Showing papers in "Clinical Autonomic Research in 2018"
TL;DR: The epidemiology, pathogenesis, and management of takotsubo syndrome are reviewed and several pathophysiological mechanisms involving myocardial ischemia and autonomic nervous system dysfunction have been proposed.
Abstract: Takotsubo syndrome is a recently recognized acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome. The typical takotsubo syndrome patient has a unique circumferential left (bi-) ventricular contraction abnormality profile that extends beyond a coronary artery supply territory and appears to follow the anatomical cardiac sympathetic innervation. The syndrome predominantly affects postmenopausal women and is often preceded by emotional or physical stress. Patients with predisposing factors such as malignancy and other chronic comorbidities are more prone to suffer from takotsubo syndrome. The pathogenesis of takotsubo syndrome is elusive. Several pathophysiological mechanisms involving myocardial ischemia (multivessel coronary artery spasm, microvascular dysfunction, aborted myocardial infarction), left ventricular outlet tract obstruction, blood-borne catecholamine myocardial toxicity, epinephrine-induced switch in signal trafficking, and autonomic nervous system dysfunction have been proposed. The syndrome is usually reversible; nevertheless, during the acute stage, a substantial number of patients develop severe complications such as arrhythmias, heart failure including pulmonary edema and cardiogenic shock, thromboembolism, cardiac arrest, and rupture. Treatment of precipitating factors, predisposing diseases, and complications is fundamental during the acute stage of the disease. The epidemiology, pathogenesis, and management of takotsubo syndrome are reviewed in this paper.
154 citations
Innsbruck Medical University1, University of Cologne2, Vanderbilt University3, University of Bologna4, Mayo Clinic5, University of Milan6, Icahn School of Medicine at Mount Sinai7, New York University8, French Institute of Health and Medical Research9, University of Calgary10, University of Lisbon11, University of Health Sciences Antigua12, Leiden University13, National and Kapodistrian University of Athens14
TL;DR: The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.
Abstract: Patients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure. As a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension. In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management. The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.
149 citations
TL;DR: Autonomic dysfunction may be responsible for additional morbidity in some infectious diseases, including leprosy, and bacterial infections releasing toxins that affect the autonomic nervous system.
Abstract: To review infectious diseases that may cause autonomic dysfunction. Review of published papers indexed in medline/embase. Autonomic dysfunction has been reported in retrovirus (human immunodeficiency virus (HIV), human T-lymphotropic virus), herpes viruses, flavivirus, enterovirus 71 and lyssavirus infections. Autonomic dysfunction is relatively common in HIV-infected patients and heart rate variability is reduced even in early stages of infection. Orthostatic hypotension, urinary dysfunction and hypohidrosis have been described in tropical spastic paraparesis patients. Varicella zoster reactivation from autonomic ganglia may be involved in visceral disease and chronic intestinal pseudo-obstruction. Autonomic and peripheral nervous system dysfunction may happen in acute tick-borne encephalitis virus infections. Hydrophobia, hypersalivation, dyspnea, photophobia, and piloerection are frequently observed in human rabies. Autonomic dysfunction and vagal denervation is common in Chagas disease. Neuronal depopulation occurs mainly in chagasic heart disease and myenteric plexus, and megacolon, megaesophagus and cardiomyopathy are common complications in the chronic stage of Chagas disease. Parasympathetic autonomic dysfunction precedes left ventricle systolic dysfunction in Chagas disease. A high prevalence of subclinical autonomic neuropathy in leprosy patients has been reported, and autonomic nerve dysfunction may be an early manifestation of the disease. Autonomic dysfunction features in leprosy include anhidrosis, impaired sweating function, localised alopecia ,and reduced heart rate variability. Urinary retention and intestinal pseudo-obstruction have been described in Lyme disease. Diphtheritic polyneuropathy, tetanus and botulism are examples of bacterial infections releasing toxins that affect the autonomic nervous system. Autonomic dysfunction may be responsible for additional morbidity in some infectious diseases.
66 citations
TL;DR: The first symptoms of MSA are frequently autonomic and may predate recognition of motor manifestations, and Orthostatic hypotension and erectile failure are among the first symptoms that, when evaluated in the context of associated clinical findings, may facilitate accurate and earlier diagnosis.
