Novel neurophysiological evidence for preserved pain habituation across chronic pain conditions.

OBJECTIVE: The present study aimed to investigate whether subjective and objective measures of pain habituation can be used as potential markers for central sensitization across various chronic pain patients. METHODS: Two blocks of contact-heat stimuli were applied to a non-painful area in 93 chronic pain patients (low back pain, neuropathic pain, and complex regional pain syndrome) and 60 healthy controls (HC). Habituation of pain ratings, contact-heat evoked potentials (CHEP), and sympathetic skin responses (SSR) was measured. RESULTS: There was no significant difference in any measure of pain habituation between patients and HC. Even patients with apparent clinical signs of central sensitization showed no reduced pain habituation. However, prolonged baseline CHEP and SSR latencies (stimulation block 1) were found in patients compared to HC (CHEP: Δ-latency = 23 ms, p = 0.012; SSR: Δ-latency = 100 ms, p = 0.022). CONCLUSION: Given the performed multimodal neurophysiological testing protocol, we provide evidence indicating that pain habituation may be preserved in patients with chronic pain and thereby be of limited use as a sensitive marker for central sensitization. These results are discussed within the framework of the complex interactions between pro- and antinociceptive mechanism as well as methodological issues. The prolonged latencies of CHEP and SSR after stimulation in non-painful areas may indicate subclinical changes in the integrity of thermo-nociceptive afferents, or a shift towards antinociceptive activity. This shift could potentially affect the relay of ascending signals. SIGNIFICANCE: Our findings challenge the prevailing views in the literature and may encourage further investigations into the peripheral and central components of pain habituation, using advanced multimodal neurophysiological techniques.

Renal autonomic dynamics in hypertension: how can we evaluate sympathetic activity for renal denervation?

This review explores the various pathophysiological factors influencing antihypertensive effects, involving the regulation of vascular resistance, plasma volume, cardiac function, and the autonomic nervous system, emphasizing the interconnected processes regulating blood pressure (BP). The kidney's pivotal role in BP control and its potential contribution to hypertension is complicated but important to understand the effective mechanisms of renal denervation (RDN), which may be a promising treatment for resistant hypertension. Excessive stimulation of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) can elevate BP through various physiological changes, contributing to chronic hypertension. Renal sympathetic efferent nerve activation leads to elevated norepinephrine levels and subsequent cascading effects on vasoconstriction, renin release, and sodium reabsorption. RDN reduces BP in resistant hypertension by potentially disrupting sensory afferent nerves, decreasing feedback activation to the central nervous system, and reducing efferent sympathetic nerve activity in the heart and other structures. RDN may also modulate central sympathetic outflow and inhibit renal renin-angiotensin system overactivation. While evidence for RDN efficacy in hypertension is increasing, accurate patient selection becomes crucial, considering complex interactions that vary among patients. This review also discusses methods to evaluate autonomic nerve activity from the golden standard to new potential examination for finding out optimization in stimulation parameters or rigorous patient selection based on appropriate biomarkers.

Neuroimmune modulation in liver pathophysiology.

The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.

From fasting to fat reshaping: exploring the molecular pathways of intermittent fasting-induced adipose tissue remodeling.

Obesity, characterised by excessive fat accumulation, is a complex chronic condition that results from dysfunctional adipose tissue expansion due to prolonged calorie surplus. This leads to rapid adipocyte enlargement that exceeds the support capacity of the surrounding neurovascular network, resulting in increased hypoxia, inflammation, and insulin resistance. Intermittent fasting (IF), a dietary regimen that cycles between periods of fasting and eating, has emerged as an effective strategy to combat obesity and improve metabolic homeostasis by promoting healthy adipose tissue remodeling. However, the precise molecular and cellular mechanisms behind the metabolic improvements and remodeling of white adipose tissue (WAT) driven by IF remain elusive. This review aims to summarise and discuss the relationship between IF and adipose tissue remodeling and explore the potential mechanisms through which IF induces alterations in WAT. This includes several key structural changes, including angiogenesis and sympathetic innervation of WAT. We will also discuss the involvement of key signalling pathways, such as PI3K, SIRT, mTOR, and AMPK, which potentially play a crucial role in IF-mediated metabolic adaptations.

