Circulating Catecholamine Levels Research Articles

Inhibition of circulating dipeptidyl-peptidase 3 by procizumab in experimental septic shock reduces catecholamine exposure and myocardial injury

BackgroundDipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock.MethodsIn this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65–75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin–angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples.ResultsPCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression.ConclusionsIn an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.Graphical

Activation of Sympathetic Nervous System Contributes to Erthroprotein Gene Upregulation by Hypobaric Hypoxia

Hypobaric hypoxia (HH) experienced at high altitude initiates a series of physiological adaptations to maintain homeostasis. One such adaptation is the activation of the Epo gene which encodes the glycoprotein hormone erythropoietin (EPO). Increased circulating EPO levels defend against HH by facilitating blood O2 transport through increasing red blood cell production. HH also increases blood pressure (BP) through activation of the sympathetic nervous system and the ensuing elevation of circulating catecholamine levels. The present study examined the role of sympathetic nerve activation in HH‐evoked Epo gene activation and elevated circulating levels of EPO. Studies were performed on adult, male wild‐type (WT) mice treated with 18 hours of HH (0.4 atmospheres), simulating low O2 condition experienced at high altitude. Our results showed increased renal Epo gene abundance and elevated plasma EPO levels. Remarkably, these responses were either markedly attenuated or absent in mice with selective ablation of adrenal medulla as well as after treatment with propranolol, a non‐selective beta‐adrenergic receptor blocker. Moreover, infusion of epinephrine alone activated renal Epo gene and elevated plasma EPO levels. These results suggest that sympathetic nerve activation and the ensuing increase in plasma epinephrine contribute to Epo gene activation by HH.

Acute and chronic cold exposure differentially affect cardiac control, but not cardiorespiratory function, in resting Atlantic salmon (Salmo salar).

No studies have examined the effects of cold temperatures (∼0–1 °C) on in vivo cardiac function and control, and metabolism, in salmonids. Thus, we examined: 1) how acclimation to 8 °C vs. acclimation (>3 weeks) or acute exposure (8-1 °C at 1 °C h−1) to 1 °C influenced cardiorespiratory parameters in resting Atlantic salmon; and 2) if/how the control of cardiac function was affected. Oxygen consumption () and cardiac function [i.e., heart rate (fH) and cardiac output (] were 50% lower in the acutely cooled and 1oC-acclimated salmon as compared to 8 °C fish, whereas stroke volume (VS) was unchanged. Intrinsic fH was not affected by whether the fish were acutely exposed or acclimated to 1 °C (values ∼51, 24 and 21 beats min−1 in 8 and 1 °C-acclimated fish, and 8-1 °C fish, respectively), and in all groups fH was primarily under adrenergic control/tone (cholinergic tone 13–18%; adrenergic tone 37–70%). However, β-adrenergic blockade resulted in a 50% increase in VS in the 1oC-acclimated group, and this was surprising as circulating catecholamine levels were ∼1–3 nM in all groups. Overall, the data suggest that this species has a limited capacity to acclimate to temperatures approaching 0 °C. However, we cannot exclude the possibility that cardiac and metabolic responses are evoked when salmon are cooled to ∼ 0–1 °C, and that this prevented further declines in these parameters (i.e., they ‘reset’ quickly). Our data also provide further evidence that VS is temperature insensitive, and strongly suggest that changes in adrenoreceptor mediated control of venous pressure/capacitance occur when salmon are acclimated to 1 °C.

The evaluation of urinary vanillylmandelic acid level in patients with generalized anxiety disorder

