White-coat effect and masked hypertension in patients with high-normal office blood pressure: results of the Hungarian ABPM Registry.

OBJECTIVE: Blood pressure (BP) lowering therapy in hypertension can markedly reduce the risk of cardiovascular diseases. In case of high-normal office blood pressure (oBP), the initiation of antihypertensive medication is recommended by guidelines in patients with very high cardiovascular risk. The aims of this study were to evaluate the presence of white-coat high-normal BP (WhHNBP) and masked hypertension in high-normal oBP and to explore the prevalence of untreated very high cardiovascular risk patients. METHODS: Data of the Hungarian Ambulatory Blood Pressure Monitoring (ABPM) Registry between September 2020 and November 2023 were used in our analysis. RESULTS: From 38 720 uploaded ABPM curves with clinical data, 4300 individuals were categorized as having high-normal oBP. Among those, 3285 (76.4%) were on antihypertensive treatment. Based on the ABPM recordings, high-normal BP was confirmed in 20.5% ( n  = 881), while WhHNBP was present in 27.6% ( n  = 1188) and masked hypertension in 51.9% ( n  = 2231). Similar results were found in treated and untreated subjects or patients as well. Independent predictors of WhHNBP were age [odds ratio (OR) 1.02 (95% confidence interval, 95% CI: 1.01-1.02), P  < 0.001], female sex [OR: 1.59 (1.32-1.92), P  < 0.001] and snoring [OR: 0.70 (0.57-0.86), P  < 0.001]. Independent predictors of masked hypertension were male sex [OR: 1.31 (1.12-1.54), P  < 0.001] and obesity [OR: 1.71 (1.39-2.09), P  < 0.001]. Five hundred and two individuals had very high cardiovascular risk with high-normal oBP and only 25 of them were untreated. CONCLUSION: In high-normal oBP, WhHNBP or masked hypertension is present in three out of four individuals. Most of the patients with high-normal oBP and very high cardiovascular risk are already treated with antihypertensive drugs.

A Guideline for Guidelines: A Novel Method to Assess the Helpfulness of Medical Guidelines.

Background/Objectives: The recommendations included in medical guidelines (GLs) provide important help to medical professionals for making clinical decisions regarding the diagnosis and treatment of various diseases. However, there are no systematic methods to measure the helpfulness of GLs. Thus, we developed an objective assessment of GLs which indicates their helpfulness and quality. We hypothesized that a simple mathematical analysis of 'Recommendations' and 'Evidence' would suffice. Methods: As a proof of concept, a mathematical analysis was conducted on the '2020 European Society of Cardiology Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease Guideline' (SCE-guideline). First, the frequencies of Classes of Recommendations (CLASS) and the Levels of Evidence (LEVEL) (n = 159) were analysed. Then, LEVEL areas under CLASS were calculated to form a certainty index (CI: -1 to +1). Results: The frequency of CLASS I ('to do') and CLASS III ('not to do') was relatively high in the SCE-guideline (52.2%). Yet, the most frequent LEVEL was C (41.2-83.8%), indicating only a relatively low quality of scientific evidence in the SCE-guideline. The SCE-guideline showed a relatively high CI (+0.57): 78.4% certainty and 21.6% uncertainty. Conclusions: The SCE-guideline provides substantial help in decision making through the recommendations (CLASS), while the supporting evidence (LEVEL) in most cases is of lower quality. This is what the newly introduced certainty index showed: a tool for 'quality control' which can identify specific areas within GLs, and can promote the future improvement of GLs. The newly developed mathematical analysis can be used as a Guideline for the Guidelines, facilitating the assessment and comparison of the helpfulness and quality of GLs.

Liposomal nanocarriers of preassembled glycocalyx restore normal venular permeability and shear stress sensitivity in sepsis: assessed quantitatively with a novel microchamber system.

