The autonomic nervous system and heart failure.

Cardiac Autonomic Nerve Stimulation in the Treatment of Heart Failure

high blood pressure associated with sympathetic overactivity is often associated with cardiovascular related mortality and/or morbidity. A therapeutic approach now considered for the treatment of resistant forms of the disease involves the selective denervation of the kidney ([16][1], [51][2], [52][

Heart failure (HF) is one of the major causes of morbidity and mortality in the world. According to a 2019 American Heart Association report, about 6.2 million American adults had HF between 2013 and 2016, being responsible for almost 1 million admissions. As the population ages, the prevalence of HF is anticipated to increase, with 8 million Americans projected to have HF by 2030, posing a significant public health and financial burden. Acute decompensated HF (ADHF) is a syndrome characterized by volume overload and inadequate cardiac output associated with symptoms including some combination of exertional shortness of breath, orthopnea, paroxysmal nocturnal dyspnea (PND), fatigue, tissue congestion (e.g., peripheral edema) and decreased mentation. The pathology is characterized by hemodynamic abnormalities that result in autonomic imbalance with an increase in sympathetic activity, withdrawal of vagal activity and neurohormonal activation (NA) resulting in increased plasma volume in the setting of decreased sodium excretion, increased water retention and in turn an elevation of filling pressures. These neurohormonal changes are adaptive mechanisms which in the short term are associated with increased contractility of the left ventricular (LV) and improvement in cardiac output. But chronically, the failing heart is unable to overcome the excessive pressure and volume leading to worsening HF. The primary symptomatic management of ADHF includes intravenous (IV) diuresis to help with decongestion and return to euvolemic status. Even though diuretics have not been shown to provide any mortality benefit, they have been clinically proven to be of significant benefit in the acute decompensated phase, as well as in chronic management of HF. Loop diuretics remain the mainstay of therapy for symptomatic management of HF with use of thiazide diuretics for synergistic effect in the setting of diuretic resistance. Poor diuretic efficacy has been linked with higher mortality and increased rehospitalizations.

there are three major cardiovascular reflexes: the baroreflex, chemoreflex, and cardiac sympathetic afferent reflex (CSAR). This commentary provides a brief overview of these three reflexes and also discusses the interplay among them. In addition, it outlines the potential centrally integrative

Sleep apnoea in heart failure increases mortality risk, possibly as a result of greater activation of the sympathetic nervous system. In healthy subjects, simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller manoeuvres) increase muscle sympathetic activity equally, primarily through chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause greater reductions in blood pressure than breath holds. We hypothesized that in heart failure, the summation of arterial baroreceptor unloading and chemoreceptor stimulation would increase sympathetic activity more during obstructive than central apnoeas. Healthy human subjects and heart failure patients (seven of each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds evoked a progressive increase in muscle sympathetic nerve activity in both groups, but had no effect on blood pressure. In healthy subjects, breath holds and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast, in heart failure patients, Mueller manoeuvres caused a progressive decrease in blood pressure (P < 0.05) and greater increases in sympathetic activity than breath holds (P < 0.01). In heart failure, simulated obstructive apnoea elicits greater increases in sympathetic activity than simulated central apnoea, due to its additional hypotensive effect. These present findings offer novel insight into the potential role of sleep apnoea in augmenting sympathetic activity and accelerating disease progression in heart failure.

Sleep apnoea in heart failure increases mortality risk, possibly as a result of greater activation of the sympathetic nervous system. In healthy subjects, simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller manoeuvres) increase muscle sympathetic activity equally, primarily through chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause greater reductions in blood pressure than breath holds. We hypothesized that in heart failure, the summation of arterial baroreceptor unloading and chemoreceptor stimulation would increase sympathetic activity more during obstructive than central apnoeas. Healthy human subjects and heart failure patients (seven of each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds evoked a progressive increase in muscle sympathetic nerve activity in both groups, but had no effect on blood pressure. In healthy subjects, breath holds and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast, in heart failure patients, Mueller manoeuvres caused a progressive decrease in blood pressure (P&lt;0.05) and greater increases in sympathetic activity than breath holds (P&lt;0.01). In heart failure, simulated obstructive apnoea elicits greater increases in sympathetic activity than simulated central apnoea, due to its additional hypotensive effect. These present findings offer novel insight into the potential role of sleep apnoea in augmenting sympathetic activity and accelerating disease progression in heart failure.