Background and objectives: The prevalence of anxiety disorders is increasing in the world. Studies revealed that generalized anxiety disorder may lead to change in circulating catecholamine levels. Thus, the changes of catecholamine metabolite like urinary vanillylmandelic acid may increase the future risk of thrombotic diseases in patients with generalized anxiety disorder (GAD). The aim of this present study is to evaluate urinary vanillylmandelic acid (VMA) levels in patients with generalized anxiety disorder. Materials and methods: A cross-sectional study was performed in the Department of Physiology, Dhaka Medical College, Dhaka from July 2019 to June 2020.After obtaining ethical clearance, a total 144 individuals were selected based on inclusion and exclusion criteria with age ranging from 18-50 years. Group A was study group selected from Out Patient Department of Psychiatry of Dhaka Medical College Hospital, Dhaka diagnosed by the experienced psychiatrist. Group B was control group who were apparently healthy adults selected from different area of Dhaka city. The subjects were interviewed and detailed history regarding personal, family, medical and drug history were taken. Prior to sample collection, informed written consent was taken from the participants. Urinary vanillylmandelic acid levels were measured in the Department of Endocrinology, BIRDEM General Hospital, Dhaka. Statistical analysis: For statistical analysis, Unpaired Student’s ‘t’ test was considered using SPSS 25.0 version. Results: Urinary vanillylmandelic acid of generalized anxiety disorder patients was significantly higher (p< 0.001) than control group. Conclusion: It can be concluded that generalized anxiety disorder patients may have more chance of thrombotic diseases due to significantly higher urinary vanillylmandelic acid (VMA) levels than healthy adults.

Gene expression level of renalase in the skeletal muscles is increased with high-intensity exercise training in mice on a high-fat diet.

Exercise training is beneficial for reducing obesity. In particular, exercise training can lower the catecholamine concentration in circulation. Renalase, whose expression was first confirmed in the kidneys, is a physiologically active substance that decomposes circulating catecholamines; additionally, it has been reported to be present in the skeletal muscles. The aim of this study was to clarify the expression of renalase in the skeletal muscles and kidneys after high-intensity exercise training in obese mice. The mice were divided into four groups: normal diet and sedentary, normal diet and exercise training, high-fat diet and sedentary, and high-fat diet and exercise training, and the test was performed for 8 weeks. Body weight and skeletal muscle wet weight were reduced by high-fat diet intake but were rescued by training. Skeletal muscle renalase gene expression was significantly increased by exercise training. However, in the kidneys the gene expression of renalase was significantly increased by high-fat diet intake and exercise training. No significant changes were observed in the gene expression of catecholamine-degrading enzymes, catechol-O-methyltransferase and monoamine oxidase A and B. We demonstrated that exercise training increased the gene expression of renalase in the skeletal muscles and kidneys, thus lowering circulating catecholamine levels. This may lead to amelioration of obesity as catecholamines are lipolytic.

In Vivo Stimulation of α- and β-Adrenoceptors in Mice Differentially Alters Small RNA Content of Circulating Extracellular Vesicles.

When myocardial function is compromised as in heart failure (HF), there is activation of the sympathetic nervous system with elevated circulating catecholamine levels. These catecholamines activate cardiac and extra-cardiac adrenergic receptors (ARs). Interest in secreted extracellular vesicles (EVs) from the heart is growing and in HF, it is not known whether excessive activation of α- or β-adrenergic receptors (ARs) could induce specific changes in EV content. In this study, we have evaluated, by next generation sequencing, the small RNA content, including micro-RNAs (miRs), of circulating EVs of mice exposed to chronic selective α- or β- AR stimulation. EVs from mouse blood were purified by differential ultracentrifugation resulting in EVs with an average size of 116.6 ± 4.8 nm that by immunoblotting included protein markers of EVs. We identified the presence of miRs in blood EVs using miR-21-5p and -16-5p real-time PCR as known constituents of blood exosomes that make up a portion of EVs. We next performed next generation sequencing (NGS) of small non-coding RNAs found in blood EVs from mice following 7 days of chronic treatment with isoproterenol (ISO) or phenylephrine (PE) to stimulate α- or β-ARs, respectively. PE increased the percent of genomic repeat region reads and decreased the percent of miR reads. In miR expression analysis, PE and ISO displayed specific patterns of miR expression that suggests differential pathway regulation. The top 20 KEGG pathways predicted by differential expressed miRs show that PE and ISO share 11 of 20 pathways analyzed and reveal also key differences including three synapse relative pathways induced by ISO relative to PE treatment. Both α-and β-AR agonists can alter small RNA content of circulating blood EVs/exosomes including differential expression and loading of miRs that indicate regulation of distinct pathways. This study provides novel insight into chronic sympathetic nervous system activation in HF where excessive catecholamines may not only participate in pathological remodeling of the heart but alter other organs due to secretion of EVs with altered miR content.