Sympathetic response following unannounced loss of balance during walking in young adults - laboratory study.

BACKGROUND: An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event that changes the activity of the Sympathetic Nervous System (SNS). We examined SNS response to unannounced balance perturbation during walking, simulating real-life conditions of balance loss. RESEARCH QUESTION: Do laboratory-induced unannounced balance losses during walking cause a sympathetic response, and if so - does it habituate after a series of perturbations? METHODS: 34 young adults underwent a series of six successive unannounced balance perturbations while walking on a treadmill. Sympathetic activity was monitored continuously using Electrodermal Activity and compared before and immediately after each unannounced perturbation. RESULTS: All perturbations elicited a significant increase in Electrodermal Activity (p<0.001), indicating a phasic increase in the sympathetic drive. The relative phasic increase of Electrodermal Activity caused by the first perturbation was significantly higher than the last perturbation (p<0.05). Three types of Electrodermal Activity behavior were observed: Steady level tonic SNS activity, increased SNS activity, and decreased SNS activity. SIGNIFICANCE: Balance loss during walking triggers phasic SNS response, this response habituates after a series of unannounced balance perturbations. In addition, three distinct patterns of tonic sympathetic activity may imply variations in the ability of the SNS response to habituate across individuals.

The Neurophysiological Effects of Craniosacral Treatment on Heart Rate Variability: A Systematic Review of Literature and Meta-Analysis.

Craniosacral treatment (CST) is an osteopathic technique grounded in the assumption that there is an intrinsic, fine movement of the cerebrospinal fluid. This rhythmic movement can be utilized for diagnostic and therapeutic purposes by palpation and manipulation of the skull, spine, and associated connective tissues. Therapeutic benefit is likely due to action on the autonomic nervous system (ANS), specifically through the vagus nerve. Current literature on the neurophysiological effects of CST is limited, which has contributed to controversy regarding its effectiveness. Heart rate variability (HRV) as a measure of cardiovascular stress and autonomic system activity is thus proposed as a tool to evaluate the neurophysiologic effects of CST. HRV can be analyzed in two different bands, high-frequency (HF) and low-frequency (LF) power associated with a parasympathetic and sympathetic response. In this meta-analysis, we provide a brief introduction to CST, analyze three primary studies, and summarize the therapeutic benefits and pitfalls of this alternative treatment on the ANS. A significant negative HF standardized mean difference after CST was observed; standardized mean difference = -0.46; 95% CI (-0.79,-0.14). No significant effect on LF power was observed. We conclude that CST does provide a moderate short-term increase in parasympathetic activity. These findings suggest that CST may be used to treat patients with an overactive sympathetic state. Further studies should be conducted for comparison against a control group to eliminate the possibility of a placebo effect and to elucidate long-term effects.

Author Reply to Letter to the Editor: In Response to: Comment on Fonollosa et al.'s "Hyper-Reflective Outer Nuclear Layer (HONL) in Vogt-Koyanagi-Harada Disease and Sympathetic Ophthalmia".

We have recently described an OCT sign in two patients (one with Vogt-Koyanagi-Harada (VKH) and the other with Sympathetic Ophthalmia) consisting of hyperreflectivity of the outer nuclear layer (HONL) that subsequently evolved into outer retina atrophy and associated with poor functional outcomes. Ali et al. have published a comment on our letter regarding HONL. They have evaluated it in 90 eyes of VKH patients. It was observed in 37 eyes (41.1%) and no associations were found between HONL and structural outcomes or final visual acuity, and no cases of retinal atrophy were described. In the present author's reply, we point out two reasons for these contradictory observations. First, we considered HONL a full thickness hyperreflectivity of the outer nuclear layer, whereas they included cases with partial thickness hyperreflectivity, hence probably milder cases. Second: they have assessed visual function by means of visual acuity, so cases with extrafoveal involvement whose functional deficiency might only be measured by other tests (i.e. visual field) might have been missed.

