Sympathetic Hyperactivity Research Articles

Spiked Helmet Sign: An Uncommon Electrocardiographic Marker.

The spiked helmet sign (SHS) is a rare electrocardiographic marker associated with an increased risk of lethal ventricular tachyarrhythmias and sudden cardiac death. To our knowledge, this is the first study aimed at reviewing recent research progress on this electrocardiogram (ECG) pattern to summarize its electrophysiological mechanisms, epidemiological features, clinical characteristics, and clinical significance. SHS formation is attributed to sympathetic hyperactivity, which mediates increased dispersion of ventricular repolarization, leading to marked QT prolongation and macroscopic T-wave alternans. This pattern can be observed in critically ill patients with cardiac or noncardiac conditions. In particular, immediate identification of this ECG abnormality is crucial in recognizing and treating noncardiac conditions in older male patients.

Treatment of non-epileptic episodes of anxious, fearful behavior in adolescent juvenile neuronal ceroid lipofuscinosis (CLN3 disease).

Recurrent non-epileptic episodes of frightened facial and body expression occur in more than half of post-adolescent patients with juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3 disease). Clinically, the episodes look similar to the attacks of paroxysmal sympathetic hyperactivity (PSH) commonly seen following traumatic brain injury (TBI). The episodes occur when the patients are exposed to separation, hear loud sounds or are otherwise bothered by discomfort and as in PSH following TBI, the attacks are difficult to prevent and/or treat. Based on present knowledge of triggering factors, the neural anxiety/fear circuit, its afferent and efferent pathways and documented CLN3 disease-impact on these tracks, the current study discusses a rational approach how to prevent and/or treat the attacks. Patients with JNCL have a disturbed somatosensory modulation leading to a reduced threshold of pain; a degeneration within the neural anxiety/fear circuit leading to an imbalance of central network inhibition and excitation pathways; and finally, an, with advancing age, increasing autonomic imbalance leading to a significant dominance of the sympathetic neural system. Theoretically, there are three points of attack how to prevent or treat the episodes: (1) increase in threshold of discomfort impact; (2) modulation of imbalance of central network inhibition and excitation, and (3) restoring the balance between the sympathetic and parasympathetic neural systems prompted by a parasympathetic withdrawal. As to (1) and (2), prevention should have the greatest priority. As regards (3), research of transcutaneous vagal stimulation treatment in JNCL is warranted.

Abstract P412: Microglia Via P2y 12 Transmit Hemodynamic Signal To Promote Sympathetic Activation In Hypertension

Hypertension is characterized by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not fully understood. Recent studies reveal that microglia highly involve in the regulation of sympathetic neuronal activity in the hypothalamic paraventricular nucleus (PVN). In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels, and found that microglia in the PVN were the earliest responders to hypertensive challenge. Comprehensive vasculature analysis unveiled that PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology compared to other brain regions. PVN is susceptible to the penetration of ATP derived from the vasculature in response to hemodynamic disturbance upon pressor challenge. Furthermore, either pharmacological blockade or genetic ablation of microglia P2Y12 could substantially restrain pressor response under hypertensive stimulation Together, these findings suggest that a unique vasculature pattern endows PVN with susceptibility to hypertension-associated hemodynamic insults, which is mediated by microglia.

Pro-arrhythmic role of adrenergic spatial densities in the human atria: An in-silico study.