The endothelial glycocalyx (EG), covering the luminal side of endothelial cells, regulates vascular permeability and senses wall shear stress. In sepsis, EG undergoes degradation leading to increased permeability and edema formation. We hypothesized that restoring EG integrity using liposomal nanocarriers of preassembled glycocalyx (LNPG) will restore normal venular permeability in lipopolysaccharide (LPS)-induced sepsis model of mice. To test this hypothesis, we designed a unique perfusion microchamber in which the permeability of isolated venules could be assessed by measuring the concentration of Evans blue dye (EBD) in microliter samples of extravascular solution (ES). Histamine-induced time- and dose-dependent increases in EBD in the ES could be measured, confirming the sensitivity of the microchamber system. Notably, the histamine-induced increase in permeability was significantly attenuated by histamine receptor (H1) antagonist, triprolidine hydrochloride. Subsequently, mice were treated with LPS or LPS + LNPG. When compared with control mice, venules from LPS-treated mice showed a significant increased permeability, which was significantly reduced by LNPG administration. Moreover, in the presence of wall shear stress, intraluminal administration of LNPG significantly reduced the permeability in isolated venules from LPS-treated mice. We have found no sex differences. In conclusion, our newly developed microchamber system allows us to quantitatively measure the permeability of isolated venules. LPS-induced sepsis increases permeability of mesenteric venules that is attenuated by in vivo LNPG administration, which also reestablished endothelial responses to shear stress. Thus, LNPG presents a promising therapeutic potential for restoring EG function and thereby mitigating vasogenic edema due to increased permeability in sepsis.NEW & NOTEWORTHY In sepsis, the degradation of the endothelial glycocalyx leads to increased venular permeability. In this study, we developed a potentially new therapeutic approach by in vivo administration of liposomal nanocarriers of preassembled glycocalyx to mice, which restored venular sensitivity to wall shear stress and permeability in lipopolysaccharide-induced sepsis, likely by restoring the integrity of the endothelial glycocalyx. Using a new microchamber system, the permeability of Evans blue dye could be quantitatively determined.

Frequency of office blood pressure measurements and the seasonal variability of blood pressure: results of the Hungarian Hypertension Registry.

PURPOSE: Hypertension is a major public health problem, thus, its timely and appropriate diagnosis and management are crucial for reducing cardiovascular morbidity and mortality. The aim of the new Hungarian Hypertension Registry is to evaluate the blood pressure measurement practices of general practitioners (GPs), internists and cardiologists in outpatient clinics, as well as to assess the seasonal variability of blood pressure. MATERIALS AND METHODS: Omron M3 IT devices were used during four-month periods between October 2018 and April 2023 in GP practices and in hypertension clinics. The blood pressure data were then transmitted online from the monitors' cuffs to a central database using the Medistance system of Omron. RESULTS: Family physicians (n = 2491), and internists/cardiologists (n = 477) participated in the study. A total of 4804 821 blood pressure measurements were taken during 10 four-month evaluation periods. In the ten periods, the daily average number of measurements was between 3.0 and 5.6. Following ESH diagnostic criteria, the proportion of subjects in optimal, normal and high-normal blood pressure categories were 14, 13.4 and 16.7%, respectively. Altogether 56% of the measurements belonged to stage 1, stage 2 or stage 3 hypertension categories (31.6, 17.1 and 7.4%, respectively). On average, a difference of 5/2 mmHg was observed between winter and summer data in systolic and diastolic blood pressures, respectively. The average systolic blood pressure values were higher in GP practices with more than 2000 patients than in the ones with less than 1500 patients (141.86 mmHg versus 140.02 mmHg, p < 0.05). CONCLUSION: In conclusion, the low daily average number of blood pressure measurements indicates a limited blood pressure screening awareness/capacity in the case of Hungarian family physicians. In GP practices with more patients, blood pressure is usually less well-controlled. These results suggest that the further promotion of home blood pressure monitoring is necessary.