Abstract: The initial symptoms of multiple system atrophy (MSA) and, in particular, early autonomic symptoms, have received less attention than motor symptoms. Whereas pathognomonic motor signs are essential to diagnostic specificity, early symptoms important to recognition of a neurodegenerative disorder may be less apparent or diagnostically ambiguous. This observational study sought to identify the very earliest symptoms in the natural history of MSA. Detailed clinical histories focusing on early symptoms were obtained from 30 subjects recently diagnosed with MSA. Historical data were correlated with neurological examinations and laboratory autonomic testing. Subjects’ mean age was 63.9 years. Ten were classified as having MSA-P and 20 MSA-C. The evaluations occurred 2.9 ± 0.4 months after diagnosis. The first symptom of MSA was autonomic in 22 (73%) and motor in 3 (10%) subjects (p < 0.0001). The most frequent first symptom was erectile failure, which occurred in all men beginning 4.2 ± 2.6 years prior to diagnosis. After erectile failure, postural lightheadness or fatigue following exercise, urinary urgency or hesitancy, and violent dream enactment behavior consistent with REM behavioral sleep disorder were the most frequent initial symptoms. Neither the order of symptom progression, which was highly variable, nor autonomic severity scores differentiated between MSA-P and MSA-C. The first symptoms of MSA are frequently autonomic and may predate recognition of motor manifestations. Orthostatic hypotension and, in men, erectile failure are among the first symptoms that, when evaluated in the context of associated clinical findings, may facilitate accurate and earlier diagnosis.
54 citations
TL;DR: The ventilatory and cerebrovascular changes at altitude are reviewed and how they are both implicated in the maintenance of oxygen delivery to the brain and the interdependence of ventilation and cerebral blood flow is discussed.
Abstract: Ascent to high-altitude elicits compensatory physiological adaptations in order to improve oxygenation throughout the body. The brain is particularly vulnerable to the hypoxemia of terrestrial altitude exposure. Herein we review the ventilatory and cerebrovascular changes at altitude and how they are both implicated in the maintenance of oxygen delivery to the brain. Further, the interdependence of ventilation and cerebral blood flow at altitude is discussed. Following the acute hypoxic ventilatory response, acclimatization leads to progressive increases in ventilation, and a partial mitigation of hypoxemia. Simultaneously, cerebral blood flow increases during initial exposure to altitude when hypoxemia is the greatest. Following ventilatory acclimatization to altitude, and an increase in hemoglobin concentration-which both underscore improvements in arterial oxygen content over time at altitude-cerebral blood flow progressively decreases back to sea-level values. The complimentary nature of these responses (ventilatory, hematological and cerebral) lead to a tightly maintained cerebral oxygen delivery while at altitude. Despite this general maintenance of global cerebral oxygen delivery, the manner in which this occurs reflects integration of these physiological responses. Indeed, ventilation directly influences cerebral blood flow by determining the prevailing blood gas and acid/base stimuli at altitude, but cerebral blood flow may also influence ventilation by altering central chemoreceptor stimulation via central CO2 washout. The causes and consequences of the integration of ventilatory and cerebral blood flow regulation at high altitude are outlined.
48 citations
TL;DR: The purpose of this review was to define the central nervous system nuclei regulating sleep and cardiovascular function and to identify reciprocal networks that may underlie autonomic symptoms of disorders such as insomnia, sleep apnea, restless leg syndrome, rapid eye movement sleep behavior disorder, and narcolepsy/cataplexy.
Abstract: Cardiovascular and respiratory parameters change during sleep and wakefulness This observation underscores an important, albeit incompletely understood, role for the central nervous system in the differential regulation of autonomic functions Understanding sleep/wake-dependent sympathetic modulations provides insights into diseases involving autonomic dysfunction The purpose of this review was to define the central nervous system nuclei regulating sleep and cardiovascular function and to identify reciprocal networks that may underlie autonomic symptoms of disorders such as insomnia, sleep apnea, restless leg syndrome, rapid eye movement sleep behavior disorder, and narcolepsy/cataplexy In this review, we examine the functional and anatomical significance of hypothalamic, pontine, and medullary networks on sleep, cardiovascular function, and breathing
46 citations
TL;DR: Because cholinergic urticaria is not a homogeneous disease, its subtype classification is essential for selection of the most suitable therapeutic method.
Abstract: The aim of this study was to review the evidence on the epidemiology, physiopathology, categorization, and management of cholinergic urticaria. We specifically focused on several subtypes of cholinergic urticaria and investigated the relationship between cholinergic urticaria and idiopathic anhidrosis. Using an integrative approach, we reviewed publications addressing the epidemiology, clinical features, diagnostic approach, physiopathology, subtype classification, and therapeutic approach to cholinergic urticaria. Multiple mechanisms were found to contribute to the development of cholinergic urticaria. This disorder should be classified based on the pathogenesis and clinical characteristics of each subtype. Such a classification system would lead to better management of this resistant condition. In particular, sweating function should be given more attention when examining patients with cholinergic urticaria. Because cholinergic urticaria is not a homogeneous disease, its subtype classification is essential for selection of the most suitable therapeutic method.
