Treating heart failure by targeting the vagus nerve.

Increased sympathetic and reduced parasympathetic nerve activity is associated with disease progression and poor outcomes in patients with chronic heart failure. The demonstration that markers of autonomic imbalance and vagal dysfunction, such as reduced heart rate variability and baroreflex sensitivity, hold prognostic value in patients with chronic heart failure despite modern therapies encourages the research for neuromodulation strategies targeting the vagus nerve. However, the approaches tested so far have yielded inconclusive results. This review aims to summarize the current knowledge about the role of the parasympathetic nervous system in chronic heart failure, describing the pathophysiological background, the methods of assessment, and the rationale, limits, and future perspectives of parasympathetic stimulation either by drugs or bioelectronic devices.

Interaction of simultaneous hypoxia and baroreflex loading on control of sympathetic action potential subpopulations.

Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multi-unit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors (intravenous phenylephrine) alone and in combination with systemic hypoxia (SpO2 80%) in 9 healthy young men. We extracted sympathetic APs using wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared to baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.

The combined effects of temperature and posture on regional blood flow and haemodynamics.

Under simultaneous ambient temperature and postural stressors, integrated regional blood flow responses are required to maintain blood pressure and thermoregulatory homeostasis. The aim of the present study was to assess the effect of ambient temperature and body posture on regional regulation of microvascular blood flow, specifically in the arms and legs. Participants (N = 11) attended two sessions in which they experienced transient ambient conditions, in a climatic chamber. During each 60-min trial, ambient temperature increased from 15.7 (0.6) °C to 38.9 (0.6) °C followed by a linear decrease, and the participants were either standing or in a supine position throughout the trial; relative humidity in the chamber was maintained at 25.9 (6.6) %. Laser doppler flowmetry of the forearm (SkBFarm) and calf (SkBFcalf), and haemodynamic responses (heart rate, HR; stroke volume, SV; cardiac output, CO; blood pressure, BP), were measured continuously. Analyses of heart rate variability and wavelet transform were also conducted. SkBFarm increased significantly at higher ambient temperatures (p = 0.003), but not SkBFcalf. The standing posture caused lower overall SkBF in both regions throughout the protocol, regardless of temperature (p < 0.001). HR and BP were significantly elevated, and SV significantly lowered, in response to separate and combined effects of higher ambient temperatures and a standing position (all p < 0.05); CO remained unchanged. Mechanistic analyses identified greater sympathetic nerve activation, and higher calf myogenic activation at peak temperatures, in the standing condition. Mechanistically and functionally, arm vasculature responds to modulation from both thermoregulation and baroreceptor activity. The legs, meanwhile, are more sensitive to baroreflex regulatory mechanisms.

[Baroreflex failure syndrome after the resection of complex paragangliomas of head and neck: a case report].

Protection of cranial nerves is one of the major challenges in the resection of paragangliomas of head and neck, especially in complex paragangliomas. We report a case of bilateral jugular tumor with unilateral carotid body tumor. Baroreflex failure syndrome（BFS） occurred after staged resection of bilateral lesions. There is still a lack of effective treatment for this complication. More prudent and reasonable treatment strategy is important to reduce the incidence of BFS.

Impaired neurocirculatory control in chronic kidney disease: New evidence for blunted sympathetic baroreflex and reduced sympathetic transduction.

BACKGROUND: Chronic kidney disease (CKD) is characterized by over-activation of the sympathetic nervous system (SNS) that increases cardiovascular risk. Whether sympathetic baroreflex sensitivity (sBRS) is impaired or intact in CKD remains under-studied and controversial. Furthermore, the downstream effect of SNS activation on blood pressure transduction has not been previously examined in CKD. We tested the hypothesis that sBRS is attenuated, while sympathetic transduction is augmented in CKD. METHODS: In 18 sedentary patients with CKD stages III-IV (eGFR: 40±14 ml/min) and 13 age-matched controls (eGFR: 95±10 ml/min), beat-to-beat blood pressure (BP; finger photoplethysmography), heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest for 10-min. Weighted linear regression analysis between MSNA burst incidence and diastolic BP was used to determine the spontaneous sBRS. Sympathetic-BP transduction was quantified using signal averaging, whereby the BP response to each MSNA burst was tracked over 15 cardiac cycles and averaged to derive the peak change in BP. RESULTS: Compared with controls, CKD patients had an attenuated sBRS [CKD: -1.34±0.59 versus CON: -2.91±1.09 bursts (100 heartbeats)-1 mmHg-1; P=0.001]. |sBRS| was significantly associated with eGFR (r=0.69, P<0.001). CKD patients had attenuated sympathetic-BP transduction compared to controls (0.75±0.7 vs. 1.60±0.8 mmHg; P=0.010). Resting MSNA was negatively associated with sympathetic transduction (r=-0.57, P=0.002). CONCLUSION: CKD patients exhibit impaired sBRS that may contribute to SNS overactivation and cardiovascular risk in this patient population. In addition, CKD patients had an attenuated sympathetic transduction that may counteract the vascular effects of SNS overactivation.

