible if they employed passive heating protocols and investigated cardiovascular autonomic control by spontaneous methods, such as heart rate variability (HRV), systolic blood pressure variability (SBPV), and baroreflex sensitivity (BRS), in healthy adults. The revised Cochrane risk-of-bias tool (RoB-2) was used to assess the risk of bias in each study.Main results.Twenty-seven studies were included in the qualitative synthesis. Whole-body heating protocols caused a reduction in cardiac vagal modulation in 14 studies, and two studies reported both increased sympathetic modulation and vagal withdrawal. Contrariwise, local-heating protocols and sauna bathing seem to increase cardiac vagal modulation. A reduction of BRS was reported in most of the studies that used whole-body heating protocols. However, heating effects on BRS remain controversial due to methodological differences among baroreflex analysis and heating protocols.Significance.Whole-body heat stress may increase sympathetic and reduce vagal modulation to the heart in healthy adults. On the other hand, local-heating therapy and sauna bathing seem to increase cardiac vagal modulation, opposing sympathetic modulation. Nonetheless, further studies should investigate acute and chronic effects of thermal therapy on cardiovascular autonomic control.

Cardiopulmonary function during exercise in heart failure with reduced ejection fraction following baroreflex activation therapy.

PURPOSE: Baroreflex activation therapy has favorable effects in heart failure patients. We report the results of a single-center study of baroreflex activation therapy in heart failure with reduced ejection fraction including cardiopulmonary exercise testing for the first time to show the effect on exercise capacity. METHODS: A total of 17 patients were treated with baroreflex activation therapy. Eligibility criteria were the New York Heart Association class ⩾III and ejection fraction ⩽35% on guideline-directed medical and device therapy. The New York Heart Association class, quality of life, and 6-min hall walk distance were assessed in all patients. Twelve patients underwent cardiopulmonary exercise testing before and 8.9 ± 6.4 months after initiation of baroreflex activation therapy. RESULTS: The New York Heart Association class and 6-min hall walk distance improved after baroreflex activation therapy, while quality of life remained stable. Weight-adapted peak oxygen uptake increased significantly from 10.1 (8.2-12.9) ml/min/kg to 12.1 (10.4-14.6) ml/min/kg (p = 0.041). Maximal heart rate was stable. Maximal oxygen pulse increased from 9.7 (5.5-11.3) to 9.9 (7.1-12.1) ml/heartbeat (p = 0.047) in 10 patients with low maximal oxygen pulse at baseline (<16.5 ml/heartbeat). There was no significant change in maximal oxygen pulse in the whole cohort. Ventilatory efficiency remained stable. CONCLUSION: Weight-adapted peak oxygen uptake improved after baroreflex activation therapy, pointing to an enhanced exercise capacity. Ventilatory efficiency and heart rate did not change, while oxygen pulse increased in patients with low oxygen pulse at baseline, indicating an improvement in circulatory efficiency, that is, a beneficial effect on stroke volume and peripheral oxygen extraction.

Repeated warm water baths decrease sympathetic activity in humans.

Acute whole body heat stress evokes sympathetic activation. However, the chronic effects of repeated moderate heat exposure (RMHE) on muscle sympathetic nerve activity (MSNA) in healthy individuals remain unclear. We performed RMHE with 4 wk (5 days/wk) of warm baths (∼40°C, for 30 min) in nine healthy older (59 ± 2 yr) volunteers. Hemodynamic variables and MSNA were examined before, 1 day after, and 1 wk following 4 wk of RMHE in a laboratory at ∼23°C. Cold pressor test (CPT) and handgrip (HG) exercise were performed during the tests. Under normothermic condition, the resting MSNA burst rate (prior, post, post 1-wk: 31.6 ± 2.0, 25.2 ± 2.0, and 27.7 ± 1.7 bursts/min; P < 0.001) and burst incidence (P < 0.001) significantly decreased after RMHE. Moreover, the resting heart rate significantly decreased after RMHE (62 ± 2, 60 ± 2, and 58 ± 2 beats/min, P = 0.031). The sensitivity of baroreflex control of MSNA and heart rate were not altered by RMHE, although the operating points were reset. The MSNA and hemodynamic responses (i.e., changes) to handgrip exercise or cold pressor test were not significantly altered. These data suggest that the RMHE evoked by warm baths decreases resting sympathetic activity and heart rate, which can be considered beneficial effects. The mechanism(s) should be examined in future studies.NEW & NOTEWORTHY To our knowledge, this is the first study to observe the effects of repeated warm baths on sympathetic nerve activity during rest and stress in healthy middle age and older individuals. The data suggest that the repeated warm baths decreased resting sympathetic activity and heart rate, which can be considered beneficial effects. This study also provides the first evidence that the repeated warm baths did not alter the baroreflex sensitivity and the sympathetic responses to stress.