44 citations
TL;DR: Bladder dysfunction not only impairs an individual’s quality of life, it can also cause emergency hospitalizations due to acute retention and early institutionalization, so care should be taken for the management of bladder dysfunction.
Abstract: Parkinson’s disease (PD) and multiple system atrophy (MSA) are major neurogenerative diseases characterized pathologically by abnormal alpha-synuclein aggregation. PD and MSA are clinically characterized by motor disorder and bladder dysfunction (mainly urinary urgency and frequency, also called overactive bladder). However, few literatures are available concerning bladder dysfunction in PD or MSA. A systematic review. The bladder dysfunction in MSA is more severe than that in PD for large post-void residual or urinary retention. These bladder dysfunctions presumably reflect the different nervous system pathologies. Overactive bladder in PD reflects lesions in the brain, e.g., in the prefrontal-nigrostriatal D1 dopaminergic bladder-inhibitory pathway. Overactive bladder in MSA reflects lesions similar to PD and the cerebellum (bladder-inhibitory), and the urinary retention in MSA presumably reflects lesions in the pontine micturition center and the sacral intermediolateral nucleus of the spinal cord (bladder-facilitatory). Bladder dysfunction not only impairs an individual’s quality of life, it can also cause emergency hospitalizations due to acute retention and early institutionalization. Anticholinergics are the first-line treatment for bladder dysfunction in PD and MSA patients, but care should be taken for the management of bladder dysfunction—particularly in MSA patients due to the high prevalence of difficult emptying, which needs clean, intermittent catheterization. This review summarizes the epidemiology, pathophysiology, and management of bladder dysfunction in individuals with PD or MSA.
41 citations
TL;DR: Although there is much that is unclear in its pathophysiology, recognition of neurogenic hypertension is of considerable clinical importance in individualizing drug therapy and achieving blood pressure control.
Abstract: Discussions about the cause and treatment of essential hypertension usually focus on mechanisms such as sodium/volume and the renin–angiotensin system. Less often discussed is hypertension driven by the sympathetic nervous system, i.e., neurogenic hypertension. In this review I discuss the pathophysiology of neurogenic hypertension, the controversy of renal versus central origin, the clinical clues that suggest neurogenic hypertension, and the interventions best suited in its treatment. Neurogenic hypertension is most likely to occur in patients with labile or paroxysmal hypertension, but evidence of increased sympathetic tone also suggests a neurogenic component in hypertension in patients with severe or resistant hypertension, chronic renal disease, comorbidities associated with increased sympathetic tone, and ingestion of drugs that stimulate sympathetic tone. The importance of combined alpha- and beta-blockade in pharmacologic treatment and the status of renal denervation are discussed. Although there is much that is unclear in its pathophysiology, recognition of neurogenic hypertension is of considerable clinical importance in individualizing drug therapy and achieving blood pressure control.
41 citations
TL;DR: Increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function, and new discoveries are paving the way for the identification of novel drugs and therapeutic targets.
Abstract: Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders.
To summarize the literature surrounding the eCB system in cardiovascular function and disease and the new compounds that may potentially extend the range of available interventions. Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects.
Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.
34 citations
TL;DR: An updated summary of the links between NC and autonomic cardiovascular dysfunction from a translational perspective suggests that, compared with control subjects, the heart rate in patients and animal models with NC is variable during wakefulness and normal to high during sleep.
Abstract: Narcolepsy is a rare disease that entails excessive daytime sleepiness, often associated with sudden episodes of muscle weakness known as cataplexy. Narcolepsy with cataplexy (NC) is due to the loss of hypothalamic neurons that release the neuropeptides orexin A and B. Orexin neuron projections prominently target brain structures involved in wake-sleep state switching and the central autonomic network. This review provides an updated summary of the links between NC and autonomic cardiovascular dysfunction from a translational perspective. The available evidence suggests that, compared with control subjects, the heart rate in patients and animal models with NC is variable during wakefulness and normal to high during sleep. Responses of the heart rate to internal stimuli (arousal from sleep, leg movements during sleep, defense response) are blunted. These alterations result from orexin deficiency and, at least during wakefulness before sleep, involve decreased parasympathetic modulation of the heart rate. On the other hand, NC in patients and animal models is associated with a blunted fall in arterial blood pressure from wakefulness to sleep, and particularly to the REM state, coupled to a variable decrease in arterial blood pressure during wakefulness. The former effect is caused, at least in part, by deranged control of the heart, whereas the latter may be due to decreased vasoconstrictor sympathetic activity. Systematic studies are warranted to help clarify whether and how the links between NC and autonomic dysfunction impact on the cardiovascular risk of patients with narcolepsy.