Cardiac cycle modulates social pain.

Social pain is a painful feeling evoked by social rejection, exclusion, or the loss of other important people. Previous research suggests that physical pain is reduced by increased signals from baroreceptors that monitor blood pressure. This pre-registered study investigated whether social pain is attenuated by increased baroafferent signals, as observed in physical pain. Given that baroafferent signals increase during cardiac systole and decrease during diastole, we hypothesized that feelings of pain induced by social rejection would be lower when exclusion events are presented at the cardiac systole than when they are presented at the diastole. Participants completed the cyberball task, a computerized ball-tossing game involving two other players. In the rejection condition, the ball was rarely thrown to the participant, while the other players kept tossing it to each other. Throws between other players were defined as exclusion events and were presented either at the cardiac systole (a systole condition) or at the diastole (a diastole condition). We found that exclusion events evoked significantly less social pain in the systole condition than in the diastole condition. Furthermore, the effects of cardiac cycle were more pronounced in participants with higher heart rate variability than those with lower heart rate variability. Our results suggest that cardiac afferent signals contribute not only to physical pain but also to social pain.

Sympathetic baroreflex sensitivity is enhanced in postmenopausal women.

The sympathetic nervous system is critical for regulating blood pressure (BP) via the arterial baroreflex and sympathetic transduction in the peripheral vasculature. These mechanisms interact, and both may be altered with aging and impacted by menopause. Although age-related decreases in sympathetic transduction have been demonstrated in women, it remains unclear whether sympathetic baroreflex sensitivity (BRS) is impaired in postmenopausal women (POST). We tested the hypothesis that sympathetic BRS would be enhanced in POST compared with premenopausal women (PRE). We examined beat-by-beat BP and muscle sympathetic nerve activity (MSNA) in 19 PRE (22 ± 2 yr, 22 ± 3 kg/m2) and 12 POST (57 ± 5 yr, 24 ± 2 kg/m2) during 10 min of rest. Spontaneous sympathetic BRS was quantified as the slope of a linear regression between MSNA burst incidence and diastolic BP. Sympathetic transduction to mean arterial pressure (MAP) for the 10 cardiac cycles following spontaneous MSNA bursts was assessed via signal averaging method. Resting MAP was similar (PRE: 82 ± 8 vs. POST: 85 ± 8 mmHg, P = 0.43), whereas resting MSNA was elevated in POST (PRE: 10 ± 6 vs. POST: 45 ± 16 bursts/100 heart beats, P < 0.0001). Spontaneous sympathetic BRS was enhanced in POST (PRE: -2.0 ± 1.2 vs. POST: -5.2 ± 1.9 bursts/beat/mmHg, P < 0.0005). Sympathetic transduction to MAP was attenuated in POST (time: P < 0.001, group: P < 0.001, interaction: P < 0.01). These data suggest that sympathetic BRS may be enhanced in POST. Consistent with recent hypotheses, enhanced sensitivity of the arterial baroreflex's neural arc may signify a compensatory response to reduced efficiency of the peripheral arterial baroreflex arc (i.e., sympathetic transduction) to preserve BP buffering capacity.NEW & NOTEWORTHY Studies examining sympathetic baroreflex function with aging remain equivocal, with some studies showing an increase, decrease, or no change in sympathetic baroreflex sensitivity (BRS) in older adults compared with younger adults. With aging, women experience unique physiological changes due to menopause that influence autonomic function. For the first time, we show that postmenopausal women exhibit a greater sympathetic BRS compared with young premenopausal women.

Real-time closed-loop brainstem stimulation modality for enhancing temporal blood pressure reduction.