What is the background?The standard method for the diagnosis of hypertension and for the control of treatment efficacy in hypertensive patients is office blood pressure measurement.Until now we had no real-life data on the blood pressure measurement practices of general practitioners (GPs), internists and cardiologists.Although seasonal differences in blood pressure values are well known, we had no data on the extent of these changes.What is new?In this real-world, nationwide observational study we were able to measure the frequency of blood pressure measurements in the daily practice of GPs, internists and cardiologists in Hungary, which was found to be very low compared to the number of patients they treat. In practices with more patients, blood pressure is generally less well-controlled.We could also detect a significant seasonal variation in systolic and diastolic blood pressure values over the observed time periods.What is the impact?The low daily average number of blood pressure measurements indicates a limited blood pressure screening awareness/capacity in the case of Hungarian family physicians, supporting the further promotion of home blood pressure measurement.The marked seasonal blood pressure changes demonstrated by our study require attention and the individual adjustment of treatment in different seasons.

Higher level of physical activity reduces mental and neurological symptoms during and two years after COVID-19 infection in young women.

Previous studies found that regular physical activity (PA) can lower the risk of SARS-CoV-2 (COVID-19) infection and post-COVID-19 condition (PCC), yet its specific effects in young women have not yet been investigated. Thus, we aimed to examine whether regular physical activity reduces the number of symptoms during and after COVID-19 infection among young women aged between 18 and 34 (N = 802), in which the confounding effect of other morbidities could be excluded. The average time since infection was 23.5 months. Participants were classified into low, moderate, and high PA categories based on the reported minutes per week of moderate and vigorous PA. Using the Post-COVID-19 Case Report Form, 50 different symptoms were assessed. Although regular PA did not decrease the prevalence of COVID-19 infection and PCC but significantly reduced the number of mental and neurological symptoms both in acute COVID-19 and PCC. Importantly, the high level of PA had a greater impact on health improvements. In addition, the rate of reinfection decreased with an increased level of PA. In conclusion, a higher level of regular PA can reduce the risk of reinfection and the number of mental and neurological symptoms in PCC underlying the importance of regular PA, even in this and likely other viral disease conditions.

Gravity sedimentation reveals functionally and morphologically different platelets in human blood.

In contrast to red blood cells, platelets float rather than sediment when a column of blood is placed in the gravitational field. By the analogy of erythrocyte sedimentation (ESR), it can be expressed with the platelet antisedimentation rate (PAR), which quantitates the difference in platelet count between the upper and lower halves of the blood column after 1 h of 1 g sedimentation. Venous blood samples from 21 healthy subjects were analyzed for PAR. After a 1-h sedimentation, the upper and lower fractions of blood samples were analyzed for platelet count, mean platelet volume (MPV), immature platelet fraction (IPF), and high-fluorescence IPF (H-IPF). The mechanisms behind platelet flotation were explored by further partitioning of the blood column, time-dependent measurements of platelet count and comparison with ESR. The structure and function of the platelets were assessed by electron microscopy (EM) and atomic force microscopy (AFM), and platelet aggregometry, respectively. Platelet antisedimentation is driven by density differences and facilitated by a size-exclusion mechanism caused by progressive erythrocyte sedimentation. The area under the curve (AUC) of the whole blood adenosine diphosphate (ADP) aggregation curves showed significant differences between the upper and lower samples (p < .005). AUC in the upper samples of 38% of healthy subjects exceeded the top of the normal range (53-122) suggesting that ascending platelets show an intensified ADP-induced aggregability ex vivo. H-IPF was significantly higher in the upper samples (p < .05). EM and AFM revealed that platelets in the upper samples were larger in volume and contained 1.6 times more alpha granules compared to platelets in the lower samples. Our results indicate that antisedimentation is able to differentiate platelet populations based on their structural and functional properties. Therefore, PAR may be a suitable laboratory parameter in various thromboinflammatory disorders.

It is less known that platelets do not sediment in response to gravitational force but float on the top of the blood column. This phenomenon is called antisedimentation, the rate of which, however, can be different, yet this feature has not been widely studied and used in clinical practice or diagnosis. We tested the idea that antisedimentation of platelets from venous blood samples can be a potential biomarker. We have found that platelet antisedimentation is driven by density differences and facilitated by a size-exclusion mechanism caused by progressive erythrocyte sedimentation and after 1-h upper and lower fractions develop. Interestingly, the aggregation curves showed significant differences between the upper and lower samples, suggesting that the ascending platelets show ex vivo hyperaggregability. Electron and atomic force microscopy revealed that platelets in the upper samples were larger in volume and contained more alpha granules than platelets in the lower samples. Subsequently, antisedimentation can be used to differentiate platelet populations based on their structural and functional properties; thus, it may be a promising biomarker for various thromboinflammatory disorders.

