Microvascular Disorders Research Articles

К вопросу об осложнениях сахарного диабета: систематический обзор литературы

INTRODUCTION. The article presents an overview of the trigger role of diabetes mellitus in the development of periodontal pathology in patients aged 40-70 years. During the analytical systematic review, the emphasis was placed on the currently studied issues related to the characteristics of the clinic, glycemic status and risks of a complicated course, including with regard to microvascular, neurological and other disorders. The focus is on the dental status and glycemic profile of patients with diabetes mellitus and its role in regulating the adaptive potential of patients with diabetes mellitus. AIM. To assess the risks of diabetes in the regulation of periodontal pathology and other most significant complications. MATERIAL AND METHODS. the search was conducted in the database on evidence-based physiotherapy (PEDro), by keywords: "diabetes mellitus", "rehabilitation", "microvascular and other complications", "periodontal pathology" from 2000 to 2024. A total of 284 sources were selected as of March 2024, of which 26 were systematic reviews, 9 were Cochrane reviews, 17 – Clinical recommendations (American Association for Diabetes Mellitus), as well as Clinical recommendations for diabetes mellitus (70.5%). The search was conducted in the sources Web of Science, PubMed and Scopus in accordance with the principles of PRISMA and initially revealed 185 entries. Of these, 40 articles were included in the 2013-2024 publication study. Keywords were used: "periodontal pathology", "diabetes mellitus", "rehabilitation", "microvascular and other complications". RESULTS: the analysis of the collected Russian and foreign literature allowed us to summarize that in the treatment of patients with type 2 diabetes with periodontal pathology, the participation of specialists (endocrinologist, dentist, rehabilitologist, hygienist, neurologist) of a multidisciplinary team is necessary to compile an optimal rehabilitation program aimed at preventing the occurrence of complications and their progression, to achieve a speedy and complete restoration of lost dental functions and reduce glycemic risks. CONCLUSION. A personalized approach, individually selected therapies with an assessment of the dental status and glycemic profile in patients with diabetes mellitus and periodontal pathology will help to achieve the best results in recovery and elimination of complications. KEYWORDS: diabetes mellitus patients, dental status, glycemic profile, microvascular, neurological disorders

The Association between the Severity of Distal Sensorimotor Polyneuropathy and Increased Carotid Atherosclerosis in Individuals with Type 2 Diabetes.

Diabetes contributes to a spectrum of complications encompassing microvascular and macrovascular disorders. This study aimed to explore the correlation between distal sensorimotor polyneuropathy (DSPN) severity and heightened carotid atherosclerosis among individuals with type 2 diabetes mellitus (T2DM). Method: Participants underwent comprehensive assessments including nerve conduction studies (NCS), Toronto Clinical Neuropathy Score (TCNS) evaluations, assessment of cardiometabolic risk factors, and carotid sonography studies covering dynamic and morphological parameters. The resistance index (RI), pulsatility index (PI), peak systolic velocity (PSV), and end-diastolic velocity (EDV) in both the common carotid artery (CCA) and internal carotid artery (ICA), carotid intima-media thickness (IMT), and carotid plaque score (CPS) were also measured. Peripheral nerve function severity was assessed using composite amplitude scores (CAS) derived from NCS. Individuals with DSPN exhibited lower EDV in the CCA and ICA (p < 0.0001 and p = 0.002), higher PI and RI in both CCA and ICA (all p < 0.0001), and higher CPS (p = 0.002). They also demonstrated a higher prevalence of retinopathy as an underlying condition, higher index HbA1c, and reduced estimated glomerular filtration rate (eGFR) (all p < 0.0001). Multiple linear regression analysis revealed significant associations where eGFR, ICA-PI, index HbA1c, waist circumference, and age were correlated with CAS. Meanwhile, diabetes duration, waist circumference, age, and index HbA1c showed significant associations with TCNS. Our study suggests that individuals with T2DM who exhibit more severe carotid atherosclerosis may not only be at increased risk of developing DSPN but also may experience greater severity of DSPN. PI in both the CCA and ICA, along with the CPS, serve as surrogate biomarkers for DSPN severity.

