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Journal of the American College of... Jan 2024Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial...
BACKGROUND
Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease.
OBJECTIVES
The aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA).
METHODS
Patients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%.
RESULTS
A total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%.
CONCLUSIONS
In patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.
Topics: Humans; Female; Middle Aged; Aged; Male; Exercise Test; Coronary Artery Disease; Acetylcholine; Electrocardiography; Myocardial Ischemia; Vascular Diseases; Ischemia
PubMed: 38199706
DOI: 10.1016/j.jacc.2023.10.034 -
Consciousness and Cognition Jan 2024Acetylcholine is a neurotransmitter and neuromodulator involved in a variety of cognitive functions. Additionally, acetylcholine is involved in the regulation of REM... (Review)
Review
Acetylcholine is a neurotransmitter and neuromodulator involved in a variety of cognitive functions. Additionally, acetylcholine is involved in the regulation of REM sleep: cholinergic neurons in the brainstem and basal forebrain project to and innervate wide areas of the cerebral cortex, and reciprocally interact with other neuromodulatory systems, to produce the sleep-wake cycle and different sleep stages. Consciousness and cognition vary considerably across and within sleep stages, with metacognitive capacity being strikingly reduced even during aesthetically and emotionally rich dream experiences. A notable exception is the phenomenon of lucid dreaming-a rare state whereby waking levels of metacognitive awareness are restored during sleep-resulting in individuals becoming aware of the fact that they are dreaming. The role of neurotransmitters in these fluctuations of consciousness and cognition during sleep is still poorly understood. While recent studies using acetylcholinesterase inhibitors suggest a potential role of acetylcholine in the occurrence of lucid dreaming, the underlying mechanisms by which this effect is produced remains un-modelled and unknown; with the causal link between cholinergic mechanisms and upstream psychological states being complex and elusive. Several theories and approaches targeting the association between acetylcholine and metacognition during wakefulness and sleep are highlighted in this review, moving through microscopic, mesoscopic and macroscopic levels of analysis to detail this phenomenon at several organisational scales. Several exploratory hypotheses will be developed to guide future research towards fully articulating how metacognition is affected by activity at the acetylcholine receptor.
Topics: Humans; Metacognition; Acetylcholine; Acetylcholinesterase; Sleep; Dreams; Wakefulness
PubMed: 38042119
DOI: 10.1016/j.concog.2023.103608 -
International Journal of Environmental... Mar 2022Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and a major cause of anovulatory infertility. A diagnosis of PCOS is established based... (Review)
Review
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and a major cause of anovulatory infertility. A diagnosis of PCOS is established based the presence of two out of three clinical symptoms, which are criteria accepted by the ESHRE/ASRM (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine). Gonadotropin-releasing hormone (GnRH) is responsible for the release of luteinizing hormone, and follicle stimulating hormone from the pituitary and contributes a leading role in controlling reproductive function in humans. The goal of this review is to present the current knowledge on neuroendocrine determinations of PCOS. The role of such neurohormones as GnRH, and neuropeptides kisspeptin, neurokinin B, phoenixin-14, and galanin is discussed in this aspect. Additionally, different neurotransmitters (gamma-aminobutyric acid (GABA), glutamate, serotonin, dopamine, and acetylcholine) can also be involved in neuroendocrine etiopathogenesis of PCOS. Studies have shown a persistent rapid GnRH pulse frequency in women with PCOS present during the whole ovulatory cycle. Other studies have proved that patients with PCOS are characterized by higher serum kisspeptin levels. The observations of elevated serum kisspeptin levels in PCOS correspond with the hypothesis that overactivity in the kisspeptin system is responsible for hypothalamic-pituitary-gonadal axis overactivity. In turn, this causes menstrual disorders, hyperandrogenemia and hyperandrogenism. Moreover, abnormal regulation of Neurokinin B (NKB) is also suspected of contributing to PCOS development, while NKB antagonists are used in the treatment of PCOS leading to reduction in Luteinizing hormone (LH) concentration and total testosterone concentration. GnRH secretion is regulated not only by kisspeptin and neurokinin B, but also by other neurohormones, such as phoenixin-14, galanin, and Glucagon-like peptide-1 (GLP-1), that have favorable effects in counteracting the progress of PCOS. A similar process is associated with the neurotransmitters such as GABA, glutamate, serotonin, dopamine, and acetylcholine, as well as the opioid system, which may interfere with secretion of GnRH, and therefore, influence the development and severity of symptoms in PCOS patients. Additional studies are required to explain entire, real mechanisms responsible for PCOS neuroendocrine background.
Topics: Acetylcholine; Dopamine; Female; Galanin; Glutamic Acid; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Neurokinin B; Neurotransmitter Agents; Polycystic Ovary Syndrome; Serotonin; United States; gamma-Aminobutyric Acid
PubMed: 35270780
DOI: 10.3390/ijerph19053089 -
International Journal of Molecular... May 2024Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic... (Review)
Review
Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic receptors. Each class encompasses several structurally related receptor subtypes with distinct patterns of tissue expression and post-receptor signal transduction mechanisms. The activation of both nicotinic and muscarinic cholinergic receptors has been associated with the induction and progression of gastrointestinal neoplasia. Herein, after briefly reviewing the classification of acetylcholine-activated receptors and the role that nicotinic and muscarinic cholinergic signaling plays in normal digestive function, we consider the mechanics of acetylcholine synthesis and release by neuronal and non-neuronal cells in the gastrointestinal microenvironment, and current methodology and challenges in measuring serum and tissue acetylcholine levels accurately. Then, we critically evaluate the evidence that constitutive and ligand-induced activation of acetylcholine-activated receptors plays a role in promoting gastrointestinal neoplasia. We focus primarily on adenocarcinomas of the stomach, pancreas, and colon, because these cancers are particularly common worldwide and, when diagnosed at an advanced stage, are associated with very high rates of morbidity and mortality. Throughout this comprehensive review, we concentrate on identifying novel ways to leverage these observations for prognostic and therapeutic purposes.