TAKOTSUBO CARDIOMYOPATHY SECONDARY TO ACUTE BACTERIAL MENINGITIS

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Infection and sepsis are not uncommon causes of cardiomyopathy due to a decrease in ventricular function. Cardiovascular dysfunction in sepsis can be seen as septic cardiomyopathy, Takotsubo cardiomyopathy, refractory shock or myocardial injury. A study showed that Takotsubo cardiomyopathy was present in 0.15% of admissions with severe sepsis. It should be considered in the differential diagnosis of acute coronary syndrome especially post-menopausal women with preceding stressful events. We present a case of bacterial meningitis leading to Takotsubo’s cardiomyopathy in the setting of CSF leak. CASE PRESENTATION: A 67-year-old woman with no past medical history presented to the emergency department with diarrhea, vomiting, and confusion. On arrival, she was hypotensive to 87/66mmHg, tachycardic 116bpm and hypoxic to 83% on room air. Laboratory evaluation was significant for leukocytosis of 29.2 k/ul, troponin 5.02 ng/ml, lactic acid 2.9 mmol/l, BNP 788 pg/ml. Cerebrospinal fluid showed a white blood cell count of 5011 (91% neutrophils), protein 791 mg/dl, glucose 95 mg/dl. She was admitted with a diagnosis of an NSTEMI, acute meningeal encephalitis and treated with aztreonam, vancomycin, doxycycline, and dexamethasone. Cultures revealed streptococcus viridians and treatment was narrowed to ceftriaxone. Facial CT showed a possible area of dehiscence concern for possible CSF leak. No significant coronary artery disease on the angiogram Echocardiogram was consistent with Takotsubo cardiomyopathy. The patient's cardiomyopathy was treated with goal-directed medical therapy with complete resolution of symptoms. DISCUSSION: Takotsubo cardiomyopathy is defined as a transient regional left ventricular systolic dysfunction without obstructive coronary artery disease and usually triggered by emotional or physical stress. During sepsis, there is an activation of the sympathoadrenergic system with rapid elevation in circulating catecholamine levels. Pathogenesis is related to myocardial stunning, catecholamine toxicity, impaired myocyte metabolism. According to Mayo Clinic criteria there should be: 1) transient hypokinetic, akinesias or dyskinesia of the LV midsegments, 2) absence of CAD, 3) EKG abnormalities or troponin elevation, 4) absence of pheochromocytoma or myocarditis. Patients can present with mild to moderate congestive heart failure or hypotension due to a reduction in stroke volume. The mean age of presentation ranges from around 60 to 75 years. The prognosis is excellent, mortality from 0%-8% and a recurrence occurs in <10% of patients. The treatment is based on the management of the underlying etiology and supportive cardiovascular care. CONCLUSIONS: Patients with suspected TTC need to be work up to rule out ACS with coronary angiogram. Takotsubo’s cardiomyopathy has a good prognosis with recovery on the EF and cardiac function once infection or physical stress disappears. Reference #1: De Giorgi, A., Fabbian, F., Pala, M., Parisi, C., Misurati, E., Molino, C., et al. (2015). Takotsubo Cardiomyopathy and Acute Infectious Diseases: A Mini-Review of Case Reports. Angiology, 66(3), 257–261. Reference #2: Pilgrim, TM, Wyss, TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol. 2008;124(3):283–292. Reference #3: Prasad, A, Lerman, A, Rihal, CS. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155(3):408–417. DISCLOSURES: No relevant relationships by Daniel Colon Hidalgo, source=Web Response No relevant relationships by Diana Estefania Espinoza Barrera, source=Web Response No relevant relationships by Hugues Orozco, source=Web Response No relevant relationships by Jose Zabala-Genovez, source=Web Response

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

Effect of Sacubitril/Valsartan on circulating catecholamine levels during a 6-month follow-up in heart failure patients. Timeo Danaos et dona ferentes?

