Mechanisms of Vascular Inflammation and Potential Therapeutic Targets: A Position Paper From the ESH Working Group on Small Arteries.

Inflammatory responses in small vessels play an important role in the development of cardiovascular diseases, including hypertension, stroke, and small vessel disease. This involves various complex molecular processes including oxidative stress, inflammasome activation, immune-mediated responses, and protein misfolding, which together contribute to microvascular damage. In addition, epigenetic factors, including DNA methylation, histone modifications, and microRNAs influence vascular inflammation and injury. These phenomena may be acquired during the aging process or due to environmental factors. Activation of proinflammatory signaling pathways and molecular events induce low-grade and chronic inflammation with consequent cardiovascular damage. Identifying mechanism-specific targets might provide opportunities in the development of novel therapeutic approaches. Monoclonal antibodies targeting inflammatory cytokines and epigenetic drugs, show promise in reducing microvascular inflammation and associated cardiovascular diseases. In this article, we provide a comprehensive discussion of the complex mechanisms underlying microvascular inflammation and offer insights into innovative therapeutic strategies that may ameliorate vascular injury in cardiovascular disease.

Effect of series of periodic limb movements in sleep on blood pressure, heart rate and high frequency heart rate variability.

INTRODUCTION: The phenomenon known as periodic limb movements in sleep (PLMS) has been linked to a change in autonomic nervous system (ANS) activity and its effect on circulatory regulation. Autonomic dysfunction or dysregulation in patients with PLMS has been described in some domains; however, any relationship between heart rate variability (HRV) and PLMS has not been clearly established. HRV analysis is a recognised, non-invasive research method that describes the influence of the ANS on heart rate (HR). The aim of our study was to further investigate the dysregulation of autonomic HR control in patients with PLMS. MATERIAL AND METHODS: We undertook a retrospective analysis of the polysomnographic (PSG), demographic and medical data of five patients with a total number of 1,348 PLMS. We analysed HR, HRV HF, systolic blood pressure (SBP), and diastolic blood pressure (DBP) for 10 heartbeats before the series of PLMS and 10 consecutive heartbeats as beat-to-beat measurements. The presented method of using successive, short, 10 RR interval segments refers to the time-frequency measurement, which is very clear and useful for presenting changes in the calculated parameters over time and thereby illustrating their dynamics. This method allowed us to assess dynamic changes in HRV HF during successive PLMS series. Statistical analysis was performed using IBM SPSS Statistics (v. 28.0.0.0). The Kruskal-Wallis test was performed to find statistically significant changes from baseline. RESULTS: No statistically significant changes in HR, SBP, or DBP were found in our group, although an increase in the value of the HRV HF was noted, suggesting an increase in intracardiac parasympathetic activity during the subsequent series of PLMS. CONCLUSIONS: Our study indicates an increase in parasympathetic activity during the appearance of successive PLMS, which, with the simultaneous lack of changes in HR, may suggest an increase in sympathetic activity, and therefore the appearance of so-called 'autonomic co-activation' resulting in the possibility of life-threatening cardiac events. CLINICAL IMPLICATIONS: Our findings add to the literature information regarding HRV in PLMS, and highlight the need for further studies to elucidate the effects of these conditions on the ANS, and on cardiovascular health.

Comment on Muth et al. Assessing Critical Flicker Fusion Frequency: Which Confounders? A Narrative Review. Medicina 2023, 59, 800.

We first want to thank the authors of the excellent review for their contributions to summarizing the confounders associated with critical flicker fusion frequency (CFFF) [...].

The importance of microvascular inflammation in ageing and age-related diseases: a position paper from the ESH working group on small arteries, section of microvascular inflammation.

Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.

Physical activity and the brain myelin content in humans.