Diabetic Cardiomyopathy and Anesthesia

1. Heart Failure (HF) is a serious, debilitating condition with poor survival rates and an increasing level of prevalence. A characteristic of HF is a compensatory neurohumoral activation that increases with the severity of the condition. 2. The increase in sympathetic activity may be beneficial initially, providing inotropic support to the heart and peripheral vasoconstriction, but in the longer term it promotes disease progression and worsens prognosis. This is particularly true for the increase in cardiac sympathetic nerve activity, as shown by the strong inverse correlation between cardiac noradrenaline spillover and prognosis and by the beneficial effect of beta-adrenoceptor antagonists. 3. Possible causes for the raised level of sympathetic activity in HF include altered neural reflexes, such as those from baroreceptors and chemoreceptors, raised levels of hormones, such as angiotensin II, acting on circumventricular organs, and changes in central mechanisms that may amplify the responses to these inputs. 4. The control of sympathetic activity to different organs is regionally heterogeneous, as demonstrated by a lack of concordance in burst patterns, different responses to reflexes, opposite responses of cardiac and renal sympathetic nerves to central angiotensin and organ-specific increases in sympathetic activity in HF. These observations indicate that, in HF, it is essential to study the factors causing sympathetic activation in individual outflows, in particular those that powerfully, and perhaps preferentially, increase cardiac sympathetic nerve activity.