Topics: Humans; Gastrointestinal Neoplasms; Acetylcholine; Animals; Signal Transduction; Receptors, Muscarinic; Receptors, Nicotinic
PubMed: 38791353
DOI: 10.3390/ijms25105316 -
Frontiers in Neural Circuits 2021Here, we present and discuss the characteristics and properties of neurotransmitter segregation, a subtype of neurotransmitter cotransmission. We review early evidence... (Review)
Review
Here, we present and discuss the characteristics and properties of neurotransmitter segregation, a subtype of neurotransmitter cotransmission. We review early evidence of segregation and discuss its properties, such as plasticity, while placing special emphasis on its probable functional implications, either in the central nervous system (CNS) or the autonomic nervous system. Neurotransmitter segregation is a process by which neurons separately route transmitters to independent and distant or to neighboring neuronal processes; it is a plastic phenomenon that changes according to synaptic transmission requirements and is regulated by target-derived signals. Distant neurotransmitter segregation in the CNS has been shown to be related to an autocrine/paracrine function of some neurotransmitters. In retinal amacrine cells, segregation of acetylcholine (ACh) and GABA, and glycine and glutamate to neighboring terminals has been related to the regulation of the firing rate of direction-selective ganglion cells. In the rat superior cervical ganglion, segregation of ACh and GABA to neighboring varicosities shows a heterogeneous regional distribution, which is correlated to a similar regional distribution in transmission strength. We propose that greater segregation of ACh and GABA produces less GABAergic inhibition, strengthening ganglionic transmission. Segregation of ACh and GABA varies in different physiopathological conditions; specifically, segregation increases in acute sympathetic hyperactivity that occurs in cold stress, does not vary in chronic hyperactivity that occurs in hypertension, and rises in early ages of normotensive and hypertensive rats. Given this, we propose that variations in the extent of transmitter segregation may contribute to the alteration of neural activity that occurs in some physiopathological conditions and with age.
Topics: Acetylcholine; Amacrine Cells; Animals; Glutamic Acid; Neurotransmitter Agents; Rats; Synaptic Transmission
PubMed: 34720888
DOI: 10.3389/fncir.2021.738516 -
Nature Communications Oct 2023Striatal dopamine encodes reward, with recent work showing that dopamine release occurs in spatiotemporal waves. However, the mechanism of dopamine waves is unknown....
Striatal dopamine encodes reward, with recent work showing that dopamine release occurs in spatiotemporal waves. However, the mechanism of dopamine waves is unknown. Here we report that acetylcholine release in mouse striatum also exhibits wave activity, and that the spatial scale of striatal dopamine release is extended by nicotinic acetylcholine receptors. Based on these findings, and on our demonstration that single cholinergic interneurons can induce dopamine release, we hypothesized that the local reciprocal interaction between cholinergic interneurons and dopamine axons suffices to drive endogenous traveling waves. We show that the morphological and physiological properties of cholinergic interneuron - dopamine axon interactions can be modeled as a reaction-diffusion system that gives rise to traveling waves. Analytically-tractable versions of the model show that the structure and the nature of propagation of acetylcholine and dopamine traveling waves depend on their coupling, and that traveling waves can give rise to empirically observed correlations between these signals. Thus, our study provides evidence for striatal acetylcholine waves in vivo, and proposes a testable theoretical framework that predicts that the observed dopamine and acetylcholine waves are strongly coupled phenomena.
Topics: Mice; Animals; Acetylcholine; Dopamine; Corpus Striatum; Neostriatum; Cholinergic Agents; Interneurons
PubMed: 37891198
DOI: 10.1038/s41467-023-42311-5 -
Anesthesiology Apr 2021
Topics: Acetylcholine; Anesthesia; Animals; Consciousness; Isoflurane; Ketamine; Mice; Prosencephalon
PubMed: 33635939
DOI: 10.1097/ALN.0000000000003696 -
Molecules (Basel, Switzerland) Sep 2022In recent years, an impressive number of research studies have been conducted to improve the understanding of the structure and function of the cholinergic system, and...
In recent years, an impressive number of research studies have been conducted to improve the understanding of the structure and function of the cholinergic system, and significant progress has also been made in elucidating the roles of neuronal and non-neuronal acetylcholine (ACh) in the pathogenesis and treatment of human disease [...].
Topics: Acetylcholine; Cholinergic Agents; Humans; Neurons; Signal Transduction
PubMed: 36144707
DOI: 10.3390/molecules27185971 -
Nature Immunology Apr 2022Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic)...
Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor (LepR) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.
Topics: Acetylcholine; Animals; B-Lymphocytes; Cholinergic Agents; Hematopoiesis; Mice; Stem Cell Niche
PubMed: 35352063
DOI: 10.1038/s41590-022-01165-7 -
International Journal of Molecular... Apr 2021Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of... (Review)
Review
Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.
Topics: Acetylcholine; Animals; Choline; Choline Deficiency; Diabetic Retinopathy; Dry Eye Syndromes; Eye Diseases; Eye Pain; Glaucoma; Glycerylphosphorylcholine; Humans; Lacrimal Apparatus; Lens, Crystalline; Nociception; Optic Nerve; Parasympathetic Nervous System; Phosphatidylcholines; Phospholipids; Receptors, Nicotinic; Retina; Retinal Vessels; Tears
PubMed: 33946979
DOI: 10.3390/ijms22094733