Chronic stress among young patients (≤ 45 years old) could result in autonomic dysfunction. Autonomic dysfunction could be exhibited via sympathetic hyperactivity, sympathetic nerve sprouting, and diffuse adrenergic stimulation in the atria. Adrenergic spatial densities could alter atrial electrophysiology and increase arrhythmic susceptibility. Therefore, we examined the role of adrenergic spatial densities in creating arrhythmogenic substrates in silico. We simulated three 25 cm2 atrial sheets with varying adrenergic spatial densities (ASD), activation rates, and external transmembrane currents. We measured their effects on spatial and temporal heterogeneity of action potential durations (APD) at 50% and 20%. Increasing ASD shortens overall APD, and maximum spatial heterogeneity (31%) is achieved at 15% ASD. The addition of a few (5% to 10%) adrenergic elements decreases the excitation threshold, below 18 μA/cm2, while ASDs greater than 10% increase their excitation threshold up to 22 μA/cm2. Increase in ASD during rapid activation increases APD50 and APD20 by 21% and 41%, respectively. Activation times of captured beats during rapid activation could change by as much as 120 ms from the baseline cycle length. Rapidly activated atrial sheets with high ASDs significantly increase temporal heterogeneity of APD50 and APD20. Rapidly activated atrial sheets with 10% ASD have a high likelihood (0.7 ± 0.06) of fragmenting otherwise uniform wavefronts due to the transient inexcitability of adrenergically stimulated elements, producing an effective functional block. The likelihood of wave fragmentation due to ASD highly correlates with the spatial variations of APD20 (ρ = 0.90, p = 0.04). Our simulations provide a novel insight into the contributions of ASD to spatial and temporal heterogeneities of APDs, changes in excitation thresholds, and a potential explanation for wave fragmentation in the human atria due to sympathetic hyperactivity. Our work may aid in elucidating an electrophysiological link to arrhythmia initiation due to chronic stress among young patients.

Assessment of Risks for Gastrointestinal Bleeding in Patients with Brain Injury

The aim of the study was to develop a risk model for upper gastrointestinal tract (GIT) bleeding in patients with brain injury of various etiologies.Material and methods. Case histories of 33 patients were included into a retrospective descriptive study: 22 patients had severe brain injury of various etiologies, and 11 patients after elective surgery for cerebral aneurisms with uneventful postop period were taken for comparison. The patients were grouped in two arms: Group 1 included patients with obvious signs of GIT bleeding (N=11) and Group 2 had no obvious signs of bleeding (N=22). Complaints, life and medical history, comorbidities, specialists’ exams data, results of laboratory and instrumental examinations, therapeutic regimens were analyzed. Presence of disproportionate pathologic sympathetic overreaction to acute brain injury, i.e., paroxysmal sympathetic hyperactivity (PSH), was assessed on admission and on Days 1, 3 and 5 after brain injury. Results. A model for upper GIT bleeding risk assessment was designed using logistic regression. The resulting model gains high quality rating: χ²=33,78, 3; p<0,001; OR=315. The risk of upper GIT bleeding exceeded 95% in patients having combination of 4 symptoms in their medical history (presence of PSH on Day 1 after acute brain injury; Karnofsky performance scale index 75; lack of neurovegetative stabilization in the acute period of brain injury; gastric and/or duodenal ulcer).Conclusion. Determining the risk factors thresholds enables stratification of patients by the risk for upper GIT bleeding. Modification of the identified four risk factors (presence of PSH on Day 1after acute brain injury; Karnofsky performance scale index 75; lack of neurovegetative stabilization in the acute period of brain injury; gastric and/or duodenal ulcer) will probably reduce the occurrence of upper GIT bleeding in patients with acute brane injury of various etiology.

Elevated Blood Pressure Occurs without Endothelial Dysfunction in a Rat Model of Pulmonary Emphysema.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease involving airway closure and parenchyma destruction (emphysema). Cardiovascular diseases are the main causes of morbi-mortality in COPD and, in particular, hypertension and heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link has currently been established between the onset of COPD, elevated blood pressure (BP) and systemic vascular impairment (endothelial dysfunction). Thus, we aimed to characterize BP and vascular function and remodeling in a rat model of exacerbated emphysema focusing on the role of sympathetic hyperactivity. Emphysema was induced in male Wistar rats by four weekly pulmonary instillations of elastase (4UI) and exacerbation by a single dose of lipopolysaccharides (LPS). Five weeks following the last instillation, in vivo and ex vivo cardiac and vascular functions were investigated. Exacerbated emphysema induced cardiac dysfunction (HFpEF) and a BP increase in this COPD model. We observed vasomotor changes and hypotrophic remodeling of the aorta without endothelial dysfunction. Indeed, changes in contractile and vasorelaxant properties, though endothelium-dependent, were pro-relaxant and NO-independent. A β1-receptor antagonist (bisoprolol) prevented HFpEF and vascular adaptations, while the effect on BP increase was partial. Endothelial dysfunction would not trigger hypertension and HFpEF in COPD. Vascular changes appeared as an adaptation to the increased BP. The preventing effect of bisoprolol revealed a pivotal role of sympathetic hyperactivation in BP elevation. The mechanistic link between HFpEF, cardiac sympathetic activation and BP deserves further studies in this exacerbated-emphysema model, as well as in COPD patients.