Impaired cerebrovascular reactivity correlates with reduced retinal vessel density in patients with carotid artery stenosis: Cross-sectional, single center study.

BACKGROUND: The cerebral and retinal circulation systems are developmentally, anatomically, and physiologically interconnected. Thus, we hypothesized that hypoperfusion due to atherosclerotic stenosis of the internal carotid artery (ICA) can result in disturbances of both cerebral and retinal microcirculations. We aimed to characterize parameters indicating cerebrovascular reactivity (CVR) and retinal microvascular density in patients with ICA stenosis, and assess if there is correlation between them. METHODS: In this cross-sectional study the middle cerebral artery (MCA) blood flow velocity was measured by transcranial Doppler (TCD) and, simultaneously, continuous non-invasive arterial blood pressure measurement was performed on the radial artery by applanation tonometry. CVR was assessed based on the response to the common carotid artery compression (CCC) test. The transient hyperemic response ratio (THRR) and cerebral arterial resistance transient hyperemic response ratio (CAR-THRR) were calculated. Optical coherence tomography angiography (OCTA) was used to determine vessel density (VD) on the papilla whole image for all (VDP-WIall) and for small vessels (VDP-WIsmall). The same was done in the peripapillary region: all (VDPPall), and small (VDPPsmall) vessels. The VD of superficial (VDMspf) and deep (VDMdeep) macula was also determined. Significance was accepted when p<0.05. RESULTS: Twenty-four ICA stenotic patients were evaluated. Both CVR and retinal VD were characterized. There was a significant, negative correlation between CAR-THRR (median = -0.40) and VDPPsmall vessels (median = 52%), as well as between VDPPall vessels (median = 58%), and similar correlation between CAR-THRR and VDP-WIsmall (median = 49.5%) and between VDP-WIall (median = 55%). CONCLUSION: The significant correlation between impaired cerebrovascular reactivity and retinal vessel density in patients with ICA stenosis suggests a common mechanism of action. We propose that the combined use of these diagnostic tools (TCD and OCTA) helps to better identify patients with increased ischemic or other cerebrovascular risks.

Assessment of cerebral autoregulatory function and inter-hemispheric blood flow in older adults with internal carotid artery stenosis using transcranial Doppler sonography-based measurement of transient hyperemic response after carotid artery compression.

Unhealthy vascular aging promotes atherogenesis, which may lead to significant internal carotid artery stenosis (CAS) in 5 to 7.5% of older adults. The pathogenic factors that promote accelerated vascular aging and CAS also affect the downstream portion of the cerebral microcirculation in these patients. Primary treatments of significant CAS are eversion endarterectomy or endarterectomy with patch plasty. Factors that determine adequate hemodynamic compensation and thereby the clinical consequences of CAS as well as medical and surgical complications of carotid reconstruction surgery likely involve the anatomy of the circle of Willis (CoW), the magnitude of compensatory inter-hemispheric blood flow, and the effectiveness of cerebral microcirculatory blood flow autoregulation. This study aimed to test two hypotheses based on this theory. First, we hypothesized that patients with symptomatic and asymptomatic CAS would exhibit differences in autoregulatory function and inter-hemispheric blood flow. Second, we predicted that anatomically compromised CoW would associate with impaired inter-hemispheric blood flow compensation. We enrolled older adults with symptomatic or asymptomatic internal CAS (>70% NASCET criteria; n = 46) and assessed CoW integrity by CT angiography. We evaluated transient hyperemic responses in the middle cerebral arteries (MCA) after common carotid artery compression (CCC; 10 s) by transcranial Doppler sonography (TCD). We compared parameters reflecting autoregulatory function (e.g., transient hyperemic response ratio [THRR], return to baseline time [RTB], changes of vascular resistance) and inter-hemispheric blood flow (residual blood flow velocity). Our findings revealed that CAS was associated with impaired cerebral vascular reactivity. However, we did not observe significant differences in autoregulatory function or inter-hemispheric blood flow between patients with symptomatic and asymptomatic CAS. Moreover, anatomically compromised CoW did not significantly affect these parameters. Notably, we observed an inverse correlation between RTB and THRR, and 49% of CAS patients exhibited a delayed THRR, which associated with decreased inter-hemispheric blood flow. Future studies should investigate how TCD-based evaluation of autoregulatory function and inter-hemispheric blood flow can be used to optimize surgical techniques and patient selection for internal carotid artery revascularization.