Event Abstract Back to Event PERSONALIZED EXERCISE TRAINING PROGRAM AS A COUNTERMEASURE TO ORTHOSTATIC INTOLERANCE AFTER SPACE FLIGHTS. Ferdinando Iellamo1, 2*, Maurizio Casasco3, Chiara Fossati4, Giuseppe Caminiti2 and Maurizio Volterrani2 1 Università degli Studi di Roma Tor Vergata, Italy 2 IRCCS San Raffaele Pisana, Italy 3 Federazione Medico Sportiva Italiana (FMSI), Italy 4 Foro Italico University of Rome, Italy NTRODUCTION Approximately 83% of astronauts experience pre-syncope and even fainting during upright position on landing days after long-term space flights. The inability to adequately elevate peripheral vascular resistance (i.e. vasoconstriction) along with the hypovolemia occurring during flight are considered the main factors of post-flight orthostatic intolerance 2,3,10 . Among the countermeasures tested against orthostatic intolerance, in-flight physical exercise has been the most obvious, because of its predictable capability to positively affect exercise capacity, autonomic nervous system regulation, muscle strength, and power, all of which are impaired as a consequence of weightlessness. Accordingly, 2-3 hours per day are devoted by astronauts to physical activity during flights. Yet, despite widespread in-flight utilization, physical exercise has proven only partially effective in counteracting orthostatic intolerance after space flights. It is arguable that most of the inconsistencies about the effectiveness of exercise reflect the poor knowledges that exist on the optimal dose of exercise (i.e. intensity and volume) to be performed to achieve a given physiological benefit, in this case orthostatic tolerance. To date, physical activity of astronauts during space flights has been mainly self-selected using conventional levels of dynamic exercise (according to general recommendations) in addition to some forms of resistance exercises. Recently, a new training method, referred to as the “individualized TRaining IMPulses” (TRIMPi)8, which is an individually determined, integrated measure of responses to physical load, that permits to account, in a single term, for both intensity and volume effects of endurance exercise training, has been developed. By this method, the dose of exercise has been repeatedly reported to affect neural cardiovascular regulation in on-ground studies.5 We report the case of an astronaut who performed a TRIMPi-based training program on board of the ISS during the expeditions 52/53 of the NASA/ASI-sponsored “Missione Vita” in order to investigate the feasibility and effectiveness of this structured, individually tailored, exercise training program in preventing/improving space flight-induced orthostatic intolerance and its underlying neural mechanisms. A 60 years old astronaut who took part to the NASA/ASI-sponsored Missione Vita for 139 days performed a TRIMPi-based training program during the last two months of permanence on the ISS (according to the time-schedule allotted by NASA to this experiment). Spectral analysis of heart rate (HR), blood pressure (BP) variability and baroreflex sensitivity (BRS, by mean of the sequences technique) were used as consolidated methodologies to assess the neural control of the cardiovascular system 9 during orthostatic stress before and after flight. The astronaut performed an active orthostatic test (10 min supine rest followed by 20 min of unaided standing-up with continuous one-lead ECG and continuous non-invasive BP recording (by Finometer device) before flight and 4 days after landing (time-constraints by NASA). The astronaut underwent a pre-flight progressive exercise test on a treadmill with continuous ECG monitoring and intermittent capillary sampling for blood lactate determination in order to establish the personalized exercise program by TRIMPi.8 The TRIMPi-based exercise training program was performed on alternate days. Each 30-min exercise session consisting in treadmill running, at pre-flight determined training loads as calculated by the TRIMPi, was performed during astronaut’s usual scheduled physical activity time so as to not disturb his daily routines. The astronaut’s HR was monitored by a cardiotachograph during the whole exercise training sessions and downloaded periodically to the Earth. N adverse effects were reported during exercise training. In comparison to pre-flight, the orthostatic tolerance test (OT) performed after flight showed a greater decrease in BP on going from supine to standing position (SAP: -30 vs – 10 mmHg; DAP – 10 vs -5 mmHg). This was accompanied by a greater increase in HR (+17 vs +8 b/min). No change in BRS was observed between pre-flight and post-flight OT. After-flight, OT showed a greater increase in the Low-Frequency (LF) component of HRV (indicator of mainly sympathetic modulation) and a greater decrease in the High-Frequency (HF) component of HRV (indicator of vagal modulation) (Fig. 1) with