Neutrophil extracellular traps facilitate sympathetic hyperactivity by polarizing microglia toward M1 phenotype after traumatic brain injury.

Traumatic brain injury (TBI), particularly diffuse axonal injury (DAI), often results in sympathetic hyperactivity, which can exacerbate the prognosis of TBI patients. A key component of this process is the role of neutrophils in causing neuroinflammation after TBI by forming neutrophil extracellular traps (NETs), but the connection between NETs and sympathetic excitation following TBI remains unclear. Utilizing a DAI rat model, the current investigation examined the role of NETs and the HMGB1/JNK/AP1 signaling pathway in this process. The findings revealed that sympathetic excitability intensifies and peaks 3 days post-injury, a pattern mirrored by the activation of microglia, and the escalated NETs and HMGB1 levels. Subsequent in vitro exploration validated that HMGB1 fosters microglial activation via the JNK/AP1 pathway. Moreover, in vivo experimentation revealed that the application of anti-HMGB1 and AP1 inhibitors can mitigate microglial M1 polarization post-DAI, effectively curtailing sympathetic hyperactivity. Therefore, this research elucidates that post-TBI, NETs within the PVN may precipitate sympathetic hyperactivity by stimulating M1 microglial polarization through the HMGB1/JNK/AP1 pathway.

Arterial Stiffness Associated with Sympathetic Hyperactivity in Obese Individuals with Moderate to Severe Obstructive Sleep Apnea.

Obstructive Sleep Apnea (OSA) is a chronic disorder associated with several risk factors, and increased Body Mass Index (BMI) and waist circumference are correlated with it is severity. Toevaluate vascular function, central hemodynamics, and autonomic modulation in obese individuals with moderate and severe OSA. Individuals of both sexes, aged 40-70 years and BMI ≥ 30 and < 40 kg/m2, were submitted to assessment of heart rate variability, endothelial function by flow-mediated dilatation, central parameters by oscillometry and carotid ultrasound. The sleep study was performed through a portable home sleep test device (WatchPAT). Patients (n = 76) were divided according to Apnea-Hypopnea Index (AHI): absent-mild group (AHI < 15 events/h, n = 30) and Moderate-Severe (MS) group (AHI ≥ 15 events/h, n = 46). The Low/High Frequency (LF/HF) ratio (0.81 ± 0.48 vs 1.39 ± 1.08 ms2, p = 0.035), Pulse Wave Velocity (PWV; 6.9 ± 0.7 vs 7.7 ± 1.6m/s, p = 0.004), vascular age (48 ± 6 vs 53 ± 9 years, p = 0.05) and mean intima-media thickness (0.59 ± 0.08 vs 0.66 ± 0.13 mm, p = 0.011) were significantly higher in the MS group. AHI was significantly correlated with PWV (r = 0.26, p = 0.024) and LF/HF ratio (r = 0.40, p < 0.001). Only in the MS group, PWV was significantly correlated with SD2/SD1 ratio (r = 0.611, p ≤ 0.001), and flow-mediated dilation with central systolic blood pressure (r = 0.364, p = 0.018), even after adjustment for age and sex. In this sample of obese individuals, moderate to severe OSA was associated with sympathetic hyperactivity and evidence of accelerated vascular aging with arterial stiffness and subclinical atherosclerosis.