Microglia in the hypothalamic paraventricular nucleus sense hemodynamic disturbance and promote sympathetic excitation in hypertension.

Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.

[Myofascial pain syndrome-a neurovegetative complaints pattern]. / Das myofasziale Schmerzsyndrom (MFSS)­ ein neurovegetatives Beschwerdebild.

The diagnosis of myofascial pain syndrome is usually made after structural-morphological explanations have been ruled out. The lack of positive findings to guide treatment inevitably leaves room for interpretation despite the extensive use of all imaging, neurophysiological or serological diagnostics. Under these circumstances, a careful differential diagnosis must be made between functional and structural aspects, both of which in many cases must be assessed in their different relevance. Particular attention must be paid to indications of vegetative-sympathetic adjustment disorders.The great importance of a clinical, experience-based approach to this symptom pattern becomes clear here, especially if the technical diagnostic data is of no help. The dominance of imaging findings naturally promotes a structure-based, mechanistic understanding of the illness. In contrast, the emotional, vegetative mood of the patient should be given greater consideration as a diagnostic and therapeutic focus. Treatment measures should have a high success rate, as persistent reductions in stimulus thresholds may lead to prognostically unfavorable chronification.

Binge Alcohol Consumption Elevates Sympathetic Transduction to Blood Pressure: A Randomized Controlled Trial.

BACKGROUND: Alcohol consumption is associated with cardiovascular disease, and the sympathetic nervous system is a suspected mediator. The present study investigated sympathetic transduction of muscle sympathetic nerve activity to blood pressure at rest and in response to cold pressor test following evening binge alcohol or fluid control, with the hypothesis that sympathetic transduction would be elevated the morning after binge alcohol consumption. METHODS: Using a randomized, fluid-controlled (FC) crossover design, 26 healthy adults (12 male, 14 female, 25±6 years, 27±4 kg/m2) received an evening binge alcohol dose and a FC. All participants underwent next-morning autonomic-cardiovascular testing consisting of muscle sympathetic nerve activity, beat-to-beat blood pressure, and heart rate during a 10-minute rest period and a 2-minute cold pressor test. Sympathetic transduction was assessed at rest and during the cold pressor test in both experimental conditions. RESULTS: Evening alcohol increased heart rate (FC: 60±9 versus alcohol: 64±9 bpm; P=0.010) but did not alter resting mean arterial pressure (FC: 80±6 versus alcohol: 80±7 mm Hg; P=0.857) or muscle sympathetic nerve activity (FC: 18±9 versus alcohol: 20±8 bursts/min; P=0.283). Sympathetic transduction to mean arterial pressure (time×condition; P=0.003), diastolic blood pressure (time×condition; P=0.010), and total vascular conductance (time×condition; P=0.004) was augmented after alcohol at rest. Sympathetic transduction during the cold pressor test was also elevated after evening binge alcohol consumption (P=0.002). CONCLUSIONS: These findings suggest that evening binge alcohol consumption leads to augmented morning-after sympathetic transduction of muscle sympathetic nerve activity to blood pressure, highlighting a new mechanism whereby chronic or excessive alcohol consumption contributes to cardiovascular disease progression via altered end-organ responsiveness to sympathetic neural outflow. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03567434.

Risk Factors Affecting the Outcomes of CT-Guided Radiofrequency Thermocoagulation of the T3 Sympathetic Nerve in the Treatment of Craniofacial Hyperhidrosis.