TL;DR: There was a marked cardiac autonomic alteration in AAS users, with a shift toward sympathetic modulation predominance and vagal attenuation, and this association may constitute an important mechanism linking AAS abuse to increased cardiovascular risk.
Abstract: The aims of this study were to examine the hypothesis that users of anabolic androgenic steroids (AAS) would have cardiac autonomic disorders and that there is a correlation between sympathetic modulation, high blood pressure (BP) and alterations to cardiac dimensions. Forty-five male subjects were enrolled in the study. They were categorized into three groups comprising bodybuilders actively using AAS (AAS users; n = 15), bodybuilders who had never used AAS (nonusers; n = 15) and age-paired healthy sedentary controls (n = 15). Hemodynamic parameters, linear and nonlinear analyses of heart rate variability and electrocardiography and echocardiography analyses were performed at rest. Bodybuilders in the AAS group had a higher mean BP than those in the ASS nonuser group (p < 0.05) and the sedentary controls (p < 0.001). Cardiac sympathetic modulation was higher in AAS users than in AAS nonusers (p < 0.05) and the sedentary controls (p < 0.001), and parasympathetic modulation was lower in AAS users than in nonusers and the sedentary controls (p < 0.05). Shannon entropy was lower in AAS users than in the sedentary (p < 0.05) controls, and the corrected QT interval and QT dispersion were higher in AAS users than in the sedentary controls (p < 0.05). The interventricular septal thickness, left ventricle posterior wall thickness and relative diastolic wall thickness were higher in AAS users than in AAS nonusers and the sedentary controls (p < 0.001). AAS users showed a positive correlation between increased sympathetic modulation and high BP (r = 0.48, p < 0.005), as well as sympathetic modulation and cardiac hypertrophy (r = 0.66, p < 0.001). There was a marked cardiac autonomic alteration in AAS users, with a shift toward sympathetic modulation predominance and vagal attenuation. The high BP observed in our group of bodybuilders using AAS was associated with increased sympathetic modulation, and this increased sympathetic modulation was associated with structural alterations in the heart. This association may constitute an important mechanism linking AAS abuse to increased cardiovascular risk.
TL;DR: A systematic review of the literature related to POTS and gastrointestinal symptoms proposed possible mechanisms and discussed diagnosis and treatment approaches for delayed gastric emptying, the most common gastrointestinal abnormality reported in patients with POTS.
Abstract: Gastrointestinal symptoms are among the most common complaints in patients with postural tachycardia syndrome (POTS). In some cases, they dominate the clinical presentation and cause substantial disabilities, including significant weight loss and malnutrition, that require the use of invasive treatment to support caloric intake. Multiple cross-sectional studies have reported a high prevalence of gastrointestinal symptoms in POTS patients with connective tissue diseases, such as Ehlers-Danlos, hypermobile type, and in patients with evidence of autonomic neuropathy. Previous studies that evaluated gastric motility in these patients reported a wide range of abnormalities, particularly delayed gastric emptying. The pathophysiology of gastrointestinal symptoms in POTS is likely multifactorial and probably depends on the co-morbid conditions. In patients with POTS and Ehlers-Danlos syndromes, structural and functional abnormalities in the gastrointestinal connective tissue may play a significant role, whereas in neuropathic POTS, the gastrointestinal tract motility and gut hormonal secretion may be directly impaired due to localized autonomic denervation. In patients with normal gastrointestinal motility but persistent gastrointestinal symptoms, gastrointestinal functional disorders should be considered. We performed a systematic review of the literature related to POTS and gastrointestinal symptoms have proposed possible mechanisms and discussed diagnosis and treatment approaches for delayed gastric emptying, the most common gastrointestinal abnormality reported in patients with POTS.
TL;DR: It is found that the sacral autonomic outflow is sympathetic, not parasympathetic as has been thought for more than a century, and it is argued that the novel genetic definition helps integrating neglected anatomical and physiological observations and clearing the path for future research.
Abstract: We recently defined genetic traits that distinguish sympathetic from parasympathetic neurons, both preganglionic and ganglionic (Espinosa-Medina et al., Science 354:893–897, 2016). By this set of criteria, we found that the sacral autonomic outflow is sympathetic, not parasympathetic as has been thought for more than a century. Proposing such a belated shift in perspective begs the question why the new criterion (cell types defined by their genetic make-up and dependencies) should be favored over the anatomical, physiological and pharmacological considerations of long ago that inspired the “parasympathetic” classification. After a brief reminder of the former, we expound the weaknesses of the latter and argue that the novel genetic definition helps integrating neglected anatomical and physiological observations and clearing the path for future research.