Improving Traumatic Brain Injury Outcomes: Early Identification and Management of Paroxysmal Sympathetic Hyperactivity

Improving Traumatic Brain Injury Outcomes: Early Identification and Management of Paroxysmal Sympathetic Hyperactivity

Paroxysmal sympathetic hyperactivity in a child with stroke: a case report

BackgroundParoxysmal sympathetic hyperactivity (PSH) is the result of dysregulated autonomic function with sympathetic symptoms characterised by increased heart rate, respiratory rate, blood pressure and temperature with abnormal posture, which predominately occur periodically but can be persistent in severe cases. Common causes that present in similar fashion such as infectious process (bacteremia, meningitis, etc.); non-PSH neurological deterioration (increased intracranial pressure, intracranial haemorrhage, intracranial oedema, seizures, encephalitis); pulmonary embolism; thyrotoxicosis, alcohol or drug withdrawal; neuroleptic malignant syndrome; serotonin syndrome; and malignant hyperthermia need to be excluded before diagnosing PSH. The earlier the diagnosis made, the better the prognosis.Case presentationWe report a case of a 3-year-old male child who was a diagnosed case of Tetralogy of Fallot presented with left focal seizure with secondary generalisation. Child also had respiratory complaints prior to convulsion. He had developed signs of raised intracranial pressure. Blood culture sent to rule out infective endocarditis was negative. CT brain showed bilateral diffuse cortical infarct. Child developed signs and symptoms of PSH such as fever, tachycardia, tachypnoea, hypertension, diaphoresis, dystonia and bilateral completely dilated pupils. Other common causes such as infective endocarditis, increased intracranial pressure, intracranial oedema, intracranial haemorrhage, seizure, encephalitis and infectious processes (bacteremia, meningitis and infective endocarditis) were ruled out. The diagnosis of PSH was made and started on propranolol along with clonidine. Child responded well to the treatment.ConclusionThe complex pathophysiology of PSH warrants extensive work-up to rule out other common causes. The outcome of our patient shows the importance of early diagnosis and multidisciplinary treatment for better outcome.

Activation of transient receptor potential channels is involved in reactive oxygen species (ROS)-dependent regulation of blood flow by (-)-epicatechin tetramer cinnamtannin A2

Intervention trials confirmed that blood flow-mediated dilatation increases significantly after intake of astringent (-)-epicatechin (EC) oligomers (procyanidins)-rich foods, but the mechanism remains unclear. We have previously found that procyanidins can activate the sympathetic nervous and subsequently increase blood flow. Here, we examined whether procyanidin-derived reactive oxygen species (ROS) activate transient receptor potential (TRP) channels in gastrointestinal sensory nerves and consequently induce sympathoexcitation. We evaluated the redox properties of EC and its tetramer cinntamtannin A2 (A2) at pH 5 or 7, mimicking plant vacuole or oral cavity/small intestine using a luminescent probe. At pH 5, A2 or EC showed O2·- scavenging ability, but they promoted O2·- generation at pH 7. We observed blood flow in rat cremaster arterioles using laser Doppler, a single oral dose of 10 µg/kg A2 markedly increased blood flow, while EC showed little activity. This change with A2 was significantly dampened by co-administration of adrenaline blocker, ROS scavenger N-acetyl-L-cysteine (NAC), TRP vanilloid 1, or ankyrin 1 antagonist. We also performed a docking simulation of EC or A2 with the binding site of a typical ligand for each TRP channel and calculated the respective binding affinities. The binding energies were notably higher for A2 than typical ligands, suggesting that A2 is less likely to bind to these sites. ROS produced at neutral pH following the orally administered A2 to the gastrointestinal tract could activate TRP channels, triggering sympathetic hyperactivation and causing hemodynamic changes.

Microglia-Mediated Neuroimmune Response Regulates Cardiac Remodeling After Myocardial Infarction.