Baroreflex activation therapy with the Barostim™ device in patients with heart failure with reduced ejection fraction: a patient level meta-analysis of randomized controlled trials.

AIMS: Heart failure with reduced ejection fraction (HFrEF) remains associated with high morbidity and mortality, poor quality of life (QoL) and significant exercise limitation. Sympatho-vagal imbalance has been shown to predict adverse prognosis and symptoms in HFrEF, yet it has not been specifically targeted by any guideline-recommended device therapy to date. Barostim™, which directly addresses this imbalance, is the first Food and Drug Administration approved neuromodulation technology for HFrEF. We aimed to analyse all randomized trial evidence to evaluate the effect of baroreflex activation therapy (BAT) on heart failure symptoms, QoL and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFrEF. METHODS AND RESULTS: An individual patient data (IPD) meta-analysis was performed on all eligible trials that randomized HFrEF patients to BAT + guideline-directed medical therapy (GDMT) or GDMT alone (open label). Endpoints included 6-month changes in 6-min hall walk (6MHW) distance, Minnesota Living With Heart Failure (MLWHF) QoL score, NT-proBNP, and New York Heart Association (NYHA) class in all patients and three subgroups. A total of 554 randomized patients were included. In all patients, BAT provided significant improvement in 6MHW distance of 49 m (95% confidence interval [CI] 33, 64), MLWHF QoL of -13 points (95% CI -17, -10), and 3.4 higher odds of improving at least one NYHA class (95% CI 2.3, 4.9) when comparing from baseline to 6 months. These improvements were similar, or better, in patients who had baseline NT-proBNP <1600 pg/ml, regardless of the cardiac resynchronization therapy indication status. CONCLUSION: An IPD meta-analysis suggests that BAT improves exercise capacity, NYHA class, and QoL in HFrEF patients receiving GDMT. These clinically meaningful improvements were consistent across the range of patients studies. BAT was also associated with an improvement in NT-proBNP in subjects with a lower baseline NT-proBNP.

My Life in HRV Biofeedback Research.

This paper reviews the published work of me along with my students and close colleagues on the topic of heart rate variability biofeedback (HRVB). It includes early research by Vaschillo documenting resonance characteristics of the baroreflex system that causes large oscillations in heart rate when breathing at resonance frequency, research on heart rate variability as a marker of parasympathetic stress response in asthma, and HRVB as a treatment for asthma and depression. Many questions about HRVB remain unresolved, and important questions for future research are listed.

Early changes of immunoreactivity to orexin in hypothalamus and to RFamide peptides in brainstem during the development of hypertension.

Baroreflex sensitivity (BRS) is an important function of the nervous system and essential for maintaining blood pressure levels in the physiological range. In hypertension, BRS is decreased both in man and animals. Although increased sympathetic activity is thought to be the main cause of decreased BRS, hence the development of hypertension, the BRS is regulated by both sympathetic (SNS) and parasympathetic (PNS) nervous system. Here, we analyzed neuropeptide changes in the lateral hypothalamus (LH), which favours the SNS activity, as well as in PNS nuclei in the brainstem of spontaneously hypertensive rats (SHR) and their normotensive controls (Wistar Kyoto rats- WKY). The analyses revealed that in the WKY rats the hypothalamic orexin system, known for its role in sympathetic activation, showed a substantial decrease when animals age. At the same time, however, such a decrease was not observed when hypertension developed in the SHR. In contrast, Neuropeptide FF (NPFF) and Prolactin Releasing Peptide (PrRP) expression in the PNS associated Nucleus Tractus Solitarius (NTS) and Dorsal Motor Nucleus of the Vagus (DMV) diminished substantially, not only after the establishment of hypertension but also before its onset. Therefore, the current results indicate early changes in areas of the central nervous system involved in SNS and PNS control of blood pressure and associated with the development of hypertension.