We assessed the effect of Sacubitril/Valsartan on circulating catecholamine levels in patients with HF in an observational cohort study. We included 108 consecutive HF patients attending our HF Outpatients Clinic who were eligible to Sacubitril/Valsartan according to the PARADIGM-HF inclusion and exclusion criteria. We furthermore included 58 stable HF patients under optimal medical therapy as a control group. Norepinephrine and epinephrine were measured with immunoradiometric assays at baseline, at 3- and at 6-month time follow-up. Compared to baseline levels there was no change at three months in epinephrine (p = 0.177) or norepinephrine (p = 0.815) concentrations. At 6 months norepinephrine remained unchanged (p = 0.359). However, at 6 months we observed a significant increase in epinephrine levels compared to baseline [66 pg/mL (37−93) vs 38 pg/mL (18–74), p < 0.001]. In the control group no change was observed in epinephrine levels compared to baseline (p = 0.838). This study is the first to report on the effect of the new drug Sacubitril/Valsartan on circulating catecholamine levels in HF patients. Our data show a significant increase in epinephrine levels during a 6 month follow up in stable HF patients.

Intrinsic Sinoatrial Node Dysfunction Impairs Autonomic Regulation of Heart Rate Variability in Hypertensive Heart Disease

Vagal control of the sinoatrial node (SAN) is a major mechanism that regulates beat-to-beat heart rate variability (HRV) at rest. Classically, reduced HRV in the setting of hypertensive heart disease and heart failure has been attributed to chronically elevated sympathetic and reduced vagal regulation of heart rate. However, both of these conditions are also associated with intrinsic SAN dysfunction which may change the gain and dynamic response of the SAN to autonomic stimulation. The relationship between autonomic nerve activity and the responsiveness of SAN myocytes to descending neural signals in hypertension remain unclear. Here, we investigated how intrinsic SAN dysfunction impacts autonomic regulation of HRV in a mouse model of angiotensin II (AngII) mediated hypertensive heart disease. Mice infused with AngII via mini-osmotic pumps (2.5mg/kg/day for 3 weeks) had reduced HRV and increased adrenergic tone indicated by elevated renal sympathetic nerve activity and circulating catecholamine levels. Interestingly, AngII infused mice had no change in vagal nerve activity compared to saline treated controls. Electrograms recorded from isolated atrial preparations devoid of neural input, as well as isolated SAN myocytes assessed through patch clamp electrophysiology, demonstrated increased beating rate variability and reduced responsiveness to both the β-adrenergic agonist isoproterenol and the muscarinic agonist carbachol. Together, these data suggest that the SAN is a major contributor to the loss of regular HRV in hypertensive heart disease due to desensitization of descending neural signals. Our data suggests that elevated sympathetic tone, in conjunction with reduced responsiveness of the SAN to parasympathetic agonists, are responsible for diminished HRV in the setting of hypertensive heart disease. Thus, the interpretation of HRV as a pure measure of cardiac autonomic tone may be inappropriate in the setting of diseases with concurrent SAN dysfunction.

β-1 adrenoceptors and AT1 receptors may not be involved in catecholamine-induced lethal arrhythmias 1.

An excessive amount of catecholamines produce arrhythmias, but the exact mechanisms of this action are not fully understood. For this purpose, Sprague-Dawley rats were treated with or without atenolol, a β1-adrenoceptor blocker (20 mg/kg per day), for 15 days followed by injections of epinephrine for cumulative doses of 4 to 128 μg/kg. Another group of animals were pretreated with losartan, an angiotensin receptor (AT1) blocker (20 mg/kg per day), for comparison. Control animals received saline. Varying degrees of ventricular arrhythmias were seen upon increasing the dose of epinephrine, but the incidence and duration of the rhythm abnormalities as well as the number of episodes and severity of arrhythmias were not affected by treating the animals with atenolol or losartan. The levels of both epinephrine and norepinephrine were increased in the atenolol-treated rats but were unchanged in the losartan-treated animals after the last injection of epinephrine; the severity of arrhythmias did not correlate with the circulating catecholamine levels. These results indicate that both β1-adrenoceptors and AT1 receptors may not be involved in the pathogenesis of catecholamine-induced arrhythmias and support the view that other mechanisms, such as the oxidation products of catecholamines, may play a crucial role in the occurrence of lethal arrhythmias.

Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure.

Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor/Ca2+ release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor/Ca2+ release channels resulting in diastolic sarcoplasmic reticulum Ca2+ leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca2+ leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca2+ handling because of leaky RyR channels in CHF. Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca2+ leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca2+ leak was assessed using flow cytometry to measure Ca2+ fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca2+ stores within the endoplasmic reticulum. Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca2+ stores, consistent with chronic intracellular Ca2+ leak. This Ca2+ leak correlated with circulating catecholamine levels. The intracellular Ca2+ leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response. In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca2+ stores consistent with chronic intracellular Ca2+ leak. RyR1-mediated Ca2+ leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca2+ handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.