TL;DR: In this review, REM sleep physiology and relevant brain anatomy is briefly mentioned and integrated with neuroanatomical and physiological concepts regarding the central autonomic network and clinical and electrophysiological features of RBD in synucleinopathies are discussed.
Abstract: From newfound parasomnia to a marker of future synucleinopathy, since its first description in 1986, REM sleep behavior disorder (RBD) has been systematically tackled from virtually many viewpoints in basic, translational, and clinical studies. The time delay between RBD and synucleinopathy onset offers an exceptional window for observation and design of neuroprotective trials. In the last few years, research has focused on characterizing possible differences within RBD patients in order to draw potential profiles more or less susceptible to further neurodegeneration. Attention has been drawn towards autonomic dysfunction in RBD as one of such variables. In this review, REM sleep physiology and relevant brain anatomy is briefly mentioned and integrated with neuroanatomical and physiological concepts regarding the central autonomic network. A detailed summary of works showing the presence of autonomic dysfunction in RBD is provided, and clinical and electrophysiological features of RBD in synucleinopathies are discussed. A short overview of RBD in other neurodegenerative diseases is also provided.
TL;DR: This seronegative autoimmune autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG, and key differences from seropositive AAG emerge.
Abstract: Autoimmune autonomic ganglionopathy (AAG) is associated with ganglionic acetylcholine receptor (gAChR) antibodies. We describe a similar but distinct series of patients with autoimmune autonomic failure lacking this antibody. Retrospective chart review. Six patients presented with subacute autonomic failure, seronegative for gAChR antibodies. Orthostatic hypotension and gastrointestinal complaints were common. Autonomic testing revealed predominant sympathetic failure and no premature pupillary redilation. All patients had sensory symptoms and/or pain, which was severe in three. Immunotherapy with plasma exchange, intravenous immunoglobulin, and rituximab was ineffective. Three patients responded to intravenous steroids. In these cases of autoimmune autonomic failure, key differences from seropositive AAG emerge. Testing showed prominent sympathetic (rather than cholinergic) failure, specific pupillary findings of AAG were absent, and sensory symptoms were prominent. AAG responds to antibody-targeted immunotherapy, while these patients responded best to steroids. This seronegative autoimmune autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG.
TL;DR: Recent insights into the neural pathways activated by and involved in infection-induced inflammation are summarized and potential clinical applications are discussed.
Abstract: Although the immune and nervous systems have long been considered independent biological systems, they turn out to mingle and interact extensively. The present review summarizes recent insights into the neural pathways activated by and involved in infection-induced inflammation and discusses potential clinical applications. The simplest activation concerns a reflex action within C-fibers leading to neurogenic inflammation. Low concentrations of pro-inflammatory cytokines or bacterial fragments may also act on these afferent nerve fibers to signal the central nervous system and bring about early fever, hyperalgesia and sickness behavior. In the brain, the preoptic area and the paraventricular hypothalamus are part of a neuronal network mediating sympathetic activation underlying fever while brainstem circuits play a role in the reduction of food intake after systemic exposure to bacterial fragments. A vagally-mediated anti-inflammatory reflex mechanism has been proposed and, in turn, questioned because the major immune organs driving inflammation, such as the spleen, are not innervated by vagal efferent fibers. On the contrary, sympathetic nerves do innervate these organs and modulate immune cell responses, production of inflammatory mediators and bacterial dissemination. Noradrenaline, which is both released by these fibers and often administered during sepsis, along with adrenaline, may exert pro-inflammatory actions through the stimulation of β1 adrenergic receptors, as antagonists of this receptor have been shown to exert anti-inflammatory effects in experimental sepsis.
TL;DR: The current literature on anti-arrhythmic effects of RDN is reviewed with the focus on atrial fibrillation and ventricular arrhythmias and new insights from preclinical and clinical mechanistic studies and possible clinical implications are discussed.
Abstract: Renal afferent and efferent sympathetic nerves are involved in the regulation of blood pressure and have a pathophysiological role in hypertension. Additionally, several conditions that frequently coexist with hypertension, such as heart failure, obstructive sleep apnea, atrial fibrillation, renal dysfunction, and metabolic syndrome, demonstrate enhanced sympathetic activity. Renal denervation (RDN) is an approach to reduce renal and whole body sympathetic activation. Experimental models indicate that RDN has the potential to lower blood pressure and prevent cardio-renal remodeling in chronic diseases associated with enhanced sympathetic activation. Studies have shown that RDN can reduce blood pressure in drug-naive hypertensive patients and in hypertensive patients under drug treatment. Beyond its effects on blood pressure, sympathetic modulation by RDN has been shown to have profound effects on cardiac electrophysiology and cardiac arrhythmogenesis. RDN can display anti-arrhythmic effects in a variety of animal models for atrial fibrillation and ventricular arrhythmias. The first non-randomized studies demonstrate that RDN may promote the maintenance of sinus rhythm following catheter ablation in patients with atrial fibrillation. Registry data point towards a beneficial effect of RDN to prevent ventricular arrhythmias in patients with heart failure and electrical storm. Further large randomized placebo-controlled trials are needed to confirm the antihypertensive and anti-arrhythmic effects of RDN. Here, we will review the current literature on anti-arrhythmic effects of RDN with the focus on atrial fibrillation and ventricular arrhythmias. We will discuss new insights from preclinical and clinical mechanistic studies and possible clinical implications of RDN.