New imaging sequences and biophysical models allow adopting magnetic resonance imaging (MRI) for in vivo myelin mapping in humans. Understanding myelination and remyelination processes in the brain is fundamental from the perspective of proper design of physical exercise and rehabilitation schemes that aim to slow down demyelination in the aging population and to induce remyelination in patients with neurodegenerative diseases. Therefore, in this review we strive to provide a state-of-the art summary of the existing MRI studies in humans focused on the effects of physical activity on myelination/remyelination. We present and discuss four cross-sectional and four longitudinal studies and one case report. Physical activity and an active lifestyle have a beneficial effect on the myelin content in humans. Myelin expansion can be induced in humans throughout the entire lifespan by intensive aerobic exercise. Additional research is needed to determine (1) what exercise intensity (and cognitive novelty, which is embedded in the exercise scheme) is the most beneficial for patients with neurodegenerative diseases, (2) the relationship between cardiorespiratory fitness and myelination, and (3) how exercise-induced myelination affect cognitive abilities.

Resting Heart Rate Affects Heart Response to Cold-Water Face Immersion Associated with Apnea.

The regular cardiac response to immersion of the face in cold water is reduction in heart rate (HR). The highly individualized and unpredictable course of the cardiodepressive response prompted us to investigate the relationship between the cardiac response to face immersion and the resting HR. The research was conducted with 65 healthy volunteers (37 women and 28 men) with an average age of 21.13 years (20-27 years) and a BMI of 21.49 kg/m2 (16.60-28.98). The face-immersion test consisted of stopping breathing after maximum inhaling and voluntarily immersing the face in cold water (8-10 °C) for as long as possible. Measurements included determination of minimum, average, and maximum HR at rest and minimum and maximum HR during the cold-water face-immersion test. The results indicate a strong relationship between the cardiodepressive reaction of the immersion of the face and the minimum HR before the test, as well as a relationship between the maximum HR during the test and the maximum HR at rest. The results also indicate a strong influence of neurogenic HR regulation on the described relationships. The parameters of the basal HR can, therefore, be used as prognostic indicators of the course of the cardiac response of the immersion test.

Cognitive Functions in Scuba, Technical and Saturation Diving.

Scuba diving as a recreational activity is becoming increasingly popular. However, the safety of this activity, especially in the out-of-comfort zone, has been discussed worldwide. The latest publications bring conclusions regarding negative effects on cognitive functions. We compare the acute and chronic effects of diving on cognitive functioning depending on the type of dive performed, including recreational, technical and saturation diving. However, the results of research show that acute and chronic effects on cognitive functions can be negative. While acute effects are reversible after the ascent, chronic effects include white matter lesions in magnetic resonance imaging scans. We believe that more investigations should be performed to determine the chronic effects that could be observed after a few months of observations in a group of regular, intense divers. In addition, publications referring to technical divers are very limited, which is disquieting, as this particular group of divers seems to be neglected in research concerning the effects of diving on cognitive functions.

Heart Rate Variability at Rest Predicts Heart Response to Simulated Diving.

A characteristic feature of the cardiac response to diving is the uncertainty in predicting individual course. The aim of the study was to determine whether resting regulatory heart rate determinants assessed before diving may be predictors of cardiac response in a simulated diving test. The research was conducted with 65 healthy volunteers (37 women and 28 men) with an average age of 21.13 years (20-27 years) and a BMI of 21.49 kg/m2 (16.60-28.98). The simulated diving test consisted of stopping breathing after maximum inhaling and voluntarily immersing the face in water (8-10 °C) for as long as possible. The measurements included heart rate variability (HRV) analysis before diving and determination of the course of the cardiac response to diving-minimum and maximum heart rate (HR). The results indicate that minimum HR during diving (MIN_div) is dependent on the short-term HRV measures, which proves the strong influence of the parasympathetic system on the MIN_div. The lack of dependence of MIN_div on short-term HRV in women may be associated with differences in neurogenic HR regulation in women and men. In conclusion, cardiac response to simulated diving is strictly dependent on the autonomic regulation of the heart rhythm under resting conditions. The course of the cardiac response to diving and its relationship with resting HRV appears to be gender dependent.

The usefulness of selected sequences of magnetic resonance imaging in a diagnostic model for Crohn's disease.