Abstract P274: Endothelial Dysfunction of Conduit Arteries in Amyloid Precursor Protein-Deficient Mice

Amyloid precursor protein (APP) is an integral membrane protein expressed in the peripheral arteries. However, the exact vascular physiological function of APP is unknown. Male APP-deficient (APP –/– ) and their wild-type littermates (WT) mice were used to characterize the phenotype of APP in the control of vascular function. Isometric force of isolated aortic rings was recorded in organ chambers. Circulating levels of norepinephrine and epinephrine were significantly enhanced in APP –/– mice (4723±566 pg/mL and 854±98 pg/mL, respectively P&lt;0.05 vs. WT: 1999±319 pg/mL and 429±71 pg/mL, respectively; n=13). The efficacy of phenylephrine induced contractions were significantly reduced in the aorta of APP –/– mice (21±3%, P&lt;0.05 vs. WT: 47±4%; n=10) while contractions to prostaglandin F 2α were unchanged (135±4%, P=n.s. vs. WT: 133±3%; n=9). Western blot analysis revealed that protein expression of alpha1D adrenergic receptors was significantly downregulated in APP –/– mice aortas (0.21±0.05 O.D.; P&lt;0.05 vs. WT: 0.48±0.11 O.D.; n=6). In contrast, endothelium-dependent relaxations to β-agonist isoproterenol were significantly enhanced in APP –/– mice aortas (P&lt;0.05; n=10) while endothelium-dependent relaxations to acetylcholine were unaltered (P=n.s.; n=12). Incubation of aortic rings with indomethacin significantly impaired relaxations to isoproterenol as well as acetylcholine in APP –/– mice (P&lt;0.05; n=8) while concomitant treatment with NOS inhibitor L-NAME completely abolished relaxations to both agonists (P&lt;0.05; n=6-7). Incubation of aortic rings with isoproterenol significantly increased cAMP in the aortas of APP –/– mice (16.2±4.1 pmol/mg; P&lt;0.05 vs. WT: 6.6±4.1 pmol/mg; n=7). Furthermore, cAMP levels were significantly enhanced by acetylcholine in APP –/– mice aortas (38±9 pmol/mg; P&lt;0.05 vs. WT: 14±3 pmol/mg; n=8) while acetylcholine stimulated cGMP levels were reduced (59±5 pmol/mg; P&lt;0.05 vs. WT: 83±7 pmol/mg; n=12). Our results suggest that increased circulating levels of catecholamines in APP –/– mice are responsible for observed vascular phenotype. These findings indicate that under physiological conditions, APP expression plays an important role in control of vascular endothelial function .

Gap junction communication between chromaffin cells: the hidden face of adrenal stimulus-secretion coupling.

From birth to death, catecholamine secretion undergoes continuous adjustments, allowing the organism to adapt to homeostasis changes. To cope with these stressful conditions, the neuroendocrine cells of the adrenal medulla play an immediate and crucial role. Chromaffin cell-driven catecholamine release is chiefly controlled by a neurogenic command that arises from the sympathetic nervous system, which releases acetylcholine at the splanchnic nerve terminal-chromaffin cell synapses. In addition to receiving several synaptic inputs individually, chromaffin cells are coupled by gap junctions. This raises interesting questions about the usefulness and the role of the gap junctional coupling within the chromaffin tissue, considering that secretory function is efficiently completed by the neurogenic pathway. The findings that gap junctions contribute to catecholamine secretion, both ex vivo and in vivo, provide some early answers, but their involvement in other cellular functions still remains unexplored. This review summarizes the molecular and physiological evidence that gap junctions can act either as an accelerator or a brake of stimulus-secretion coupling and discusses this functional plasticity in the context of specific needs in circulating catecholamine levels. It introduces the concept of gap junctions as sympathetic activity sensors and guardians of the functional integrity of the chromaffin tissue.

Cognitive Function and Heart Failure: The Role of the Adrenergic System.