TL;DR: Cardiac sympathetic neuroimaging by 123I-MIBG scanning merits consideration as an autonomic test, especially in patients with nOH.
Abstract: Sympathetic neuroimaging is based on the injection of compounds that either radiolabel sites of the cell membrane norepinephrine transporter (NET) or that are taken up into sympathetic nerves via the NET and radiolabel intra-neuronal catecholamine storage sites. Detection of the radioactivity is by planar or tomographic radionuclide imaging. The heart stands out among body organs in terms of the intensity of radiolabeling of sympathetic nerves, and virtually all of sympathetic neuroimaging focuses on the left ventricular myocardium. The most common cardiac sympathetic neuroimaging method worldwide is 123I-metaiodobenzylguanidine (123I-MIBG) scanning. 123I-MIBG scanning is used routinely in Europe and East Asia in the diagnostic evaluation of neurogenic orthostatic hypotension (nOH), to distinguish Lewy body diseases (e.g., Parkinson disease with orthostatic hypotension (OH), pure autonomic failure) from non-Lewy body diseases (e.g., multiple system atrophy) and to distinguish dementia with Lewy bodies from Alzheimer's disease. In the USA, 123I-MIBG scanning has been approved by the Food and Drug Administration for the evaluation of pheochromocytoma and some forms of heart failure-but not for the above-mentioned differential diagnoses. Positron emission tomographic methods based on imaging agents such as 18F-dopamine are categorized as research tools, despite more than a quarter century of clinical experience with these modalities. Considering that 123I-MIBG scanning is available at most academic medical centers in the USA, cardiac sympathetic neuroimaging by this methodology merits consideration as an autonomic test, especially in patients with nOH.
TL;DR: The roles of clinical catechol neurochemistry in autonomic function testing and measurement of plasma catechols is rarely diagnostic but often is informative are summarized.
Abstract: Catechols are a class of compounds that contain adjacent hydroxyl groups on a benzene ring. Endogenous catechols in human plasma include the catecholamines norepinephrine, epinephrine (adrenaline), and dopamine; the catecholamine precursor DOPA, 3,4-dihydroxyphenylglycol (DHPG), which is the main neuronal metabolite of norepinephrine; and 3,4-dihydroxyphenylacetic acid (DOPAC), which is the main neuronal metabolite of dopamine. In the diagnostic evaluation of patients with known or suspected dysautonomias, measurement of plasma catechols is rarely diagnostic but often is informative. This review summarizes the roles of clinical catechol neurochemistry in autonomic function testing.
TL;DR: Why the sacral outflow should remain known as parasympathetic, and suggestions for future experimentation to advance the understanding of cellular identity in the autonomic motor system are outlined.
Abstract: A recent developmental study of gene expression by Espinosa-Medina, Brunet and colleagues sparked controversy by asserting a revised nomenclature for divisions of the autonomic motor system. Should we re-classify the sacral autonomic outflow as sympathetic, as now suggested, or does it rightly belong to the parasympathetic system, as defined by Langley nearly 100 years ago? Arguments for rejecting Espinosa-Medina, Brunet et al.’s scheme subsequently appeared in e-letters and brief reviews. A more recent commentary in this journal by Brunet and colleagues responded to these criticisms by labeling Langley’s scheme as a historical myth perpetuated by ignorance. In reaction to this heated exchange, I now examine both sides to the controversy, together with purported errors by the pioneers in the field. I then explain, once more, why the sacral outflow should remain known as parasympathetic, and outline suggestions for future experimentation to advance the understanding of cellular identity in the autonomic motor system.
TL;DR: Since there are no specific biomarkers available for this disorder, physicians should rely on Rome criteria for the diagnosis, due to the lack of randomized control trials, the treatment of CVS is primarily empirical.
Abstract: Cyclic-vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder characterized by recurrent episodes of nausea and vomiting. Although once thought to be a pediatric disorder, there has been a considerable increase in recognition of CVS in adults. The exact pathogenesis is unknown and several theories have been proposed. Migraine and CVS share a similar pathophysiology as suggested by several studies. Since there are no specific biomarkers available for this disorder, physicians should rely on Rome criteria for the diagnosis. Due to the lack of randomized control trials, the treatment of CVS is primarily empirical.