BACKGROUND: Traditional pharmacological interventions are well tolerated in the management of elevated blood pressure (BP) for individuals with resistant hypertension. Although neuromodulation has been investigated as an alternative solution, its open-loop (OL) modality cannot follow the patient's physiological state. In fact, neuromodulation for controlling highly fluctuating BP necessitates a closed-loop (CL) stimulation modality based on biomarkers to monitor the patient's continuously varying physiological state. OBJECTIVE: By leveraging its intuitive linkage with BP responses in ongoing efforts aimed at developing a CL system to enhance temporal BP reduction effect, this study proposes a CL neuromodulation modality that controls nucleus tractus solitarius (NTS) activity to effectively reduce BP, thus reflecting continuously varying physiological states. METHOD: While performing neurostimulation targeting the NTS in the rat model, the arterial BP response and neural activity of the NTS were simultaneously measured. To evaluate the temporal BP response effect of CL neurostimulation, OL (constant parameter; 20 Hz, 200 µA) and CL (Initial parameter; 11 Hz, 112 µA) stimulation protocols were performed with stimulation 180 s and rest 600 s, respectively, and examined NTS activity and BP response to the protocols. RESULTS: In-vivo experiments for OL versus CL protocol for direct NTS stimulation in rats demonstrated an enhancement in temporal BP reduction via the CL modulation of NTS activity. CONCLUSION: This study proposes a CL stimulation modality that enhances the effectiveness of BP control using a feedback control algorithm based on neural signals, thereby suggesting a new approach to antihypertensive neuromodulation.

The wolf in sheep's clothing: vasovagal syncope in acute aortic dissection.

BACKGROUND: The presentation of acute aortic dissection can pose a challenge for emergency physicians, as it may occur without pain. Atypical presentations can lead to significant delays in diagnosis and increased mortality rates. CASE DESCRIPTION: Our case illustrates that isolated painless syncope can be a rare presenting symptom of acute aortic dissection type A. What is unique about our case is the limited extension of the dissection tear and the availability of Holter monitoring during the syncopal episode. CONCLUSION: This constellation provides insight into the pathophysiological mechanism of the syncope in this patient. Mechanisms of syncope related to acute aortic dissection are diverse. We show that vasovagal activation not related to pain can be the underlying mechanism of syncope in acute aortic dissection type A. Although excessive vasovagal tone in the setting of aortic dissection has been hypothesized in the past, it has never been as clearly illustrated as in the present case. This also highlights the challenge in risk stratification of syncope in the emergency department.

Closed-loop baroreflex model with biophysically detailed afferent pathway.

In this work, we couple a lumped-parameter closed-loop model of the cardiovascular system with a physiologically-detailed mathematical description of the baroreflex afferent pathway. The model features a classical Hodgkin-Huxley current-type model for the baroreflex afferent limb (primary neuron) and for the second-order neuron in the central nervous system. The pulsatile arterial wall distension triggers a frequency-modulated sequence of action potentials at the afferent neuron. This signal is then integrated at the brainstem neuron model. The efferent limb, representing the sympathetic and parasympathetic nervous system, is described as a transfer function acting on heart and blood vessel model parameters in order to control arterial pressure. Three in silico experiments are shown here: a step increase in the aortic pressure to evaluate the functionality of the reflex arch, a hemorrhagic episode and an infusion simulation. Through this model, it is possible to study the biophysical dynamics of the ionic currents proposed for the afferent limb components of the baroreflex during the cardiac cycle, and the way in which currents dynamics affect the cardiovascular function. Moreover, this system can be further developed to study in detail each baroreflex loop component, helping to unveil the mechanisms involved in the cardiovascular afferent information processing.

COVID-19-Associated Multisystem Inflammatory Syndrome in Children and Cardiovascular Autonomic Control: A Prospective Cohort Study Nine Months after SARS-CoV-2 Infection.