Inspiratory muscle training improves breathing pattern and sympatho-vagal balance but not spontaneous baroreflex sensitivity in older women.

Even though recent studies reported a positive inspiratory muscle training (IMT) effect on cardiovascular autonomic modulation, its underlying mechanisms as the breathing pattern remain unclear. The study aimed to investigate the IMT effects on resting heart rate variability (HRV), spontaneous baroreflex sensitivity (BRS), and spontaneous breathing pattern in older women. Fourteen healthy older women participated in this study, allocated in IMT (50 % MIP; n = 8) or Sham (5% MIP; n = 6) protocols for four weeks. Blood pressure, heart rate, and ventilatory data were continuously recorded before and after interventions. After four weeks, IMT-group increased maximal inspiratory pressure and vagal-mediated HRV, following by the reduction of sympatho-mediated HRV and the inspiratory time during the spontaneous breathing cycle compared to Sham-group, but did not change BRS. Therefore, the shorter inspiratory time suggests a putative mechanism behind improved vagal-mediated HRV post-IMT in older women.

Device Therapy of Hypertension.

In the past decade, efforts to improve blood pressure control have looked beyond conventional approaches of lifestyle modification and drug therapy to embrace interventional therapies. Based upon animal and human studies clearly demonstrating a key role for the sympathetic nervous system in the etiology of hypertension, the newer technologies that have emerged are predominantly aimed at neuromodulation of peripheral nervous system targets. These include renal denervation, baroreflex activation therapy, endovascular baroreflex amplification therapy, carotid body ablation, and pacemaker-mediated programmable hypertension control. Of these, renal denervation is the most mature, and with a recent series of proof-of-concept trials demonstrating the safety and efficacy of radiofrequency and more recently ultrasound-based renal denervation, this technology is poised to become available as a viable treatment option for hypertension in the foreseeable future. With regard to baroreflex activation therapy, endovascular baroreflex amplification, carotid body ablation, and programmable hypertension control, these are developing technologies for which more human data are required. Importantly, central nervous system control of the circulation remains a poorly understood yet vital component of the hypertension pathway and mandates further investigation. Technology to improve blood pressure control through deep brain stimulation of key cardiovascular control territories is, therefore, of interest. Furthermore, alternative nonsympathomodulatory intervention targeting the hemodynamics of the circulation may also be worth exploring for patients in whom sympathetic drive is less relevant to hypertension perpetuation. Herein, we review the aforementioned technologies with an emphasis on the preclinical data that underpin their rationale and the human evidence that supports their use.

Psychophysiological responses to various slow, deep breathing techniques.

Deep breathing exercises are commonly used for several health conditions including pain and hypertension. Various techniques are available to practice deep breathing, whereas possible differential psychophysiological effects have not been investigated. We compared four deep breathing techniques and examined outcomes in blood pressure variability, respiratory sinus arrhythmia, baroreflex function, and emotional state. Healthy adult volunteers performed pursed-lips breathing, left and right unilateral nostril breathing, and deep breathing with an inspiratory threshold load (loaded breathing), all at a frequency of 0.1 Hz (i.e., controlled breathing) and for three minutes each. Results showed that blood pressure variability was higher during loaded breathing versus other conditions and higher during pursed-lips breathing versus left and right unilateral nostril breathing. Respiratory sinus arrhythmia was higher during loaded breathing versus other conditions and higher during pursed-lips breathing versus left unilateral nostril breathing. The effect of breathing condition on respiratory sinus arrhythmia was mediated by alterations in blood pressure variability. There was no difference between the breathing conditions in baroreflex sensitivity or effectiveness. Participants rated pursed-lips breathing as more calming and pleasant and with more sense of control (vs. other conditions). Overall, among the four tested deep breathing techniques, loaded breathing was associated with enhanced cardiovascular effects and pursed-lips breathing with better emotional responses, while also enhancing cardiovascular effects (albeit less than loaded breathing). These findings can be informative in applying deep breathing techniques as self-management interventions for health conditions, in which baroreceptors stimulation and autonomic and emotional modulations can be beneficial, such as pain and hypertension.