TL;DR: The autonomic nervous system (ANS) complications of cancer are classified into two categories, which include direct cancer-related complications, such as primary ANS tumors, as well as autonomic manifestations induced by non-primary AnS tumors (primary brain tumors and metastases).
Abstract: The autonomic nervous system (ANS) is the main homeostatic regulatory system of the body. However, this widely distributed neural network can be easily affected by cancer and by the adverse events induced by cancer treatments. In this review, we have classified the ANS complications of cancer into two categories. The first includes direct cancer-related complications, such as primary ANS tumors (pheochromocytoma, paraganglioma or neuroblastoma), as well as autonomic manifestations induced by non-primary ANS tumors (primary brain tumors and metastases). The second comprises indirect ANS complications, which include autonomic features related to cancer therapy (chemotherapy, radiotherapy and/or surgery) and those not related to cancer therapy, such as paraneoplastic autonomic syndromes. We also review the molecular relationship and modulation between the ANS and the cancer cells and their microenvironment.
TL;DR: Clinical standards for the acquisition and analysis of TCD signals in the autonomic laboratory and the multiple methods available to assess cerebral autoregulation are reviewed.
Abstract: When cerebral blood flow falls below a critical limit, syncope occurs and, if prolonged, ischemia leads to neuronal death. The cerebral circulation has its own complex finely tuned autoregulatory mechanisms to ensure blood supply to the brain can meet the high metabolic demands of the underlying neuronal tissue. This involves the interplay between myogenic and metabolic mechanisms, input from noradrenergic and cholinergic neurons, and the release of vasoactive substrates, including adenosine from astrocytes and nitric oxide from the endothelium. Transcranial Doppler (TCD) is a non-invasive technique that provides real-time measurements of cerebral blood flow velocity. TCD can be very useful in the work-up of a patient with recurrent syncope. Cerebral autoregulatory mechanisms help defend the brain against hypoperfusion when perfusion pressure falls on standing. Syncope occurs when hypotension is severe, and susceptibility increases with hyperventilation, hypocapnia, and cerebral vasoconstriction. Here we review clinical standards for the acquisition and analysis of TCD signals in the autonomic laboratory and the multiple methods available to assess cerebral autoregulation. We also describe the control of cerebral blood flow in autonomic disorders and functional syndromes.
TL;DR: Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.
Abstract: Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson’s disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients. Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA). MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSP patient had AS co-localized with tau but not TH. Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.
TL;DR: This study suggests that RBD is related with reduction in parasympathetic modulation of heart rate variability and blunting of sleep stage related variations.
Abstract: Heart rate variability, a marker of autonomic function modulation, is known to be blunted in Parkinson disease, although data remains conflicting and a putative modifying role of REM sleep behavior disorder persists unclarified. We assessed ten patients with idiopathic REM sleep behavior disorder patients, 18 patients with Parkinson disease and REM behavior disorder and eight patients with Parkinson disease without REM sleep behavior disorder. Heart rate variability analysis was performed in 5-min epochs selected from wake, Non-REM and REM polysomnography records. We compared heart rate variability measures by stage between two sets of groups: Parkinson disease vs. idiopathic RBD and patients with vs. without RBD, by using repeated measures ANOVA. There were no heart rate variability differences between Parkinson disease and idiopathic REM sleep behavior disorder groups. There were significant stage vs. group interactions (p = 0.045) regarding the high frequencies components when comparing patients with and without REM sleep behavior disorder, with the former presenting lower values and attenuation of sleep stage variations. Our study suggests that RBD is related with reduction in parasympathetic modulation of heart rate variability and blunting of sleep stage related variations.
TL;DR: Elements of the autonomic examination include variations in the pulse, postural measurements of blood pressure and heart rate, pupillary light reactions, skin coloration and temperature, patterns of sweating, and other organ-specific physical findings relevant to the individual patient’s presentation.
Abstract: Signs of autonomic dysfunction, although at times seemingly mysterious, can contribute to diagnostic clarification and clinical investigation. Even when sophisticated autonomic testing equipment is not readily available, the experienced clinician, through educated observation and inductive reasoning—in conjunction with an intelligently obtained autonomic medical history—can discern much by a careful physical examination. Elements of the autonomic examination include variations in the pulse, postural measurements of blood pressure and heart rate, pupillary light reactions, skin coloration and temperature, patterns of sweating, and other organ-specific physical findings relevant to the individual patient’s presentation. Especially important is the often neglected practice of measuring the blood pressure standing up, for orthostatic hypotension cannot be diagnosed by symptoms alone and is a common source of potential morbidity. The examination should be carried out in the context of understanding the syndromic nature of abnormalities of components of the autonomic nervous system.