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) has emerged as a severe pediatric complication during the SARS-CoV-2 pandemic, with potential long-term cardiovascular repercussions. We hypothesized that heart rate and blood pressure control at rest and during postural maneuvers in MIS-C patients, months after the remission of the inflammatory syndrome, may reveal long-term autonomic dysfunctions. Methods: We assessed 17 MIS-C patients (13 males; 11.9 ± 2.6 years, m ± SD) 9 months after acute infection and 18 age- (12.5 ± 2.1 years) and sex- (13 males) matched controls. Heart rate and blood pressure variability, baroreflex function, and hemodynamic parameters were analyzed in supine and standing postures. Results: MIS-C patients exhibited reduced heart rate variability, particularly in parasympathetic parameters during standing (pNN50+: 6.1 ± 6.4% in controls, 2.5 ± 3.9% in MIS-C; RMSSD: 34 ± 19 ms in controls, 21 ± 14 ms in MIS-C, p < 0.05), with no interaction between case and posture. Blood pressure variability and baroreflex sensitivity did not differ between groups except for the high-frequency power in systolic blood pressure (3.3 ± 1.2 mmHg2 in controls, 1.8 ± 1.2 mmHg2 in MIS-C, p < 0.05). The MIS-C group also showed lower diastolic pressure-time indices (DPTI) and systolic pressure-time indices (SPTI), particularly in standing (DPTI: 36.2 ± 9.4 mmHg·s in controls, 29.4 ± 6.2 mmHg·s in MIS-C; SPTI: 26.5 ± 4.3 mmHg·s in controls, 23.9 ± 2.4 mmHg·s in MIS-C, p < 0.05). Conclusions: Altered cardiovascular autonomic control may persist in MIS-C patients with, however, compensatory mechanisms that may help maintain cardiovascular homeostasis during light autonomic challenges, such as postural maneuvers. These results highlight the importance of assessing long-term cardiovascular autonomic control in children with MIS-C to possibly identify residual cardiovascular risks and inform targeted interventions and rehabilitation protocols.

Severe Bradycardia Associated with the Use of Terlipressin: A Case Report.

Introduction: Although terlipressin is known to cause bradycardia, this adverse effect is usually described in association with hypertension and is considered a benign compensatory response mediated by arterial baroreceptors. Cardiac monitoring for patients receiving terlipressin is not routinely recommended. Case Presentation: A 77-year-old female patient with no history of coronary artery disease and no other coexisting risk factors for cardiac arrhythmias or conduction disturbances was admitted to intensive care unit with severe cholangitis, complicated by variceal bleeding. She developed severe sinus bradycardia following the use of terlipressin, which was associated with significant hypotension that required the infusion of norepinephrine. The bradycardia occurred again when terlipressin therapy was reattempted. Conclusion: Vasopressin is known to sensitize baroreceptor reflexes by a central mechanism though its actions on V1a receptors in the area postrema, and we speculate that vasopressin analogues such as terlipressin may act in the same manner. That this effect is not widely described in terlipressin safety literature may be due to the overall younger age range of the trial population. This raises the possibility that cardiac monitoring may be warranted for elderly patients receiving terlipressin.

Advances on the Experimental Research in Resistant Hypertension.

PURPOSE OF REVIEW: Resistant Hypertension (RH) poses a significant public health challenge, contributing to increased mortality, cardiovascular events and organ damage. Both clinical and experimental research are striving for higher standards in a translational manner to integrate new findings and confirm hypotheses. Considering that many are the aspects of RH that are still under investigation, this review aims to shed light on the advances made in experimental research concerning RH. It seeks to underscore the pivotal role of experimental studies in shaping clinical practices and also explore future perspectives. RECENT FINDINGS: It is important to emphasize the significance of experimental models, primarily for advancing our understanding: experimental models have greatly contributed to our comprehension of the underlying mechanisms in RH, including factors like sympathetic activation, endothelial dysfunction and structural vessel abnormalities. Secondly, for assessing treatment approaches: animal models have also played a crucial role in evaluating the potential effectiveness of diverse treatment approaches for RH. These encompass both pharmacological options, involving combinations of established drugs or novel pharmaceuticals, and non-pharmacological alternatives, which include surgical procedures like renal denervation, medical devices like baroreceptor stimulators, and lifestyle modifications. The most lacking component in translational research is the fact that there is no well-established animal model that perfectly replicates RH. Consequently, alternative strategies, including the combination of models, must be considered. What remains clear is that the development of animal models closely mimicking RH holds the promise of providing valuable insights into the essential mechanisms and responses necessary to combat or slow the global progression of RH.

Effects of baroreflex activation therapy on cardiac function and morphology.