a shift in the sympatho-vagal balance toward a greater cardiac sympathetic activation (as expressed by the LF/HF ratio, Fig.2, left panel).9 The LF component of systolic BP variability (reflecting the sympathetic activation at peripheral vascular level) in response to changing posture from supine to upright was less after-flight than pre-flight (Fig. 2, right panel), paralleling the greater decrease in BP. These findings suggest that prolonged exposure to actual microgravity induces an impairment of neural sympathetic mechanisms controlling peripheral vasoconstriction resulting in a greater decrease in blood pressure on the assumption of the upright posture. This greater post-flight decrease in blood pressure is opposed by an increase in sympathetic activation at cardiac level that induces a greater HR response, possibly preventing an excessive decrease in BP, and (likely) the appearance of symptoms of orthostatic intolerance. Exercise training by TRIMPi might be involved in inducing these autonomic responses. DISCUSSION This report is in agreement with several previous studies indicating the central role of sympathetic nervous system in affecting orthostatic tolerance. Blaber et al.1 used HRV to investigate the differences in autonomic regulation of the heart in a group of 29 astronauts who did (non-finishers) or did not (finishers) experience post-flight orthostatic intolerance. Finishers and non-finishers had an increase in sympathetic activity with stand on pre- flight, yet only finishers retained this response on landing. Non-finishers also had lower sympatho-vagal balance and higher pre-flight supine parasympathetic activity than finishers. These results suggest that post-flight impairment in autonomic control of the heart and vasculature may contribute to orthostatic intolerance. Moreover, it has been reported that during Lower Body Negative Pressure (LBNP), Muscle Sympathetic Nerve Activity (MSNA) was lower before symptoms of pre-syncope in orthostatic intolerant subjects, whereas the activation of MSNA was preserved in tolerant subjects after short-term bed rest.7 These results support the hypothesis of reduced peripheral sympathetic activity in subjects with orthostatic intolerance, as indirectly confirmed by our experiment. The TRIMPi-based exercise training employed in this case during a long-lasting space flight might have acted as a physiological stimulus for increasing sympathetic cardiac activity on standing up after flight. Indeed, Iellamo et al.5 have reported that very intensive endurance training shifted the cardiovascular autonomic modulation from a parasympathetic toward a sympathetic predominance in elite athletes. The same group6 reported a curvilinear dose-response relationship between individualized training load (by TRIMPi) and autonomic nervous system functioning parameters with an increase in the LF component of HR variability, at peak exercise training load in patients suffering from chronic heart failure, who shares several pathophysiological changes with humans exposed to prolonged weightlessness. In keeping with this concept, a study performed by Iellamo et al.4 during the tragically ended STS 107 spacelab mission, suggested that dynamic exercise in microgravity environment might potentiate some sympathetic activity-enhancing mechanisms, such as the muscle metaboreflex. Overall, the findings of the present report indicate the feasibility of an on ground-determined, individually tailored, training protocol as an exercise-based countermeasure to be employed during prolonged space manned missions to counteract post-flight orthostatic intolerance. Further researches on a larger number of individuals would be mandatory for a better understanding of the role of TRIMPi methodology in reducing orthostatic intolerance after space flights CAPTIONS FOR FIGURES Figure 1: : Low-frequency and High Frequency components of Heart Rate Variability recorded during pre-flight and post-flight orthostatic tolerance test. LF r-r=Low-frequency, HF r-r=High-Frequency, nu=normalized units Figure 2: cardiac LF/HF ratio and low-frequency component of systolic blood pressure variability recorded during pre-flight and post-flight orthostatic tolerance test. LF-SAP= Low-frequency component of systolic blood pressure variability Acknowledgements This work has been supported by Italian Space Agency (ASI) grant n° 2013‐039‐I.0 References REFERENCES (1) Blaber AP, Bondar RL, Kassam MS. Heart rate variability and short duration spaceflight: relationship to post-flight orthostatic intolerance. BMC Physiol 2004; 27:4–6 (2) Convertino VA. Carotid-cardiac baroreflex: relation with orthostatic hypotension following simulated microgravity and implications for development of countermeasures. Am J Physiol Heart Circ Physiol 2002; 282:2210-2215. (3) Convertino VA. Mechanisms of microgravity induced orthostatic intolerance: implications