Introduction: We hypothesized that, based on magnetic resonance enterography (MRE) and the apparent diffusion coefficient (ADC), measured in the affected parts of the intestine, it is possible to effectively differentiate active and chronic phases of Crohn's disease. Aim: To create a multidimensional diagnostic model for differentiating between the phases of Crohn's disease. Material and methods: This study included 125 patients - 55 women (aged 19 to 66 years) and 70 men (aged 12 to 67 years) - who underwent MRE and ADC measurement for the first time. Results: The group of potential explanatory variables comprised 11 variables, including the thickness and length of the occupied section, number of lymph nodes, layered bowel wall enhancement, total transitions on fat tissue, and features of restricted diffusion. The final discrimination model was based on 2 variables: ADC (A) and layered bowel wall enhancement (W). Active Crohn's disease was defined as -6.339 + 4.747 × W + 0.008 × A, while chronic Crohn's disease was defined as -11.365 + 2.812 × W + 0.012 × A. Definitive diagnosis was based on histological examination of material collected during ileocolonoscopy in 96 patients, surgery with subsequent histopathological examination in 17 patients, and capsule endoscopy in 12 patients. Conclusions: The predictive model described here could identify the active form of Crohn's disease with a probability of 93.06% and the chronic form with a probability of 75.57%. The use of classic MRE layered bowel wall enhancement and a DWI-based ADC metric eliminates the main shortcomings of both approaches.

Neuropsychological and Neurophysiological Mechanisms behind Flickering Light Stimulus Processing.

The aim of this review is to summarise current knowledge about flickering light and the underlying processes that occur during its processing in the brain. Despite the growing interest in the topic of flickering light, its clinical applications are still not well understood. Studies using EEG indicate an appearing synchronisation of brain wave frequencies with the frequency of flickering light, and hopefully, it could be used in memory therapy, among other applications. Some researchers have focused on using the flicker test as an indicator of arousal, which may be useful in clinical studies if the background for such a relationship is described. Since flicker testing has a risk of inducing epileptic seizures, however, every effort must be made to avoid high-risk combinations, which include, for example, red-blue light flashing at 15 Hz. Future research should focus on the usage of neuroimaging methods to describe the specific neuropsychological and neurophysiological processes occurring in the brain during the processing of flickering light so that its clinical utility can be preliminarily determined and randomised clinical trials can be initiated to test existing reports.

Reply to Vrijdag et al. Comment on "Mankowska et al. Critical Flicker Fusion Frequency: A Narrative Review. Medicina 2021, 57, 1096".

Thank you very much for your interest and comments [...].

Diagnostic value of diffusion tensor imaging in patients with clinical signs of cervical spondylotic myelopathy.

AIM OF THE STUDY: The aim of this study was to assess the diagnostic value of diffusion tensor imaging (DTI) in patients with symptoms of cervical myelopathy. Detailed goals included determining the diagnostic effectiveness of quantitative parameters, i.e. fractional anisotropy (FA) and apparent diffusion coefficient (ADC), in the diagnosis of cervical myelopathy, and the correlation between these parameters and clinical symptoms. CLINICAL RATIONALE FOR THE STUDY: The demonstration of an ischaemic focus in the spinal cord by standard magnetic resonance imaging (MRI) methods is associated with already accomplished spinal cord damage, and of course limited treatment options. Therefore, finding a new examination protocol that allows early diagnosis of myelopathic focus, before the onset of full neurological symptoms, has become a priority in the diagnosis and treatment of spine diseases. Such an examination increases the chances of correctly qualifying the patient for conservative vs. surgical treatment. MATERIAL AND METHODS: Between 2013 and 2017, 128 adults with clinical signs of cervical myelopathy were examined, and were divided into four symptomatic subgroups. A control group consisted of 37 healthy volunteers. DTI values were measured at the level of C2/C3, and at the most severe stenosis of the spine. RESULTS: In patients with cervical spondylotic myelopathy (CSM), the ADC values were significantly higher (p < 0.001), and FA values were significantly lower (p < 0.001), than in healthy volunteers at the stenotic level. There were significant differences in DTI parameters between the clinical subgroups (p < 0.001). CONCLUSIONS AND CLINICAL IMPLICATIONS: Changes in DTI parameters indicate a microstructural disorder of the core which is not visible in a structural MRI. FA and ADC values measured at the level of the most severe stenosis of the spinal canal allow the differentiation of patients with myelopathy of varying degrees of clinical severity. Extending standard MRI to include assessment of FA and ADC may be helpful in deciding treatment modalities (conservative vs. surgical) for patients with visible canal stenosis without full neurological symptoms. This may be useful in selecting patients for urgent rehabilitative treatment. This study is a starting point for further research, i.e. an evaluation of the extent of FA and ADC lesion withdrawal after surgical treatment.