Background Sympathetic hyperactivity contributes to pathological remodeling after myocardial infarction (MI). However, the mechanisms underlying the increase in sympathetic activity remain unknown. Microglia are the predominant immune cells in the central nervous system and can regulate sympathetic neuron activity through neuroimmune response in the hypothalamic paraventricular nucleus. The present study aimed to investigate whether microglia-mediated neuroimmune response can regulate sympathetic activity and cardiac remodeling after MI. Methods and Results PLX3397 (pexidartinib) was used to deplete central microglia via intragastric injection or intracerebroventricular injection. After that, MI was induced by ligation of the left anterior descending coronary artery. Our study showed that MI resulted in the activation of microglia in the paraventricular nucleus. Microglia depletion, which was induced by PLX3397 treatment via intragastric injection or intracerebroventricular injection, improved cardiac function, reduced infarction size, and attenuated cardiomyocyte apoptosis, fibrosis, pathological electrical remodeling, and myocardial inflammation after MI. Mechanistically, these protective effects were associated with an attenuated neuroimmune response in the paraventricular nucleus, which contributed to the decrease of sympathetic activity and attenuation of sympathetic remodeling in the heart. However, intragastric injection with PLX3397 obviously depleted macrophages and induced neutrophil and T-lymphocyte disorders in the heart, blood, and spleen. Conclusions Microglia depletion in the central nervous system attenuates pathological cardiac remodeling after MI by inhibiting neuroimmune response and sympathetic activity. Intragastric administration of PLX3397 leads to serious deleterious effects in peripheral immune cells, especially macrophages, which should be a cause for concern in animal experiments and clinical practice.

Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial

ObjectiveTo evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI).BackgroundAdministration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit.MethodsThis phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16–64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study.ResultsDose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (− 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes.ConclusionDespite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI.Trial Registration Number NCT01322048.

Adaptive responses to chronic intermittent hypoxia: contributions from the European Sleep Apnoea Database (ESADA) Cohort.

Obstructive sleep apnoea (OSA) is a common disease in the general population, and is associated with increased cardiovascular risk and several comorbidities. Obesity favours upper airway collapsibility, but other pathophysiological traits have been identified, i.e. upper airway muscle activity, modulation of the respiratory drive, and the arousal threshold. OSA causes chronic intermittent hypoxia, inflammatory activation and autonomic imbalance with diurnal and nocturnal sympathetic hyperactivity. Disentangling so many components to investigate the pathogenesis of OSA's consequences is very hard clinically. However, albeit imperfect, clinical medicine constitutes a major source of inspiration for basic research, and a mutual exchange of information is essential between clinicians and physiologists to improve our understanding of disease states. OSA is no exception, and this narrative review will summarize the results of clinical studies performed over the years by the European Sleep Apnoea Database (ESADA) Study Group, to explore the variables linked to markers of intermittent hypoxia as opposed to the traditional assessment of OSA severity based on the frequency of respiratory events during sleep (the Apnoea Hypopnoea Index). The results of the clinical studies indicate that intermittent hypoxia variables are associated with several comorbidities, although evidence of a cause-effect relationship is still missing in many cases. It is also possible that adaptive rather than maladaptive responses could be evoked by intermittent hypoxia. The intensity, duration and frequency of intermittent hypoxia episodes causing adaptive rather than maladaptive responses, and their clinical implications, deserve further investigation.

Up-regulated Expression of a TOR2A Gene Product-Salusin-β in the Paraventricular Nucleus Enhances Sympathetic Activity and Cardiac Sympathetic Afferent Reflex in Rats with Chronic Heart Failure Induced by Coronary Artery Ligation.