Effect of Standardized Hydroalcoholic Extract of Saffron Stamen on High Blood Pressure and Baroreflex Sensitivity in Anesthetized Rats.

OBJECTIVE: The stamen is a byproduct of saffron (Crocus sativus) flowers. Herein, its cardiovascular effects were evaluated on hypertension induced by angiotensin II (AngII) and NG-nitro-Larginine methyl ester (L-NAME), as well as baroreflex sensitivity (BRS). METHODS: Rats were randomly divided into 10 groups: 1) control, 2) AngII (50 ng/kg, i.v.), 3) losartan (10 mg/kg, i.p.) + AngII, 4) L-NAME (10 mg/kg, i.v.), 5) sodium nitroprusside (SNP) (50 mg/kg, i.p.) + L-NAME, 6, 7) saffron stamen extract (SS) (100 and 200 mg/kg, i.p.) + AngII and 8, 9) SS (100 and 200 mg/kg) + L-NAME, and 10) SS (200 mg/kg) + phenylephrine (Phen, i.v.). The treated rats first received two doses of SS, 30 min after the injection of L-NAME, AngII, and Phen in separate groups. The cardiovascular parameters were recorded by the PowerLab apparatus via an angiocatheter inserted into the femoral artery. The maximal changes (Δ) of mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) in the treated groups were compared with those of the hypertensive and control groups. The changes in MAP and HR induced by Phen were used for BRS evaluation. RESULTS: The SS extract did not significantly affect the basal cardiovascular parameters. The injection of AngII significantly increased the MAP and SBP (P<0.01-P<0.001) with no significant effect on the HR. The SS extract significantly attenuated the pressor effect induced by AngII (P<0.001). Increased MAP and SBP induced by L-NAME (P<0.001) were also significantly attenuated by the SS extract (P<0.01). The effect of SS extract on L-NAME was significantly higher than that of AngII (P<0.05). Moreover, BRS was significantly improved by the SS extract. CONCLUSION: Our findings provide evidence that the SS extract has anti-hypertensive effects that are probably mediated by an inhibitory effect on AngII, increasing nitric oxide production, or improving baroreflex sensitivity.

A Single Session of Heart Rate Variability Biofeedback Produced Greater Increases in Heart Rate Variability Than Autogenic Training.

Heart rate variability biofeedback (HRV-BF) has been confirmed to increase heart rate variability (HRV) and cardiac outflows by baroreflex in healthy populations and clinical patients. Autogenic training (AT) is common used in the psychological intervention. This study integrates a single-session of HRV-BF and AT into a high-technology mobile application (app), and examines the effects on HRV indices, breathing rates, and subjective relaxation scores. Healthy college students were recruited and assigned to the single-session HRV-BF group or AT group. Participants in the HRV-BF group received HRV-BF combined with paced breathing training, which gradually stepped down their breathing rates from 12, to 8, to 6 breaths/per min; and received feedback of HRV indices from the app. Participants in the AT group received autogenic training and feedback of heart rate from the app. A chest belt Zephyr BioHarness was connected through Bluetooth to a Zenfone5 mobile phone, it collected the signals of interbeat intervals and breathing rates at pre-training, mid-training, and post-training stages. The Kubios HRV software was used to analyze HRV indices. The results reveal higher HRV indices and lower breathing rates during mid-training and post-training in the HRV-BF group compared to the AT group. There were higher high-frequency of HRV at post-training than pre-training in the AT group. Participants of both groups increased their subjective relaxation scores after training. The HRV-BF protocol increased cardiac outflows by baroreflex and decreased breathing rates, and the AT protocol increased high-frequency of HRV. These high-technology wearable devices combined with psychological interventions will apply to various populations in the future.

Effects of short-term warm water immersion on cardiac baroreflex sensitivity in healthy men.