AIMS: Arterial hypertension (aHTN) plays a fundamental role in the pathogenesis and prognosis of heart failure with preserved ejection fraction (HFpEF). The risk of heart failure increases with therapy-resistant arterial hypertension (trHTN), defined as inadequate blood pressure (BP) control ≥140/90 mmHg despite taking ≥3 antihypertensive medications including a diuretic. This study investigates the effects of the BP lowering baroreflex activation therapy (BAT) on cardiac function and morphology in patients with trHTN with and without HFpEF. METHODS: Sixty-four consecutive patients who had been diagnosed with trHTN and received BAT implantation between 2012 and 2016 were prospectively observed. Office BP, electrocardiographic and echocardiographic data were collected before and after BAT implantation. RESULTS: Mean patients' age was 59.1 years, 46.9% were male, and mean body mass index (BMI) was 33.2 kg/m2. The prevalence of diabetes mellitus was 38.8%, atrial fibrillation was 12.2%, and chronic kidney disease (CKD) stage ≥3 was 40.8%. Twenty-eight patients had trHTN with HFpEF, and 21 patients had trHTN without HFpEF. Patients with HFpEF were significantly older (64.7 vs. 51.6 years, P < 0.0001), had a lower BMI (30.0 vs. 37.2 kg/m2, P < 0.0001), and suffered more often from CKD-stage ≥3 (64 vs. 20%, P = 0.0032). After BAT implantation, mean office BP dropped in patients with and without HFpEF (from 169 ± 5/86 ± 4 to 143 ± 4/77 ± 3 mmHg [P = 0.0019 for systolic BP and 0.0403 for diastolic BP] and from 170 ± 5/95 ± 4 to 149 ± 6/88 ± 5 mmHg [P = 0.0019 for systolic BP and 0.0763 for diastolic BP]), while a significant reduction of the intake of calcium-antagonists, α2-agonists and direct vasodilators, as well as a decrease in average dosage of ACE-inhibitors and α2-agonists could be seen. Within the study population, a decrease in heart rate from 74 ± 2 to 67 ± 2 min-1 (P = 0.0062) and lengthening of QRS-time from 96 ± 3 to 106 ± 4 ms (P = 0.0027) and QTc-duration from 422 ± 5 to 432 ± 5 ms (P = 0.0184) were detectable. The PQ duration was virtually unchanged. In patients without HF, no significant changes of echocardiographic parameters could be seen. In patients with HFpEF, posterior wall diameter decreased significantly from 14.0 ± 0.5 to 12.7 ± 0.3 mm (P = 0.0125), left ventricular mass (LVM) declined from 278.1 ± 15.8 to 243.9 ± 13.4 g (P = 0.0203), and e' lateral increased from 8.2 ± 0.4 to 9.0 ± 0.4 cm/s (P = 0.0471). CONCLUSIONS: BAT reduced systolic and diastolic BP and was associated with morphological and functional improvement of HFpEF.

Racial differences in baroreflex function: Implications for the cardiovascular conundrum.

Study objective: African Americans (AAs) show early signs of vascular dysfunction paired with elevated blood pressure (BP) and total peripheral resistance (TPR), which is thought to underlie their increased rates of cardiovascular health complications relative to European Americans (EAs). AAs paradoxically have higher cardiac vagal tone, indexed by heart rate variability (HRV), which is cardio-protective. This paradox has been termed the Cardiovascular Conundrum. The physiological mechanism underlying this phenomenon is not well understood. We examined race differences in baroreflex function, which might be an important mechanism underlying the Cardiovascular Conundrum. Design: Participants completed a 5-minute baseline period where resting cardiac metrics were assessed. Setting: Laboratory. Participants: 130 college-aged individuals (54 women, 57 AAs). Main outcome measures: Baroreflex function was indexed as baroreflex sensitivity (BRS; the magnitude of changes in cardiovascular activity in accordance with BP changes) and effectiveness (BEI; the ratio of BP changes that elicit changes in cardiovascular activity) in the cardiac, vascular, and myocardial limbs. Results and conclusions: Results showed AAs to have higher HRV and cardiac BRS in comparison to EAs, suggesting the baroreflex is more sensitive to correcting the heart period for changes in BP among AAs compared to EAs. However, AAs showed lower vascular BEI relative to EAs, suggesting less effective control of TPR. In sum, lower BEI in the vascular branch might be an important mechanism underlying the Cardiovascular Conundrum (i.e., higher HRV and BP) and by extension, health disparities in cardiovascular diseases between AAs and EAs.