A Systematic Review of the Impact of Physical Exercise-Induced Increased Resting Cerebral Blood Flow on Cognitive Functions.

Brain perfusion declines with aging. Physical exercise represents a low-cost accessible form of intervention to increase cerebral blood flow; however, it remains unclear if exercise-induced amelioration of brain perfusion has any impact on cognition. We aimed to provide a state-of-the art review on this subject. A comprehensive search of the PubMed (MEDLINE) database was performed. On the basis of the inclusion and exclusion criteria, 14 studies were included in the analysis. Eleven of the studies conducted well-controlled exercise programs that lasted 12-19 weeks for 10-40 participants and two studies were conducted in much larger groups of subjects for more than 5 years, but the exercise loads were indirectly measured, and three of them were focused on acute exercise. Literature review does not show a direct link between exercise-induced augmentation of brain perfusion and better cognitive functioning. However, in none of the reviewed studies was such an association the primary study endpoint. Carefully designed clinical studies with focus on cognitive and perfusion variables are needed to provide a response to the question whether exercise-induced cerebral perfusion augmentation is of clinical importance.

Arginine Vasopressin, Synaptic Plasticity, and Brain Networks.

The arginine vasopressin (AVP), a neurohypophysial hormone, is synthesized within specific sites of the central nervous system and axonally transported to multiple areas, acting as a neurotransmitter/ neuromodulator. In this context, AVP acts primarily through vasopressin receptors A and B and is involved in regulating complex social and cognition behaviors and basic autonomic function. Many earlier studies have shown that AVP as a neuromodulator affects synaptic plasticity. This review updates our current understanding of the underlying molecular mechanisms by which AVP affects synaptic plasticity. Moreover, we discuss AVP modulatory effects on event-related potentials and blood oxygen level-dependent responses in specific brain structures, and AVP effects on the network level oscillatory activity. We aimed at providing an overview of the AVP effects on the brain from the synaptic to the network level.

Impact of Hyperbaric Oxygen Therapy on Cognitive Functions: a Systematic Review.

Hyperbaric oxygen therapy (HBOT) is a modality of treatment in which patients inhale 100% oxygen inside a hyperbaric chamber pressurised to greater than 1 atmosphere. The aim of this review is to discuss neuropsychological findings in various neurological disorders treated with HBOT and to open new perspectives for therapeutic improvement. A literature search was conducted in the MEDLINE (via PubMed) database from the inception up 10 May 2020. Eligibility criteria included original articles published in English. Case studies were excluded. Full-text articles were obtained from the selected studies and were reviewed on the following inclusion criteria (1) performed cognitive processes assessment (2) performed HBOT with described protocol. Two neuropsychologists independently reviewed titles, abstracts, full texts and extracted data. The initial search retrieved 1024 articles, and a total of 42 studies were finally included after applying inclusion and exclusion criteria. The search yielded controversial results with regard to the efficiency of HBOT in various neurological conditions with cognitive disturbance outcome. To the best of our knowledge this is the first state-of-the art, systematic review in the field. More objective and precise neuropsychological assessment methods are needed to exact evaluation of the efficacy of HBOT for neuropsychological deficits. Future studies should widen the assessment of HBOT effects on different cognitive domains because most of the existing studies have focussed on a single process. Finally, there is a need for further longitudinal studies.

Mild poikilocapnic hypoxia increases very low frequency haemoglobin oxygenation oscillations in prefrontal cortex.