Covid-19 vaccines elicit effective IgG responses in an elderly thymus cancer patient with chemotherapy.

The rising need for repeated booster vaccinations against SARS-CoV-2 infections raises the question of whether chronic immunosuppressive chemotherapies influence the efficacy of vaccination. Here, we present the case of a 70-year-old post-thymoma surgery patient who received Vepesid (etoposide, Xediton Pharmaceuticals Inc) chemotherapy for six months before vaccination with Comirnaty (Pfizer-BioNTech COVID-19 mRNA Vaccine). The first two vaccinations elicited only minimal increases of IgG antibodies specific against the receptor-binding domain (RBD) on the spike protein (S1), while the third vaccination was effective in providing high, slowly subsiding antibody titers over a 7-month period. The patient also developed a cellular immune response after the third vaccination. Also, measuring of anti-polyethylene glycol (PEG) IgM titers before and after vaccinations showed no immunogenicity for PEG. Later, a single dose of Sinopharm (China National Pharmaceutical Group) inactivated virus-type vaccine was administered, which also modestly increased the level of IgG. A symptomless COVID-19 infection, however, greatly increased the serum level of anti-RBD IgG, which later subsided. This case confirms that an effective immune response can be achieved with a series of COVID-19 vaccinations despite cytostatic treatment in an old thymus cancer surviving patient in the absence of adverse reactions.

Morphological and Functional Remodeling of the Ischemic Heart Correlates with Homocysteine Levels.

BACKGROUND: Homocysteine (Hcy) is involved in various methylation processes, and its plasma level is increased in cardiac ischemia. Thus, we hypothesized that levels of homocysteine correlate with the morphological and functional remodeling of ischemic hearts. Thus, we aimed to measure the Hcy levels in the plasma and pericardial fluid (PF) and correlate them with morphological and functional changes in the ischemic hearts of humans. METHODS: Concentration of total homocysteine (tHcy) and cardiac troponin-I (cTn-I) of plasma and PF were measured in patients undergoing coronary artery bypass graft (CABG) surgery (n = 14). Left-ventricular (LV) end-diastolic diameter (LVED), LV end-systolic diameter (LVES), right atrial, left atrial (LA) area, thickness of interventricular septum (IVS) and posterior wall, LV ejection fraction (LVEF), and right ventricular outflow tract end-diastolic area (RVOT EDA) of CABG and non-cardiac patients (NCP; n = 10) were determined by echocardiography, and LV mass was calculated (cLVM). RESULTS: Positive correlations were found between Hcy levels of plasma and PF, tHcy levels and LVED, LVES and LA, and an inverse correlation was found between tHcy levels and LVEF. cLVM, IVS, and RVOT EDA were higher in CABG with elevated tHcy (>12 µM/L) compared to NCP. In addition, we found a higher cTn-I level in the PF compared to the plasma of CABG patients (0.08 ± 0.02 vs. 0.01 ± 0.003 ng/mL, p < 0.001), which was ~10 fold higher than the normal level. CONCLUSIONS: We propose that homocysteine is an important cardiac biomarker and may have an important role in the development of cardiac remodeling and dysfunction in chronic myocardial ischemia in humans.

Optimal Renal Artery-Aorta Angulation Revealed by Flow Simulation.