Baroreflex and chemoreflex interaction in high-altitude exposure: possible role on exercise performance.

The hypoxic chemoreflex and the arterial baroreflex are implicated in the ventilatory response to exercise. It is well known that long-term exercise training increases parasympathetic and decreases sympathetic tone, both processes influenced by the arterial baroreflex and hypoxic chemoreflex function. Hypobaric hypoxia (i.e., high altitude [HA]) markedly reduces exercise capacity associated with autonomic reflexes. Indeed, a reduced exercise capacity has been found, paralleled by a baroreflex-related parasympathetic withdrawal and a pronounced chemoreflex potentiation. Additionally, it is well known that the baroreflex and chemoreflex interact, and during activation by hypoxia, the chemoreflex is predominant over the baroreflex. Thus, the baroreflex function impairment may likely facilitate the exercise deterioration through the reduction of parasympathetic tone following acute HA exposure, secondary to the chemoreflex activation. Therefore, the main goal of this review is to describe the main physiological mechanisms controlling baro- and chemoreflex function and their role in exercise capacity during HA exposure.

Purported Self-Organized Criticality of the Cardiovascular Function: Methodological Considerations for Zipf's Law Analysis.

Self-organized criticality is a universal theory for dynamical systems that has recently been applied to the cardiovascular system. Precise methodological approaches are essential for understanding the dynamics of cardiovascular self-organized criticality. This study examines how the duration and quality of data recording affect the analysis of cardiovascular self-organized criticality, with a focus on the beat-by-beat heart rate variability time series obtained from seven healthy subjects in a standing position. Drawing a Zipf diagram, we evaluated the distribution of cardiovascular events of bradycardia and tachycardia. We identified tipping points for the distribution of both bradycardia and tachycardia events. By varying the recording durations (1, 2, 5, 10, 20, 30, and 40 min) and sampling frequencies (500, 250, and 100 Hz), we investigated their influence on the observed distributions. While shorter recordings can effectively capture cardiovascular events, they may underestimate the variables describing their distribution. Additionally, the tipping point of the Zipf distribution differs between bradycardia and tachycardia events. Comparisons of the distribution of bradycardia and tachycardia events should be conducted using long data recordings. Utilizing devices with lower sampling frequencies may compromise data fidelity. These insights contribute to refining experimental protocols and advancing our understanding of the complex dynamics underlying cardiovascular regulation.

Sympathetic overactivity and nocturnal diuresis in obstructive sleep apnea alter the response to hypertension therapy.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with high blood pressure that responds poorly to usual antihypertensive therapy. METHODS AND RESULTS: Forty-one subjects with OSA had 25% higher plasma norepinephrine and 42% higher epinephrine measured every 2 h over 24 h than 20 control subjects. They also excreted more sodium during sleep. This suggested that that a sympatholytic would be a more successful antihypertensive than a diuretic. To test this hypothesis we treated a second group of 23 hypertensive apneics with placebo, 6 weeks of the sympatholytic guanfacine and 6 weeks of hydrochlorothiazide in a crossover study. Guanfacine lowered 24-hour blood pressure by 9.6/6.7 mmHg, more than the 5.4/2.9 mmHg effect of hydrochlorothiazide (P < 0.05). Nighttime systolic blood pressure dipping was poor at 6.6 ± 1.8%. Hydrochlorothiazide did not alter blood pressure dipping but guanfacine improved dipping to 9.1 ± 1.2%, a better result (P = 0.03) than from the diuretic. Central aortic pressure by pulse wave analysis was 120/84 mmHg on hydrochlorothiazide and 109/72 on guanfacine, (P < 0.05). Guanfacine, but not hydrochlorothiazide, improved baroreflex sensitivity, heart rate variability and flow mediated vascular dilation, suggesting that decreasing the elevated sympathetic nerve activity of obstructive sleep apnea returned vascular function toward normal. CONCLUSIONS: OSA is the most common condition associated with antihypertensive treatment failure. It increased sympathetic nerve activity day and night. Drugs that block sympathetic nerve function are not among the 4 most commonly recommended classes of antihypertensives but diuretics are. Sympatholytic therapy was superior to diuretic treatment for hypertension associated with sleep apnea. TRIAL REGISTRATION: NCT, NCT02699125, Registered 26 February 2016 - Retrospectively registered, https://clinicaltrials.gov/study/NCT02699125 .