Background: Current studies mostly suggest that hyperhidrosis is caused by relative sympathetic hyperactivity. Sympathetic radiofrequency thermocoagulation is widely used in clinics. Previous studies have demonstrated that surgery at T3 is effective and safe compared with higher levels, so craniofacial hyperhidrosis in our hospital is selected to be treated at T3. However, some patients pursue repeat medical treatment due to an increase in hyperhidrosis at the original site after surgery. Previous studies have demonstrated the significance of Perfusion index (PI) value in the recurrence of palmar hyperhidrosis, but there is no relevant study on craniofacial hyperhidrosis. Methods: Clinical data from patients with craniofacial hyperhidrosis, who underwent T3 sympathetic radiofrequency thermocoagulation at Jiaxing First Hospital (Jiaxing, China) between January 1, 2018 and December 31, 2021, were analyzed. Recurrence in patients 1 year after surgery was recorded through a case search and telephone follow-up system that registered patient information. Clinical data were analyzed using binary logistic regression analysis to investigate risk factors associated with recurrence in patients with craniofacial hyperhidrosis 1 year after surgery. Results: Of 83 patients included in the present study, 34 (40%) experienced increased craniofacial sweating 1 year after surgery. Results of univariate logistic regression analysis revealed that computed tomography (CT) scan count, increase in pulse index (PI) at the fingertips, and differences in forehead temperature were potential risk factors for postoperative recurrence in patients with craniofacial hyperhidrosis (p<0.2), and the results were consistent on both sides. Three potential risk factors were included in the multivariate logistic regression analysis and results revealed that the risk for recurrence was reduced by 48% (left side) and 67% (right side) for every 1 unit increase in PI value. Conclusion: A small increase in PI was an independent risk factor for recurrence of hyperhidrosis in patients with craniofacial hyperhidrosis after undergoing T3 sympathetic radiofrequency thermocoagulation.

Intracerebroventricular insulin injection acutely normalizes the augmented exercise pressor reflex in male rats with type 2 diabetes mellitus.

The exercise pressor reflex (EPR) is exaggerated in type 2 diabetes mellitus (T2DM), but the underlying central nervous system aberrations have not been fully delineated. Stimulation of muscle afferents within working skeletal muscle activates the EPR, by sending information to neurons in the brainstem, where it is integrated and results in reflexively increased mean arterial pressure (MAP) and sympathetic nerve activity. Brain insulin is known to regulate neural activity within the brainstem. We hypothesize that brain insulin injection in T2DM rats attenuates the augmented EPR, and that T2DM is associated with decreased brain insulin. Using male Sprague-Dawley rats, T2DM and control rats were generated via an induction protocol with two low doses of streptozotocin (35 and 25 mg/kg, i.p.) in combination with a 14-23-week high-fat diet or saline injections and a low-fat diet, respectively. After decerebration, MAP and renal sympathetic nerve activity (RSNA) were evaluated during EPR stimulation, evoked by electrically induced muscle contraction via ventral root stimulation, before and after (1 and 2 h post) intracerebroventricular (i.c.v.) insulin microinjections (500 mU, 50 nl). i.c.v. insulin decreased peak MAP (ΔMAP Pre (36 ± 14 mmHg) vs. 1 h (21 ± 14 mmHg) vs. 2 h (11 ± 6 mmHg), P < 0.05) and RSNA (ΔRSNA Pre (107.5 ± 40%), vs. 1 h (75.4 ± 46%) vs. 2 h (51 ± 35%), P < 0.05) responses in T2DM, but not controls. In T2DM rats, cerebrospinal fluid insulin was decreased (0.41 ± 0.19 vs. 0.11 ± 0.05 ng/ml, control (n = 14) vs. T2DM (n = 4), P < 0.01). The results demonstrated that insulin injections into the brain normalized the augmented EPR in brain hypoinsulinaemic T2DM rats, indicating that the EPR can be regulated by brain insulin. KEY POINTS: The reflexive increase in blood pressure and sympathetic nerve activity mediated by the autonomic nervous system during muscle contractions is also known as the exercise pressor reflex. The exercise pressor reflex is dangerously augmented in type 2 diabetes, in both rats and humans. In type 2 diabetic rats both cerebrospinal fluid insulin and phosphoinositide 3-kinase signalling within cardiovascular brainstem neurons decrease in parallel. Brain insulin injections decrease the magnitude of the reflexive pressor and sympathetic responses to hindlimb muscle contraction in type 2 diabetic rats. Partial correction of low insulin within the central nervous system in type 2 diabetes may treat aberrant exercise pressor reflex function.