INTRODUCTION: In the circulatory system, the vessel branching angle may have hemodynamic consequences. We hypothesized that there is a hemodynamically optimal range for the renal artery's branching angle. METHODS: Data on the posttransplant kinetics of estimated glomerular filtration rate (eGFR) were analyzed according to the donor and implant sides (right-to-right and left-to-right position; n = 46). The renal artery branching angle from the aorta of a randomly selected population was measured using an X-ray angiogram (n = 44). Computational fluid dynamics simulation was used to elucidate the hemodynamic effects of angulation. RESULTS AND DISCUSSION: Renal transplant patients receiving a right donor kidney to the right side showed faster adaptation and higher eGFR values than those receiving a left donor kidney to the right side (eGFR: 65 ± 7 vs. 56 ± 6 mL/min/1.73 m2; p < 0.01). The average branching angle on the left side was 78° and that on the right side was 66°. Simulation results showed that the pressure, volume flow, and velocity were relatively constant between 58° and 88°, indicating that this range is optimal for the kidneys. The turbulent kinetic energy does not change significantly between 58° and 78°. CONCLUSION: The results suggest that there is an optimal range for the renal artery's branching angle from the aorta where hemodynamic vulnerability caused by the degree of angulation is the lowest, which should be considered during kidney transplantations.

Upregulation of exofacial peroxiredoxin-thioredoxin system of lymphocytes and monocytes in preeclampsia.

OBJECTIVES: An imbalanced redox homeostasis resulting in oxidative stress is present in preeclampsia. Peroxiredoxin-1 (PRDX1) and thioredoxin-1 (TRX1) regulatory enzymes are also contributing to the redox homeostasis, but were not investigated so far in preeclampsia. Thus, we have aimed to characterize PRDX1, TRX1 and oxidative stress biomarkers in blood samples of pregnant women with preeclampsia. STUDY DESIGN: Twelve patients with preeclampsia (PE) were enrolled into the study. Seven third trimester healthy pregnant women (HP) were accepted as control group. MAIN OUTCOME MEASURES: Peripheral venous blood samples of healthy and preeclamptic pregnant women were analyzed. Plasma level of advanced oxidation protein products (AOPP) was determined by spectrophotometry. The exofacial PRDX1 and TRX1 expression of lymphocytes and monocytes was detected by flow cytometry. RESULTS: The plasma AOPP level was significantly higher in preeclampsia compared to the healthy pregnant group. Significantly higher percentage of PRDX1 and TRX1 expressing lymphocytes and monocytes were detected in the blood samples of preeclamptic women compared to healthy pregnant controls. The ratio of circulating PRDX1 and TRX1 expressing lymphocytes and monocytes showed a significant inverse correlation with the birth weight of newborns. CONCLUSIONS: We have revealed that the level of advanced oxidation protein products is increased and the exofacial peroxiredoxin-1 and thioredoxin-1 system in lymphocytes and monocytes is upregulated in preeclampsia. In addition, the ratio of peroxiredoxin-1 and thioredoxin-1 positive circulating lymphocytes and monocytes correlates inversely with the neonatal birth weight, which finding indicates that pregnancies complicated by intrauterine growth restriction are accompanied by a higher level of oxidative stress.

Presence of SARS-CoV-2 on the conjunctival mucosa in patients hospitalized due to COVID-19: Pathophysiological considerations and therapeutic implications.

Introduction: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a worldwide pandemic, due to its great capacity to invade the human body. Previous studies have shown that the primary route of invasion of this virus is the human respiratory tract via the co-expression of ACE2 receptor and TMPRSS2, a serine protease on the cellular surface. Interestingly, this condition is present not only on the respiratory epithelium but on the conjunctival mucosa, as well. Thus, we hypothesized that SARS-CoV-2 is present on the conjunctival mucosa. Aim: To prove that SARS-CoV-2 can be detected in the conjunctiva. Methods: Previously nasopharyngeal swab-sample based real-time polymerase chain reaction (PCR) positive COVID-19 infected patients were selected at the COVID Care Centers of Semmelweis University, Budapest, Hungary. The study was approved by the ethical committee of Semmelweis University. During their recovery, both nasopharyngeal and conjunctival swab-samples were taken and PCR method was used to detect the presence of SARS-CoV-2 RNA. Appropriate statistical analysis was performed. Results: The study population consisted of 97 patients, 49 females (50.5%) and 48 males (49.5%), with a mean age of 67.2 ± 11.9 years. During recovery, with nasopharyngeal swabs, the PCR test was positive in 55 cases (56.70%), whereas with conjunctival swabs it was positive in 8 cases (8.25%). Both tests were positive in 5 cases (5.15%). In some patients, ocular symptoms were observed as well. The rest of the patients (29 cases) had negative nasopharyngeal PCR tests during recovery. Conclusions: Although only in few cases, the data of the present study provides a proof of concept that SARS-CoV-2 can be present on the conjunctival mucosa even in nasopharyngeal negative patients, a finding, which can have clinical importance. Also, on the basis of these findings one can hypothesize that - in addition to the respiratory tract - the conjunctiva can be an entrance route for SARS-CoV-2 to the human body. Thus, in high-risk conditions, in addition to covering the mouth and nose with mask, the protection of the eyes is also strongly recommended.

Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults.

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young (n = 31, 11 female, 20 male, mean age: 28.4 + / - 4.2 years) and aged volunteers (n = 32, 18 female, 14 male, mean age: 67.9 + / - 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults.

Functional and structural adaptations of the coronary macro- and microvasculature to regular aerobic exercise by activation of physiological, cellular, and molecular mechanisms: ESC Working Group on Coronary Pathophysiology and Microcirculation position paper.

Regular aerobic exercise (RAEX) elicits several positive adaptations in all organs and tissues of the body, culminating in improved health and well-being. Indeed, in over half a century, many studies have shown the benefit of RAEX on cardiovascular outcome in terms of morbidity and mortality. RAEX elicits a wide range of functional and structural adaptations in the heart and its coronary circulation, all of which are to maintain optimal myocardial oxygen and nutritional supply during increased demand. Although there is no evidence suggesting that oxidative metabolism is limited by coronary blood flow (CBF) rate in the normal heart even during maximal exercise, increased CBF and capillary exchange capacities have been reported. Adaptations of coronary macro- and microvessels include outward remodelling of epicardial coronary arteries, increased coronary arteriolar size and density, and increased capillary surface area. In addition, there are adjustments in the neural and endothelial regulation of coronary macrovascular tone. Similarly, there are several adaptations at the level of microcirculation, including enhanced (such as nitric oxide mediated) smooth muscle-dependent pressure-induced myogenic constriction and upregulated endothelium-dependent/shear-stress-induced dilation, increasing the range of diameter change. Alterations in the signalling interaction between coronary vessels and cardiac metabolism have also been described. At the molecular and cellular level, ion channels are key players in the local coronary vascular adaptations to RAEX, with enhanced activation of influx of Ca2+ contributing to the increased myogenic tone (via voltage-gated Ca2+ channels) as well as the enhanced endothelium-dependent dilation (via TRPV4 channels). Finally, RAEX elicits a number of beneficial effects on several haemorheological variables that may further improve CBF and myocardial oxygen delivery and nutrient exchange in the microcirculation by stabilizing and extending the range and further optimizing the regulation of myocardial blood flow during exercise. These adaptations also act to prevent and/or delay the development of coronary and cardiac diseases.

Platelet-derived extracellular vesicles may contribute to the hypercoagulable state in preeclampsia.

It has previously been shown that preeclampsia is associated with disturbed hemostasis and that extracellular vesicles (EVs) play important role in the regulation of hemostatic homeostasis. Thus, we hypothesized that the altered procoagulant characteristics of circulating platelet-derived EVs may contribute to the disturbed hemostasis in preeclampsia. Using multicolor flow cytometry, we have analyzed both tissue factor expressing procoagulant EVs and platelet-derived EV subpopulations derived from resting and activated thrombocytes by examining them in plasma samples of preeclamptic patients and pregnancy-matched healthy individuals. Compared to pregnancy-matched healthy individuals in preeclamptic patients a significantly (p < 0.05) higher ratio of Annexin-V positive activated platelets and a higher number of CD142+ tissue factor bearing procoagulant EVs were found, whereas the absolute amount of circulating CD41a+ platelet-derived EVs and CD62P+/CD41a+ EVs produced by activated thrombocytes was significantly lower in the plasma of preeclamptic women. In the plasma samples, there was no significant difference in the amount of CD63+ platelet-derived EVs. We propose that increased platelet activation and tissue factor expression of platelet derived extracellular vesicles may contribute to the hypercoagulable state observed in preeclampsia.

Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation.

(1) Background: Traumatic brain injury (TBI) frequently occurs worldwide, resulting in high morbidity and mortality. Here, we hypothesized that TBI impairs an autoregulatory mechanism, namely the flow-induced constriction of isolated rat middle cerebral arteries (MCAs). (2) Methods: TBI was induced in anaesthetized rats by weight drop model, and then MCAs were isolated and transferred into a pressure-flow chamber. The internal diameter was measured by a video-microscopy. (3) Results: In MCAs from intact rats, increases in flow and pressure + flow elicited constrictions (-26 ± 1.9 µm and -52 ± 2.8 µm, p < 0.05), which were significantly reduced after TBI or in the presence of thromboxane-prostanoid (TP receptor) antagonist SQ 29,548. Flow-induced constrictions were significantly reduced by HET0016, inhibitor of cytochrome P450 4A (CYP450 4A). Arachidonic acid, (AA, 10-7 M), and CYP-450 4A metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) elicited constrictions of intact MCA (-26 ± 2.3% and -31 ± 3.6%), which were significantly reduced after TBI (to 11 ± 1.3% and -16 ±2.5%). The TP receptor agonist U46619 (10-7 M) elicited substantial constrictions of MCA from intact rats (-21 ± 3.3%), which were also significantly reduced, after TBI (to -16 ± 2.4%). (4) Conclusions: Flow-induced constrictor response of MCA is impaired by traumatic brain injury, likely due to the reduced ability of cytochrome P450 4A to convert arachidonic acid to constrictor prostaglandins and the mitigated sensitivity of thromboxane-prostanoid receptors.

Angiotensin II type 1 receptor is involved in flow-induced vasomotor responses of isolated middle cerebral arteries: role of oxidative stress.

This study aimed to determine the mechanosensing role of angiotensin II type 1 receptor (AT1R) in flow-induced dilation (FID) and oxidative stress production in middle cerebral arteries (MCA) of Sprague-Dawley rats. Eleven-week old, healthy male Sprague-Dawley rats on a standard diet were given the AT1R blocker losartan (1 mg/mL) in drinking water (losartan group) or tap water (control group) ad libitum for 7 days. Blockade of AT1R attenuated FID and acetylcholine-induced dilation was compared with control group. Nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) and cyclooxygenase inhibitor indomethacin (Indo) significantly reduced FID in control group. The attenuated FID in losartan group was further reduced by Indo only at Δ100 mmHg, whereas l-NAME had no effect. In losartan group, Tempol (a superoxide scavenger) restored dilatation, whereas Tempol + l-NAME together significantly reduced FID compared with restored dilatation with Tempol alone. Direct fluorescence measurements of NO and reactive oxygen species (ROS) production in MCA, in no-flow conditions revealed significantly reduced vascular NO levels with AT1R blockade compared with control group, whereas in flow condition increased the NO and ROS production in losartan group and had no effect in the control group. In losartan group, Tempol decreased ROS production in both no-flow and flow conditions. AT1R blockade elicited increased serum concentrations of ANG II, 8-iso-PGF2α, and TBARS, and decreased antioxidant enzyme activity (SOD and CAT). These results suggest that in small isolated cerebral arteries: 1) AT1 receptor maintains dilations in physiological conditions; 2) AT1R blockade leads to increased vascular and systemic oxidative stress, which underlies impaired FID.NEW & NOTEWORTHY The AT1R blockade impaired the endothelium-dependent, both flow- and acetylcholine-induced dilations of MCA by decreasing vascular NO production and increasing the level of vascular and systemic oxidative stress, whereas it mildly influenced the vascular wall inflammatory phenotype, but had no effect on the systemic inflammatory response. Our data provide functional and molecular evidence for an important role of AT1 receptor activation in physiological conditions, suggesting that AT1 receptors have multiple biological functions.