TL;DR: While load of inertial resistance directly affects the magnitude of the transient blood pressure reduction and heart rate response to active standing, blood pressure stabilization is most rapidly attained during terrestrial +Gz.
Abstract: Since manned missions to the Moon and Mars are planned, we conducted active standing tests with lunar, Martian, terrestrial, and 1.8 loads of inertial resistance (+Gz) modeled through defined parabolic flight maneuvers. We hypothesized that the cardiovascular response to active standing is proportional to the +Gz load. During partial-+Gz parabolic flights, 14 healthy test subjects performed active stand-up maneuvers under 1 +Gz, lunar (0.16 +Gz), Martian (0.38 +Gz), and hyper inertial resistance (1.8 +Gz) while heart rate and finger blood pressure were continuously monitored. We quantified amplitudes and timing of orthostatic response immediately following standing up. The maximum early heart rate increase was 21 (SD ± 10) bpm with lunar, 23 (± 11) bpm with Martian, 34 (± 17) bpm with terrestrial +Gz, and 40 (± 11) bpm hyper +Gz. The time to maximum heart rate increased gradually with increasing loads of inertial resistance. The transient blood pressure reduction was most pronounced with hyper +Gz but did not differ significantly between lunar and Martian +Gz. The mean arterial pressure nadir was reached significantly later with Martian and lunar compared to 1 +Gz. Paradoxically, the time for blood pressure to recover was shortest with terrestrial +Gz. While load of inertial resistance directly affects the magnitude of the transient blood pressure reduction and heart rate response to active standing, blood pressure stabilization is most rapidly attained during terrestrial +Gz. The observation might suggest that the human cardiovascular system is tuned to cope with orthostatic stress on earth.
TL;DR: A review discusses the association between the three components of the triple risk hypothesis and major risk factors for SIDS, such as prone sleeping, maternal smoking, together with three “protective” factors, and cardiovascular control during sleep in infants, and discusses their potential involvement in SIDS.
Abstract: A failure of cardiorespiratory control mechanisms, together with an impaired arousal response from sleep, are believed to play an important role in the final event of sudden infant death syndrome (SIDS). The ‘triple risk model’ describes SIDS as an event that results from the intersection of three overlapping factors: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control and (3) an exogenous stressor. In an attempt to understand how the triple risk hypothesis is related to infant cardiorespiratory physiology, many researchers have examined how the known risk and protective factors for SIDS alter infant cardiovascular control during sleep. This review discusses the association between the three components of the triple risk hypothesis and major risk factors for SIDS, such as prone sleeping, maternal smoking, together with three “protective” factors, and cardiovascular control during sleep in infants, and discusses their potential involvement in SIDS.
TL;DR: An unusual case of lateral medullary infarction presenting with orthostatic hypotension with pre-syncope without vertigo or Horner’s syndrome, with results consistent with impaired sympathetic and parasympathetic cardiovascular reflexes is reported.
Abstract: We report an unusual case of lateral medullary infarction presenting with orthostatic hypotension with pre-syncope without vertigo or Horner’s syndrome. Case report with review of the literature. A 67-year-old man presented with pre-syncope and ataxia without vertigo. Initial brain CT and MRI were normal. Neurological evaluation revealed right-beating nystagmus with left gaze, vertical binocular diplopia, right upper-extremity dysmetria, truncal ataxia with right axial lateropulsion, and right-facial and lower extremity hypoesthesia. Bedside blood pressure measurements disclosed orthostatic hypotension. He had normal sinus rhythm on telemetry and normal ejection fraction on echocardiogram. A repeat brain MRI disclosed an acute right dorsolateral medullary infarct. Autonomic testing showed reduced heart rate variability during paced deep breathing, attenuated late phase II and phase IV overshoot on Valsalva maneuver, and a fall of 25 mmHg of blood pressure at the end of a 10-min head-up tilt with no significant change in heart rate. These results were consistent with impaired sympathetic and parasympathetic cardiovascular reflexes. He was discharged to acute rehabilitation a week later with residual right dysmetria and ataxia. Lateral medullary infarctions are usually reported as partial presentations of classical lateral medullary syndrome with accompanying unusual symptoms ranging from trigeminal neuralgias to hiccups. Pre-syncope from orthostatic hypotension is a rare presentation. In the first 3–4 days, absence of early DWI MRI findings is possible in small, dorsolateral medullary infarcts with sensory disturbances. Physicians should be aware of this presentation, as early diagnosis and optimal therapy are associated with good prognosis.