Pupil light reflex in young elite athletes: autonomic nervous system activity and viscoelastic properties.

Introduction: The pupil light reflex (photomotor reflex) has a duration of 3.5 s and is a highly reproducible measurement. Conventionally, the autonomic nervous system (ANS) activity evaluated by this reflex does not consider the viscoelasticity of the iris muscles. This study aims to detect differences in reflex autonomic activity in a supine position with parameters derived from the Kelvin-Voigt viscoelastic model in two distinct groups of elite athletes. Method: Groups formed using a dendrogram analysis based on basal autonomic activity assessed with heart rate variability. Heart rate variability was measured, and the photomotor reflex was modeled. Results: The model showed a high degree of adjustment to the photomotor reflex (r2 = 0.99 ± 0.01). The impulse 3, an indicator of reflex sympathetic activity, revealed a significantly higher activity (ρ ≤ 0.05) in the [sympa/para]+ group compared to the [sympa/para]⁻ group. This result was further supported by a greater relative total redilation amplitude (ρ ≤ 0.05) and a shorter duration of 75% redilation (ρ ≤ 0.01). Finally, the relative total redilation amplitude exhibited a significant correlation with the linear stiffness constant (ρ ≤ 0.001) and the maximum redilation speed with restoring force (ρ ≤ 0.001). Discussion: These results indicate that (i) the photomotor reflex can detect an alteration of the reflex autonomic activity specific to each of the two branches of the ANS (ii) the viscoelastic properties of the iris muscles play a significant role in the energy storage-restitution mechanisms during the photomotor reflex. This approach could allow athletes to benefit from reduced time spent in the analysis of ANS activity, potentially making it an almost daily and automated process.

Autonomic modulation by SGLT2i or DPP4i in patients with diabetes favors cardiovascular outcomes as revealed by skin sympathetic nerve activity.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i) are important second-line treatments for patients with type 2 diabetes mellitus (T2DM). Patients taking SGLT2i have favorable cardiovascular outcomes via various mechanisms, including autonomic nervous system (ANS) modulation. This study aimed to use neuro-electrocardiography (neuECG) to test the effects of SGLT2i or DPP4i on the ANS. Methods: Patients with T2DM, who did not reach target hemoglobin (Hb)A1C levels despite metformin treatment, were enrolled. SGLT2i or DPP4i were prescribed randomly unless a compelling indication was present. NeuECG and heart rate were recorded for 10 min before and after a 3-month treatment. The patients were treated according to standard practice and the obtained data for skin sympathetic nerve activity (SKNA) and ANS entropy were analyzed offline. Results: We enrolled 96 patients, of which 49 received SGLT2i and 47 received DPP4i. The baseline parameters were similar between the groups. No adverse event was seen during the study period. In the burst analysis of SKNA at baseline, all parameters were similar. After the 3-month treatment, the firing frequency was higher in SGLT2i group (0.104 ± 0.045 vs 0.083 ± 0.033 burst/min, p < 0.05), with increased long firing duration (7.34 ± 3.66 vs 5.906 ± 2.921, p < 0.05) in 3-s aSKNA scale; the other parameters did not show any significant change. By symbolic entropy, the most complex patterns (Rank 3) were found to be significantly higher in SGLT2i-treated patients than in DDP4i-treated group (0.084 ± 0.028 vs 0.07 ± 0.024, p = 0.01) and the direction of change in Rank 3, after SGLT2i treatment, was opposite to that observed in the DDP4i group (0.012 ± 0.036 vs. -0.005 ± 0.037, p = 0.024). Our findings demonstrated the favorable autonomic modulation by SGLTi and the detrimental effects of DPP4i on ANS. Conclusion: We demonstrated the autonomic modulation by SGLTi and DPP4i using SKNA in patients with DM, which might provide insights into the favorable outcomes of SGLT2i. Furthermore, we refined the analytical methods of neuECG, which uses SKNA to evaluate autonomic function.

Cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia in the light of the medical situation in Japan.

Progress of treadmill exercise testing in Case 1 Each electrocardiogram shows the maximum load. Before left cardiac sympathetic denervation, polymorphic ventricular tachycardias were observed. After left cardiac sympathetic denervation, no ventricular arrhythmias were induced during exercise.

Cardiac sympathetic neurons are additional cells affected in genetically determined arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes, which accounts for most cases of stress-related arrhythmic sudden death, in young and athletes. AC hearts display fibro-fatty lesions that generate the arrhythmic substrate and cause contractile dysfunction. A correlation between physical/emotional stresses and arrhythmias supports the involvement of sympathetic neurons (SNs) in the disease, but this has not been confirmed previously. Here, we combined molecular, in vitro and ex vivo analyses to determine the role of AC-linked DSG2 downregulation on SN biology and assess cardiac sympathetic innervation in desmoglein-2 mutant (Dsg2mut/mut) mice. Molecular assays showed that SNs express DSG2, implying that DSG2-mutation carriers would harbour the mutant protein in SNs. Confocal immunofluorescence of heart sections and 3-D reconstruction of SN network in clarified heart blocks revealed significant changes in the physiologialc SN topology, with massive hyperinnervation of the intact subepicardial layers and heterogeneous distribution of neurons in fibrotic areas. Cardiac SNs isolated from Dsg2mut/mut neonatal mice, prior to the establishment of cardiac innervation, show alterations in axonal sprouting, process development and distribution of varicosities. Consistently, virus-assisted DSG2 downregulation replicated, in PC12-derived SNs, the phenotypic alterations displayed by Dsg2mut/mut primary neurons, corroborating that AC-linked Dsg2 variants may affect SNs. Our results reveal that altered sympathetic innervation is an unrecognized feature of AC hearts, which may result from the combination of cell-autonomous and context-dependent factors implicated in myocardial remodelling. Our results favour the concept that AC is a disease of multiple cell types also hitting cardiac SNs. KEY POINTS: Arrhythmogenic cardiomyopathy is a genetically determined cardiac disease, which accounts for most cases of stress-related arrhythmic sudden death. Arrhythmogenic cardiomyopathy linked to mutations in desmoglein-2 (DSG2) is frequent and leads to a left-dominant form of the disease. Arrhythmogenic cardiomyopathy has been approached thus far as a disease of cardiomyocytes, but we here unveil that DSG2 is expressed, in addition to cardiomyocytes, by cardiac and extracardiac sympathetic neurons, although not organized into desmosomes. AC-linked DSG2 downregulation primarily affect sympathetic neurons, resulting in the significant increase in cardiac innervation density, accompanied by alterations in sympathetic neuron distribution. Our data supports the notion that AC develops with the contribution of several 'desmosomal protein-carrying' cell types and systems.

Coupling of ß-adrenergic and Hippo pathway signaling: Implications for heart failure pathophysiology and metabolic therapy.