for effective countermeasures. J Grav Physiol 2002; 9:1-14. (4) Iellamo F, Di Rienzo M, Lucini D, Legramante JM, Pizzinelli P, Castiglioni P, et al. Muscle metaboreflex contribution to cardiovascular regulation during dynamic exercise in microgravity: insights from the STS-107 Columbia Shuttle Mission. J Physiol 2006; 572, 829-838. (5) Iellamo F, Legramante JM, Pigozzi F, Spataro A, Norbiato G, Lucini D, et al. Conversion from vagal to sympathetic predominance with strenuous training in high performance world class athletes. Circulation 2002; 105:2719-2724. (6) Iellamo F, Manzi V, Caminiti G, Sposato B, Massaro M, Cerrito A, et al. Dose-response relationship of baroreflex sensitivity and heart rate variability to individually-tailored exercise training in patients with heart failure. Int J Cardiol. 2013;166:334-339. (7) Kamiya A, Michikami D, Fu Q, Iwase S, Hayano J, Kawada T, et al. Pathophysiology of orthostatic hypotension after bed rest: paradoxical sympathetic withdrawal. Am J Physiol Heart Circ Physiol 2003; 285:1158-1167. (8) Manzi V, Castagna C, Padua E, Lombardo M, D'Ottavio S, Massaro M, et al. Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners. Am J Physiol Heart Circ Physiol 2009;296:H1733-H1740. (9) Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology: Heart rate variability: standards and measurements, physiological interpretation, and clinical use. Circulation 1996;93:1043–1065. (10) Zhang LF. Vascular adaptation to microgravity: what have we learned? J Appl Physiol 2001; 91:2415-2430. Keywords: microgravity, orthostatic intolerance, TRIMP method, autonomic control, heart rate variability, microgravity, orthostatic intolerance test, TRIMP method, heart rate variability,, microgravity, orthostatic intolerance, TRIMPi method training, autonomic dysfunction,, microgravity, orthostatic intolerance, TRIMPi method training, autonomic dysfunction, long-lasting flight Conference: 39th ISGP Meeting & ESA Life Sciences Meeting, Noordwijk, Netherlands, 18 Jun - 22 Jun, 2018. Presentation Type: Extended abstract Topic: Analogues and Countermeasure Research Citation: Iellamo F, Casasco M, Fossati C, Caminiti G and Volterrani M (2019). PERSONALIZED EXERCISE TRAINING PROGRAM AS A COUNTERMEASURE TO ORTHOSTATIC INTOLERANCE AFTER SPACE FLIGHTS.. Front. Physiol. Conference Abstract: 39th ISGP Meeting & ESA Life Sciences Meeting. doi: 10.3389/conf.fphys.2018.26.00039 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 02 Dec 2018; Published Online: 16 Jan 2019. * Correspondence: Prof. Ferdinando Iellamo, Università degli Studi di Roma Tor Vergata, Roma, Lazio, 00173, Italy, iellamo@uniroma2.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Ferdinando Iellamo Maurizio Casasco Chiara Fossati Giuseppe Caminiti Maurizio Volterrani Google Ferdinando Iellamo Maurizio Casasco Chiara Fossati Giuseppe Caminiti Maurizio Volterrani Google Scholar Ferdinando Iellamo Maurizio Casasco Chiara Fossati Giuseppe Caminiti Maurizio Volterrani PubMed Ferdinando Iellamo Maurizio Casasco Chiara Fossati Giuseppe Caminiti Maurizio Volterrani Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Patients with major depressive disorder (MDD) have an increased risk for cardiac events. This is partly attributed to a disbalance of the autonomic nervous system (ANS) indicated by a reduced vagal tone and a (relative) sympathetic hyperactivity. However, in most studies, heart rate variability (HRV) was only examined while resting. So far, it remains unclear whether the dysbalance of the ANS in patients with MDD is restricted to resting or whether it is also evident during sympathetic and parasympathetic activation. The aim of this study was to compare the responses of the ANS to challenges that stimulated the sympathetic and, respectively, the parasympathetic nervous systems in patients with MDD. Forty-six patients with MDD (female 27 (58.7%), mean age 44 ± 17 years) and 46 healthy controls (female 26 (56.5%), mean age 44 ± 20 years) underwent measurement of time- and frequency-dependent domains of HRV at rest, while standing (sympathetic challenge), and during slow-paced breathing (SPB, vagal, i.e., parasympathetic challenge). Patients with MDD showed a higher heart rate, a reduced HRV, and a diminished vagal tone during resting, standing, and SPB compared to controls. Patients with MDD and controls responded similarly to sympathetic and vagal activation. However, the extent of modulation of the ANS was impaired in patients with MDD, who showed a reduced decrease in the vagal tone but also a reduced increase in sympathetic activity when switching from resting to standing. Assessing changes in the ANS during sympathetic and vagal activation via respective challenges might serve as a future biomarker and help to allocate patients with MDD to therapies like HRV biofeedback and psychotherapy that were recently found to modulate the vagal tone.