Heart Failure (HF) and cognitive impairment (CI) represent two high incident diseases worldwide, with extremely elevated mortality and morbidity rates. Their prevalence is expected to further increase in the next years due to the aging population, thus they pose enormous clinical, social and economic challenges. Sympathetic nervous system hyperactivity is known to play a pivotal role in HF pathophysiology and progression. In fact, increased cardiac and circulating catecholamine levels are responsible for several molecular and structural abnormalities with detrimental effects on the failing heart. The proof of this latter concept is represented by the clinical success of .-Blocker therapy that is able to attenuate HF-related morbidity and mortality. Recently, adrenergic system alterations have been implied also in the pathogenesis of CI and dementia opening the window for new fascinating and promising therapeutic opportunities. Assess the state of the art on the relationship between cognitive impairment and heart failure. In the present manuscript, we propose an updated review of literature and patent on the role of sympathetic nervous system derangement in the pathogenesis of HF and CI. We have discussed recent findings allowing the identification of new molecular targets that hopefully will contribute to the generation of effective therapeutic strategies for HF and dementia. In this article, the patents US20100048479, US7060871, WO2006052857, US7351401, US5721243, WO1994009155, US5449604, WO1999058981, US5985581, EP2319511, EP2377534, EP2650303, WO2006004939, WO2010132128 and EP1779858 are summarized.

Obesity-associated sympathetic overactivity in children and adolescents: the role of catecholamine resistance in lipid metabolism.

Obesity in children and adolescents is characterized by chronic sympathetic overdrive and reduced epinephrine-stimulated lipolysis. This resistance to catecholamines occurs during the dynamic phase of fat accumulation. This review will focus on the relationship between sympathetic-adrenal activity and lipid metabolism, thereby highlighting the role of catecholamine resistance in the development of childhood obesity. Catecholamine resistance causes lipid accumulation in adipose tissue by reducing lipolysis, increasing lipogenesis and impeding free fatty acid (FFA) transportation. Exercise improves catecholamine resistance, as evidenced by attenuated systemic sympathetic activity, reduced circulating catecholamine levels and enhanced β-adrenergic receptor signaling. Insulin resistance is mostly a casual result rather than a cause of childhood obesity. Therefore, catecholamine resistance in childhood obesity may promote insulin signaling in adipose tissue, thereby increasing lipogenesis. This review outlines a series of evidence for the role of catecholamine resistance as an upstream mechanism leading to childhood obesity.

Biased β2-adrenoceptor signalling in heart failure: pathophysiology and drug discovery.

The body is constantly faced with a dynamic requirement for blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on cues emitted by circulating catecholamine levels. Cardiac β-adrenoceptors transduce the signal produced by catecholamine stimulation via Gs proteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the needs of the body; catecholamine levels are high and β-adrenoceptors become hyperstimulated. The hyperstimulated β1-adrenoceptors induce a cardiotoxic effect, which could be counteracted by the cardioprotective effect of β2-adrenoceptor-mediated Gi signalling. However, β2-adrenoceptor-Gi signalling negates the stimulatory effect of the Gs signalling on cardiomyocyte contraction and further exacerbates cardiodepression. Here, further to the localization of β1- and β2-adrenoceptors and β2-adrenoceptor-mediated β-arrestin signalling in cardiomyocytes, we discuss features of the dysregulation of β-adrenoceptor subtype signalling in the failing heart, and conclude that Gi-biased β2-adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, β2-adrenoceptor-Gs signalling increases cardiomyocyte contractility without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using a Gs-biased β2-adrenoceptor agonist and a β1-adrenoceptor antagonist in combination. This combination treatment normalizes the β-adrenoceptor subtype signalling in the failing heart and produces therapeutic effects that outperform traditional heart failure therapies in animal models. The present review illustrates how the concept of biased signalling can be applied to increase our understanding of the pathophysiology of diseases and in the development of novel therapies.