Warm water immersion (WWI) causes dizziness presumably due to a substantial drop of blood pressure. The aim of this study was to elucidate the effects of short-term WWI on cardiac baroreflex sensitivity (BRS) and the contribution of arterial stiffness to the cardiac BRS. Twelve apparent healthy men (44 ± 12 years) performed the single stand-up test after 5-min sitting in the bathtub without (Control) and with 41 °C warm water at the heart level (WWI). Cardiac BRS gain was evaluated by R-R interval response to the standing-induced drop of systolic blood pressure. In addition, before and 10 min after the single stand-up test, carotid arterial ß-stiffness index was evaluated in the supine rest. BRS gain was blunted (2.9 ± 1.6 vs. 1.8 ± 1.1 ms/mmHg, P = 0.005), whereas ß-stiffness index was not changed significantly after WWI. BRS gain correlated with ß-stiffness index before (r = - 0.626, P = 0.028) and after WWI (r = - 0.672, P = 0.015). ANCOVA revealed that these slopes of linear regression lines remained unchanged after WWI (P = 0.350). These results indicate that a short-term WWI acutely deteriorates cardiac BRS. Individuals with stiffer arteries are relatively more susceptible to WWI because of their poor baseline BRS, which might be one of the causes of bathing-related falling in elderly persons as well as frailty.

Baroreflex Activation Therapy in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: This study demonstrated the safety and effectiveness of baroreflex activation therapy (BAT) in patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: The BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial was a multicenter, prospective, randomized, controlled trial; subjects were randomized 1:1 to receive either BAT plus optimal medical management (BAT group) or optimal medical management alone (control group). METHODS: Four patient cohorts were created from 408 randomized patients with HFrEF using the following enrollment criteria: current New York Heart Association (NYHA) functional class III or functional class II (patients who had a recent history of NYHA functional class III); ejection fraction ≤35%; stable medical management for ≥4 weeks; and no Class I indication for cardiac resynchronization therapy. Effectiveness endpoints were the change from baseline to 6 months in 6-min hall walk distance (6MHW), Minnesota Living with HF Questionnaire quality-of-life (QOL) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The safety endpoint included the major adverse neurological or cardiovascular system or procedure-related event rate (MANCE). RESULTS: Results from, timeline and rationale for, cohorts A, B, and C are presented in detail in the text. Cohort D, which represented the intended use population that reflected the U.S. Food and Drug Administration-approved instructions for use (enrollment criteria plus NT-proBNP <1,600 pg/ml), consisted of 245 patients followed-up for 6 months (120 in the BAT group and 125 in the control group). BAT was safe and significantly improved QOL, 6MHW, and NT-proBNP. In the BAT group versus the control group, QOL score decreased (Δ = -14.1; 95% confidence interval [CI]: -19 to -9; p < 0.001), 6MHW distance increased (Δ = 60 m; 95% CI: 40 to 80 m; p < 0.001), NT-proBNP decreased (Δ = -25%; 95% CI: -38% to -9%; p = 0.004), and the MANCE free rate was 97% (95% CI: 93% to 100%; p < 0.001). CONCLUSIONS: BAT was safe and significantly improved QOL, exercise capacity, and NT-proBNP. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196).

Neuronal Networks in Hypertension: Recent Advances.

Neurogenic hypertension is associated with excessive sympathetic nerve activity to the kidneys and portions of the cardiovascular system. Here we examine the brain regions that cause heightened sympathetic nerve activity in animal models of neurogenic hypertension, and we discuss the triggers responsible for the changes in neuronal activity within these regions. We highlight the limitations of the evidence and, whenever possible, we briefly address the pertinence of the findings to human hypertension. The arterial baroreflex reduces arterial blood pressure variability and contributes to the arterial blood pressure set point. This set point can also be elevated by a newly described cerebral blood flow-dependent and astrocyte-mediated sympathetic reflex. Both reflexes converge on the presympathetic neurons of the rostral medulla oblongata, and both are plausible causes of neurogenic hypertension. Sensory afferent dysfunction (reduced baroreceptor activity, increased renal, or carotid body afferent) contributes to many forms of neurogenic hypertension. Neurogenic hypertension can also result from activation of brain nuclei or sensory afferents by excess circulating hormones (leptin, insulin, Ang II [angiotensin II]) or sodium. Leptin raises blood vessel sympathetic nerve activity by activating the carotid bodies and subsets of arcuate neurons. Ang II works in the lamina terminalis and probably throughout the brain stem and hypothalamus. Sodium is sensed primarily in the lamina terminalis. Regardless of its cause, the excess sympathetic nerve activity is mediated to some extent by activation of presympathetic neurons located in the rostral ventrolateral medulla or the paraventricular nucleus of the hypothalamus. Increased activity of the orexinergic neurons also contributes to hypertension in selected models.