Systemic arterial hypertension and heart failure are cardiovascular diseases that affect millions of individuals worldwide. They are characterized by a change in the autonomic nervous system balance, highlighted by an increase in sympathetic activity associated with a decrease in parasympathetic activity. Most therapeutic approaches seek to treat these diseases by medications that attenuate sympathetic activity. However, there is a growing number of studies demonstrating that the improvement of parasympathetic function, by means of pharmacological or electrical stimulation, can be an effective tool for the treatment of these cardiovascular diseases. Therefore, this review aims to describe the advances reported by experimental and clinical studies that addressed the potential of cholinergic stimulation to prevent autonomic and cardiovascular imbalance in hypertension and heart failure. Overall, the published data reviewed demonstrate that the use of central or peripheral acetylcholinesterase inhibitors is efficient to improve the autonomic imbalance and hemodynamic changes observed in heart failure and hypertension. Of note, the baroreflex and the vagus nerve activation have been shown to be safe and effective approaches to be used as an alternative treatment for these cardiovascular diseases. In conclusion, pharmacological and electrical stimulation of the parasympathetic nervous system has the potential to be used as a therapeutic tool for the treatment of hypertension and heart failure, deserving to be more explored in the clinical setting.

Landsberg and colleagues in the 1980s first showed that an increase in the level of circulating insulin results in an increase in sympathetic activity, both in humans and in rats, even under conditions where the level of plasma glucose is clamped (for review see Landsberg, 2001). Insulin levels increase as a consequence of insulin resistance, which is commonly associated with obesity and the metabolic syndrome (Landsberg, 2001; Lambert et al. 2010). These findings led to the hypothesis that the hyperinsulinaemia associated with obesity causes an increase in sympathetic activity, which could account, at least in part, for obesity-related hypertension (Landsberg, 2001). In support of this hypothesis, epidemiological studies carried out in the 1990s showed that obese subjects had higher levels of insulin and blood pressure. The correlation between hyperinsulinaemia and hypertension is likely to be causal, because an increase in insulin levels in obese subjects leads to an increase in sympathetic activity, whereas an acute reduction in insulin levels in patients with hyperinsulinaemia results in a small but significant decrease in both sympathetic activity and blood pressure (Landsberg, 2001). In these early studies sympathetic activity was assessed indirectly by measuring urinary excretion of noradrenaline, but more recently the findings have been confirmed using the methods of noradrenaline spillover and microneurography (Lambert et al. 2010). Thus, although several other factors such as increased levels of circulating leptin are also likely to be important, there is now very substantial evidence that hyperinsulinaemia is a causal factor in obesity-related hypertension, as a consequence of its stimulatory effect on sympathetic nerve activity. Where and how does insulin act in the brain to increase sympathetic activity? A study by Cassaglia et al. in a recent issue of The Journal of Physiology provides convincing evidence that an increased level of circulating insulin acts on neurons in the arcuate nucleus in the ventromedial hypothalamus, leading to increased sympathetic activity and baroreflex sensitivity (see Fig. 1). The authors found that in anaesthetized rats intravenous infusion of insulin caused a large (over 100%) increase in lumbar sympathetic nerve activity (LSNA) and in the gain of the baroreflex control of LSNA. These effects were reversed after inhibition by microinjection of the GABA receptor agonist muscimol into either the hypothalamic paraventricular nucleus (PVN) or the arcuate nucleus. Both of these nuclei contain a high density of insulin receptors. Cassaglia et al. found, however, that insulin increased sympathetic activity and baroreflex gain when injected locally into the arcuate nucleus, but had no effect when injected into the PVN. As the authors note, confirmation that the arcuate nucleus is the site at which circulating insulin triggers sympathoexcitation will require future experiments in which the effects of specific blockade of insulin receptors within the arcuate nucleus are tested. Figure 1 Postulated central pathways subserving the effect of insulin on sympathetic activity If insulin acts on receptors in the arcuate nucleus, how is it transported from the blood? It does not readily cross the blood–brain barrier, but may access neurons within the arcuate nucleus via receptor-mediated endocytosis. On the other hand, the arcuate nucleus is unusual in that it contains highly permeable capillaries (Ciofi, 2011) like those in circumventricular organs, and so insulin may directly activate receptors in this nucleus without requiring a specific transport mechanism. Although the results showed that the PVN is also an essential part of the neural pathway mediating the effects of insulin on the sympathetic outflow (see Fig. 1), insulin microinjection into the PVN had no effect on sympathetic activity even though the PVN contains a high density of insulin receptors, as mentioned above. As the authors point out, insulin has inhibitory effects on neurons, and so it is possible that the effects of insulin on PVN neurons may not be observable in anaesthesia, when the tonic activity of PVN-sympathetic neurons may be very low. Apart from the PVN, the arcuate nucleus also projects to other brain regions that regulate the sympathetic outflow, including the dorsomedial hypothalamus, midbrain periaqueductal grey, rostral ventrolateral medulla and the nucleus of the solitary tract, (as shown in Fig. 1). These pathways may also subserve, at least in part, sympathoexcitatory responses evoked from the arcuate nucleus. Furthermore, neurons in the arcuate nucleus are also influenced by other hormones apart from insulin, such as leptin and ghrelin, which may also contribute to obesity-related hypertension (Rahmouni et al. 2005). It is clear that much remains to be discovered about the central pathways and mechanisms by which circulating insulin can affect sympathetic outflow, both in the short and the long term. The present study, however, is an important step towards that goal.