The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure

Secretion of proteins and neurotransmitters from large dense core vesicles (LDCVs) is a highly regulated process. Adrenal LDCV formation involves the granin proteins chromogranin A (CgA) and chromogranin B (CgB); CgA- and CgB-derived peptides regulate catecholamine levels and blood pressure. We investigated function of the granin VGF (nonacronymic) in LDCV formation and the regulation of catecholamine levels and blood pressure. Expression of exogenous VGF in nonendocrine NIH 3T3 fibroblasts resulted in the formation of LDCV-like structures and depolarization-induced VGF secretion. Analysis of germline VGF-knockout mouse adrenal medulla revealed decreased LDCV size in noradrenergic chromaffin cells, increased adrenal norepinephrine and epinephrine content and circulating plasma epinephrine, and decreased adrenal CgB. These neurochemical changes in VGF-knockout mice were associated with hypertension. Germline knock-in of human VGF1-615 into the mouse Vgf locus rescued the hypertensive knockout phenotype, while knock-in of a truncated human VGF1-524 that lacks several C-terminal peptides, including TLQP-21, resulted in a small but significant increase in systolic blood pressure compared to hVGF1-615 mice. Finally, acute and chronic administration of the VGF-derived peptide TLQP-21 to rodents decreased blood pressure. Our studies establish a role for VGF in adrenal LDCV formation and the regulation of catecholamine levels and blood pressure.

Changes in parasympathetic system in medulla oblongata in male pigs in the course of tachycardia-induced cardiomyopathy

Autonomic imbalance constituting a fundamental feature of heart failure (HF) has been assessed mainly at the periphery. Changes in the functioning of autonomic centers in the brain remain unclear. We investigated the molecular elements of parasympathetic system, i.e. α7 nicotinic acetylcholine receptor (α7nAChR) and enzymes metabolizing acetylcholine (acetylcholinesterase, AChE, choline acetyltransferase, ChAT) in medulla oblongata (MO) of male pigs with chronic tachycardia-induced cardiomyopathy. The mRNA levels of AChE, ChAT, α7nAChR and X-box binding protein 1 (spliced form, XBP1s) in MO were analyzed using qPCR, AChE and ChAT activities using spectrophotometry, proteasome activity using fluorometry, and the protein level of α7nAChR using Western blotting. The development of systolic HF was accompanied by an increase in circulating catecholamines, a decrease in the AChE and α7nAChR mRNA in MO, an increase in AChE activity (all p<0.05), and no change in either the mRNA or activity of ChAT. Both circulating catecholamine levels and AChE activity were inversely related to systolic function of left myocardial ventricle (p<0.05). The level of α7nAChR protein in MO and its cytoplasmatic fraction were higher in pigs with moderate and severe HF as compared to the other animals (p<0.01). There was no difference in proteasome activity in MO between diseased and healthy animals, whereas the XBP1s mRNA decreased during HF progression (p<0.05). Molecular elements of parasympathetic system are changed within the medulla oblongata during the progression of systolic non-ischemic heart failure in male pigs, indicating a functional link between MO and heart in HF.

SYMPATHOVAGAL IMBALANCE IN TAKOTSUBO CARDIOMYOPATHY

Takotsubo cardiomyopathy is an acute reversible cardiac dysfunction syndrome associated with high circulating catecholamine levels. Our objective was to investigate whether abnormal cardiovascular control might play a role in the pathophysiology.We studied autonomic cardiovascular reflexes in 10 women who had takotsubo (33±7 months after being hospitalized) and 10 age/BMI matched healthy women.In the women with takotsubo, indices of vagal modulation of heart rate induced by respiration were uniformly reduced (expiratory:inspiratory ratio: p&lt;0.01, pnn50%: p&lt;0.02, rMSSD: p&lt;0.03). Cognitive (stroop test: p&lt;0.03) and emotional arousal (event recall: p&lt;0.05) produced exaggerated pressor responses, without detectable ECG changes. Pressor responses to hemodynamic stimuli were also amplified (Valsalva SBP overshoot: p&lt;0.05). Takotsubo women had increased BP variability in the short‐term (St. Dev. SBP: p&lt;0.01). Ambulatory recordings captured an exaggerated morning surge in SBP after awakening from sleep (p&lt;0.05). Cardiovagal baroreflex gain was significantly lower in the takotsubo women (sequence analysis: p&lt;0.01, regression method: p&lt;0.001, transfer function gain: p&lt;0.001).Women with takotsubo have heightened sympathetic responsiveness, labile BP and reduced vagal modulation of the heart. This shift in sympathovagal balance could play a role in the pathophysiology.