Enhanced cardiac sympathetic afferent reflex (CSAR) promotes sympathetic hyperactivation in chronic heart failure (CHF). Salusin-β is a torsin family 2 member A gene product and a cardiovascular active peptide closely associated with cardiovascular diseases. We aimed to determine the roles of salusin-β in the paraventricular nucleus (PVN) in modulating enhanced CSAR and sympathetic hyperactivation in rats with CHF induced by coronary artery ligation and elucidate the underlying molecular mechanisms. CSAR was evaluated based on the responses of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) to the epicardial administration of capsaicin in rats under anaesthesia. Salusin-β protein expression was up-regulated in the PVN of the CHF compared with sham-operated rats. Salusin-β microinjection into the PVN dose-dependently increased MAP and RSNA and enhanced CSAR, while anti-salusin-β IgG exerted opposite effects. The effect of salusin-β was inhibited by reactive oxygen species (ROS) scavenger or NAD(P)H oxidase inhibitor but promoted by superoxide dismutase inhibitor. The effect of anti-salusin-β IgG was interdicted by nitric oxide (NO) synthase inhibitor. Furthermore, chronic salusin-β gene knockdown in PVN attenuated CSAR, reduced sympathetic output, improved myocardial remodelling and cardiac function, decreased NAD(P)H oxidase activity and ROS levels, and increased NO levels in the CHF rats. Increased salusin-β activity in the PVN contributes to sympathetic hyperactivation and CSAR in CHF by inhibiting NO release and stimulating NAD(P)H oxidase-ROS production. Reducing endogenous central salusin-β expression might be a novel strategy for preventing and treating CHF in the future.

Transcutaneous auricular vagus nerve stimulation as a potential novel treatment for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of childbearing age. The etiology of PCOS is multifactorial, and current treatments for PCOS are far from satisfactory. Recently, an imbalanced autonomic nervous system (ANS) with sympathetic hyperactivity and reduced parasympathetic nerve activity (vagal tone) has aroused increasing attention in the pathogenesis of PCOS. In this paper, we review an innovative therapy for the treatment of PCOS and related co-morbidities by targeting parasympathetic modulation based on non-invasive transcutaneous auricular vagal nerve stimulation (ta-VNS). In this work, we present the role of the ANS in the development of PCOS and describe a large number of experimental and clinical reports that support the favorable effects of VNS/ta-VNS in treating a variety of symptoms, including obesity, insulin resistance, type 2 diabetes mellitus, inflammation, microbiome dysregulation, cardiovascular disease, and depression, all of which are also commonly present in PCOS patients. We propose a model focusing on ta-VNS that may treat PCOS by (1) regulating energy metabolism via bidirectional vagal signaling; (2) reversing insulin resistance via its antidiabetic effect; (3) activating anti-inflammatory pathways; (4) restoring homeostasis of the microbiota-gut-brain axis; (5) restoring the sympatho-vagal balance to improve CVD outcomes; (6) and modulating mental disorders. ta-VNS is a safe clinical procedure and it might be a promising new treatment approach for PCOS, or at least a supplementary treatment for current therapeutics.

Potential favorable action of sodium-glucose cotransporter-2 inhibitors on sudden cardiac death: a brief overview.

The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na+/H+ exchanger (NHE) activity, but also suppression of late Na+ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na+ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.

Beta-Blockers and Hypertension: Some Questions and Answers.

International guidelines have removed b-blockers from first-line treatment of hypertension, limiting their use to patients with compelling indications. The position of guidelines stems from the results of studies performed with the 1st and 2nd generation of b-blockers, which concluded that these drugs have lower cardiovascular protection, compared with other antihypertensive agents. The aim of our mini review is to answer to some questions about the effect of b-blockers on hypertension and cardiovascular protection and if these effects are different from those of other antihypertensive drugs, particularly in young and elderly patients. We evaluated the relevant systematic reviews and meta-analyses, which reported the effectiveness of b-blockers on blood pressure and cardiovascular outcomes, compared with placebo/no treatment and with other antihypertensive agents. Beta-blockers, decreased high blood pressure with no significant difference from other common antihypertensive agents. Moreover b-blockers, compared with placebo, lowered the risk of major cardiovascular outcomes, while, compared with other drug classes, the reported results are very heterogeneous. Therefore it is difficult, globally, to find a difference between b-blockers and other drug classes. Rather than looking for differences in the cardiovascular protective effect between b-blockers and other antihypertensive agents, we have to consider the different pathophysiology of hypertension in young [sympathetic hyperactivity] and elderly patients [arterial stiffness, high aortic systolic pressure]. Considering these aspects, non-vasodilating b-blockers are preferred, as first-line, in young/middle aged hypertensive subjects, while vasodilating b-blockers, are most appropriate, in elderly patients, for the favourable hemodynamic profile.