Activation of the sympatho-ß-adrenergic receptor (ßAR) system is the hallmark of heart disease with adverse consequences that facilitate the onset and progression of heart failure (HF). Use of ß-blocking drugs has become the front-line therapy for HF. Last decade has witnessed progress in research demonstrating a pivotal role of Hippo pathway in cardiomyopathy and HF. Clinical studies have revealed myocardial Hippo pathway activation/YAP-TEAD1 inactivation in several types of human cardiomyopathy. Experimental activation of cardiac Hippo signaling or inhibition of YAP-TEAD1 have been shown to leads dilated cardiomyopathy with severe mitochondrial dysfunction and metabolic reprogramming. Studies have also convincingly shown that stimulation of ßAR activates cardiac Hippo pathway with inactivation of the down-stream effector molecules YAP/TAZ. There is strong evidence for the adverse consequences of the ßAR-Hippo signaling leading to HF. In addition to promoting cardiomyocyte death and fibrosis, recent progress is the demonstration of mitochondrial dysfunction and metabolic reprogramming mediated by ßAR-Hippo pathway signaling. Activation of cardiac ßAR-Hippo signaling is potent in downregulating a range of mitochondrial and metabolic genes, whereas expression of pro-inflammatory and pro-fibrotic factors are upregulated. Coupling of ßAR-Hippo pathway signaling is mediated by several kinases, mechanotransduction and/or Ca2+ signaling, and can be blocked by ß-antagonists. Demonstration of the converge of ßAR signaling and Hippo pathway bears implications for a better understanding on the role of enhanced sympathetic nervous activity, efficacy of ß-antagonists, and metabolic therapy targeting this pathway in HF. In this review we summarize the progress and discuss future research directions in this field.

Cardiopulmonary exercise testing in long covid shows the presence of dysautonomia or chronotropic incompetence independent of subjective exercise intolerance and fatigue.

BACKGROUND: After COVID-19 infection, 10-20% of patients suffer from varying symptoms lasting more than 12 weeks (Long COVID, LC). Exercise intolerance and fatigue are common in LC. The aim was to measure the maximal exercise capacity of the LC patients with these symptoms and to analyze whether this capacity was related to heart rate (HR) responses at rest and during exercise and recovery, to find out possible sympathetic overactivity, dysautonomia or chronotropic incompetence. METHODS: Cardiopulmonary exercise test was conducted on 101 LC patients, who were admitted to exercise testing. The majority of them (86%) had been treated at home during their acute COVID-19 infection. Peak oxygen uptake (VO2peak), maximal power during the last 4 min of exercise (Wlast4), HRs, and other exercise test variables were compared between those with or without subjective exercise intolerance, fatigue, or both. RESULTS: The measurements were performed in mean 12.7 months (SD 5.75) after COVID-19 infection in patients with exercise intolerance (group EI, 19 patients), fatigue (group F, 31 patients), their combination (group EI + F, 37 patients), or neither (group N, 14 patients). Exercise capacity was, in the mean, normal in all symptom groups and did not significantly differ among them. HRs were higher in group EI + F than in group N at maximum exercise (169/min vs. 158/min, p = 0.034) and 10 min after exercise (104/min vs. 87/min, p = 0.028). Independent of symptoms, 12 patients filled the criteria of dysautonomia associated with slightly decreased Wlast4 (73% vs. 91% of sex, age, height, and weight-based reference values p = 0.017) and 13 filled the criteria of chronotropic incompetence with the lowest Wlast4 (63% vs. 93%, p < 0.001), VO2peak (70% vs. 94%, p < 0.001), the lowest increase of systolic blood pressure (50 mmHg vs. 67 mmHg, p = 0.001), and the greatest prevalence of slight ECG-findings (p = 0.017) compared to patients without these features. The highest prevalence of chronotropic incompetence was seen in the group N (p = 0.022). CONCLUSIONS: This study on LC patients with different symptoms showed that cardiopulmonary exercise capacity was in mean normal, with increased sympathetic activity in most patients. However, we identified subgroups with dysautonomia or chronotropic incompetence with a lowered exercise capacity as measured by Wlast4 or VO2peak. Subjective exercise intolerance and fatigue poorly foresaw the level of exercise capacity. The results could be used to plan the rehabilitation from LC and for selection of the patients suitable for it.