Right ventricular (RV) function may be impaired in pulmonary hypertension (PH), congenital heart disease (CHD), and coronary artery disease and in patients with left-sided heart failure (HF) or valvular heart disease. In recent years, many studies have demonstrated the prognostic value of RV function in cardiovascular disease. In the past, however, the importance of RV function has been underestimated. This perception originated from studies on open-pericardium dog models and from the observation that patients may survive without a functional subpulmonary RV (Fontan procedure). In the 1940s, studies using open-pericardium dog models showed that cauterization of the RV lateral wall did not result in a decrease in cardiac output or an increase in systemic venous pressure.1–3 As was later demonstrated, the open-pericardium model did not take into account the complex nature of ventricular interaction. In 1982, Goldstein and colleagues2 showed that RV myocardial infarction (RVMI) in a closed-chest dog model led to significant hemodynamic compromise. These findings were further supported by clinical studies demonstrating an increased risk of death, arrhythmia, and shock in patients with RVMI.4 The study of the RV is a relatively young field. In 2006, the National Heart, Lung, and Blood Institute identified RV physiology as a priority in cardiovascular research.5 The goal of this review is to present a clinical perspective on RV physiology and pathobiology. In the first article of the series, the anatomy, physiology, embryology, and assessment of the RV were discussed. In this second part, we discuss the pathophysiology, clinical importance, and management of RV failure. RV failure is a complex clinical syndrome that can result from any structural or functional cardiovascular disorder that impairs the ability of the RV to fill or to eject blood. The cardinal clinical manifestations of RV failure are (1) fluid retention, which may lead …

CON: Persistent Central Sleep Apnea/Hunter-Cheyne-Stokes Breathing, Despite Best Guideline-Based Therapy of Heart Failure With Reduced Ejection Fraction, Is Not a Compensatory Mechanism and Should Be Suppressed.

In 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists,1 included in The Anatomy of the Brain and Nerves , 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis.1 Christopher Wren, an anatomist member of the group, was the principal illustrator1 before being asked by the City Fathers to turn his talents to town planning, architecture, and cathedral building after the 1666 Great Fire of London. Figure 1. An illustration of the human sympathetic nerves of the neck and thorax, from The Anatomy of the Brain and Sympathetic Nerves , published in 1664 by Thomas Willis and reproduced in Soul Made Flesh .1 Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely innervated, leading Stelling in 18402 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiologists, including Brown-Sequard, Waller, and Bernard,2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anesthetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the …