BACKGROUND: The aim of the study was to investigate the effect of mild cerebral hypoxia on haemoglobin oxygenation (HbO2), cerebrospinal fluid dynamics and cardiovascular physiology. To achieve this goal, four signals were recorded simultaneously: blood pressure, heart rate / electrocardiogram, HbO2 from right hemisphere and changes of subarachnoid space (SAS) width from left hemisphere. Signals were registered from 30 healthy, young participants (2 females and 28 males, body mass index = 24.5 ± 2.3 kg/m2, age 30.8 ± 13.4 years). RESULTS: We analysed the recorded signals using wavelet transform and phase coherence. We demonstrated for the first time that in healthy subjects exposed to mild poikilokapnic hypoxia there were increases in very low frequency HbO2 oscillations (< 0.052 Hz) in prefrontal cortex. Additionally, SAS fluctuation diminished in the whole frequency range which could be explained by brain oedema. CONCLUSIONS: Consequently the study provides insight into mechanisms governing brain response to a mild hypoxic challenge. Our study supports the notion that HbO2 and SAS width monitoring might be beneficial for patients with acute lung disease.

Critical Flicker Fusion Frequency: A Narrative Review.

This review presents the current knowledge of the usage of critical flicker fusion frequency (CFF) in human and animal model studies. CFF has a wide application in different fields, especially as an indicator of cortical arousal and visual processing. In medicine, CFF may be helpful for diagnostic purposes, for example in epilepsy or minimal hepatic encephalopathy. Given the environmental studies and a limited number of other methods, it is applicable in diving and hyperbaric medicine. Current research also shows the relationship between CFF and other electrophysiological methods, such as electroencephalography. The human eye can detect flicker at 50-90 Hz but reports are showing the possibility to distinguish between steady and modulated light up to 500 Hz. Future research with the use of CFF is needed to better understand its utility and application.

Coupling between Blood Pressure and Subarachnoid Space Width Oscillations during Slow Breathing.

The precise mechanisms connecting the cardiovascular system and the cerebrospinal fluid (CSF) are not well understood in detail. This paper investigates the couplings between the cardiac and respiratory components, as extracted from blood pressure (BP) signals and oscillations of the subarachnoid space width (SAS), collected during slow ventilation and ventilation against inspiration resistance. The experiment was performed on a group of 20 healthy volunteers (12 females and 8 males; BMI=22.1±3.2 kg/m2; age 25.3±7.9 years). We analysed the recorded signals with a wavelet transform. For the first time, a method based on dynamical Bayesian inference was used to detect the effective phase connectivity and the underlying coupling functions between the SAS and BP signals. There are several new findings. Slow breathing with or without resistance increases the strength of the coupling between the respiratory and cardiac components of both measured signals. We also observed increases in the strength of the coupling between the respiratory component of the BP and the cardiac component of the SAS and vice versa. Slow breathing synchronises the SAS oscillations, between the brain hemispheres. It also diminishes the similarity of the coupling between all analysed pairs of oscillators, while inspiratory resistance partially reverses this phenomenon. BP-SAS and SAS-BP interactions may reflect changes in the overall biomechanical characteristics of the brain.

Melatonin maintains the function of the blood redox system at combined ethanol-induced toxicity and subclinical inflammation in mice.

BACKGROUND: The goal of this study was to assess the effect of melatonin on blood redox systems in mice simultaneously exposed to ethanol and low-dose lipopolysaccharide (LPS). METHODS: Oxidative stress parameters were assessed in eight groups: untreated control, melatonin (10 mg kg-1, 10 days), LPS (injected once intraperitoneally at a dose of 150 µg per mouse), LPS with previous melatonin treatment, acute ethanol-induced stress (AES, 0.75 g kg-1 per day, 10 days), AES with previous melatonin treatment, LPS- and AES-induced toxicity, and melatonin treatment. RESULTS: Both ethanol and LPS induced oxidative stress. The combination of these two factors was even more toxic to the organism. Melatonin stabilized erythrocyte membranes and decreased the high level of free radical oxidation at the initial and final stages. Furthermore, melatonin limited protein damage through maintenance in the functional ability of the blood redox system to counteract pathological conditions. CONCLUSIONS: Melatonin limited the negative effects associated with alcohol consumption and low-intensity inflammation.