Sympathetic Nervous Hyperactivity Impairs Microcirculation Leading to Early Brain Injury After Subarachnoid Hemorrhage.

Although early brain injury (EBI) is recognized as a critical step following subarachnoid hemorrhage (SAH), its pathophysiology and underlying mechanisms remain poorly understood. Herein, we investigated the role of cerebral circulation in the acute phase using patient data and a mouse SAH model and evaluated its regulation via the sympathetic nervous system. The cerebral circulation time and neurological outcomes in the human body were retrospectively examined in 34 SAH cases with ruptured anterior circulation aneurysms and 85 cases with unruptured anterior circulation cerebral aneurysms at Kanazawa University Hospital from January 2016 to December 2021. In a mouse study, a SAH model was created via endovascular perforation, and India-ink angiography was performed over time. Additionally, bilateral superior cervical ganglionectomy was performed immediately before surgery, and neurological scores and brain water content were evaluated after SAH. Cerebral circulation time was prolonged in the acute phase of SAH compared with that in the unruptured cerebral aneurysm group, especially in those with electrocardiographic changes. Furthermore, it was more prolonged in the poor prognosis group (modified Rankin Scale scores 3-6) than in the good prognosis group (modified Rankin Scale scores 0-2) at discharge. In mice, cerebral perfusion was significantly reduced at 1 and 3 hours after SAH and recovered at 6 hours. superior cervical ganglionectomy improved cerebral perfusion without altering the diameter of the middle cerebral artery at 1 hour and improved neurological outcomes at 48 hours after SAH. Consistently, brain edema, quantified by brain water content, was improved by superior cervical ganglionectomy 24 hours after SAH. Sympathetic hyperactivity may play a critical role in the development of EBI by impairing cerebral microcirculation and edema in the acute phase following SAH.

Features of autonomic regulation of heart rate in patients with takotsubo syndrome

BACKGROUND: The pathophysiological mechanisms underlying takotsubo syndrome are still being actively investigated, but it is generally accepted that sympathetic nervous system hyperactivity is of key importance. The method for assessing heart rate variability allows to study the vegetative status of a patient, however, there are few scientific works on this topic at present, and the results obtained are ambiguous.&#x0D; AIM: To study heart rate variability in patients with takotsubo syndrome in acute and late periods of the disease at rest, when performing vegetative tests (the deep-breath test, active orthostatic test), as well as before and after mental stress tests and to compare the data obtained with the results of the examination of the control group.&#x0D; MATERIALS AND METHODS: The study included patients with takotsubo syndrome (n = 48), including 43 (89.6%) women; the average age of the patients was 63.3 13.5 years, and healthy volunteers of the same sex and age (control group, n = 40). All the subjects with takotsubo syndrome in the acute (first 714 days from the onset of the disease) and in the long-term periods of the disease (after 1 year and 2 years) and the ones in the control group underwent cardiorhythmography at rest to assess the heart rate variability after mental stress tests and against the background of vegetative tests.&#x0D; RESULTS: According to the cardiorhythmography at rest, in 47 (97.9%) patients with takotsubo syndrome, the influence of sympathetic nervous system on the heart rate prevailed, which persisted in the long-term period of the disease. The vegetative tests revealed a paradoxical reaction of the sympathetic nervous system and reduced activity of the parasympathetic nervous system in the acute and late periods of takotsubo syndrome, compared with the control group. In the acute and long-term periods in the patients with takotsubo syndrome after mental stress tests, in comparison with control group, there was no increase in parasympathetic nervous system activity.&#x0D; CONCLUSIONS: According to the study findings, the patients with takotsubo syndrome revealed autonomic dysfunction in the form of an excessive increase in the activity of the sympathetic nervous system both before the onset of the disease, and in the acute and long-term periods as well as a decrease in vagal tone, which was reflected in the suppressed response of the parasympathetic nervous system to the deep-breath test and mental stress tests.