Microvascular plasticity in mouse stroke model recovery: Anatomy statistics, dynamics measured by longitudinal in vivo two-photon angiography, network vectorization.

This manuscript quantitatively investigates remodeling dynamics of the cortical microvascular network (thousands of connected capillaries) following photothrombotic ischemia (cubic millimeter volume, imaged weekly) using a novel in vivo two-photon angiography and high throughput vascular vectorization method. The results suggest distinct temporal patterns of cerebrovascular plasticity, with acute remodeling peaking at one week post-stroke. The network architecture then gradually stabilizes, returning to a new steady state after four weeks. These findings align with previous literature on neuronal plasticity, highlighting the correlation between neuronal and neurovascular remodeling. Quantitative analysis of neurovascular networks using length- and strand-based statistical measures reveals intricate changes in network anatomy and topology. The distance and strand-length statistics show significant alterations, with a peak of plasticity observed at one week post-stroke, followed by a gradual return to baseline. The orientation statistic plasticity peaks at two weeks, gradually approaching the (conserved across subjects) stroke signature. The underlying mechanism of the vascular response (angiogenesis vs. tissue deformation), however, is yet unexplored. Overall, the combination of chronic two-photon angiography, vascular vectorization, reconstruction/visualization, and statistical analysis enables both qualitative and quantitative assessments of neurovascular remodeling dynamics, demonstrating a method for investigating cortical microvascular network disorders and the therapeutic modes of action thereof.

Potential Screening, Grading and Follow-Up of Diabetic Retinopathy in Primary Care Using Artificial Intelligence – How Hard Would It Be to Implement? An Ophthalmologist’s Perspective

Diabetic retinopathy (DR) is a microvascular disorder caused by the long-term effects of diabetes mellitus and among the primary causes of blindness worldwide. Early detection of DR is the key to its effective treatment and subsequent reduction of associated economic burden, but manual screening is time-consuming and of limited availability. A highly sensitive and specific automatic diagnostic tool would significantly improve screening programs and allow referring for further evaluation and treatment in an ophthalmology clinic only patients with significant lesions or with changes between two successive evaluations. Several deep learning-based automated diagnosis tools have been proposed to aid screening but their implementation with minimal costs is not accessible to physicians with no coding knowledge. We aimed to develop a fundus images classification model with no coding knowledge by using generative artificial intelligence (AI) implemented in Windows 11 operating system under subscription (Copilot Pro), a free image analysis tool (Fiji ImageJ2), and Vertex AI, a machine learning (ML) platform launched by Google in 2021. For this purpose, we selected a total of 2961 labelled cases from the APTOS 2019 database of DR fundus images. Images were batch segmented using a Java ImageJ script generated by Copilot Pro and based on the Contrast Limited Adaptive Histogram Equalization (CLAHE) algorithm. Segmented images were used to train an automated ML classification model to detect DR severity (5 classes – no DR, mild non-proliferative DR, moderate DR, severe DR, proliferative DR). The model achieved an area under the precision-recall curve of 0.889, with a precision rate of 83.8% and a recall rate of 77%. In conclusion, generative AI implemented into Windows operating system together with a free imaging processing tool and Vertex AI allow ophthalmologists with no coding knowledge to benefit from publicly available image databases (thousands of cases) to develop accurate automated diagnostic tools. Such tools have the potential to facilitate screening especially in areas with few specialists.

Relationship between Serum Zinc Level and Retinopathy in Type 2 Diabetic Patients

Abstract Background Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia caused by insulin resistance (IR) or impaired insulin production. Diabetic retinopathy (DR) is a common microvascular disorder which occurs in type 2 diabetes mellitus (T2DM) patients due to chronic hyperglycemia. Previous studies reported that serum zinc (Zn) was associated with certain diabetic microvascular complications. Objective To evaluate relation between serum zinc level and diabetic retinopathy in patients with type 2 diabetes mellitus. Subjects and Methods The current study included 60 subjects with their ages ranging from 18- 60, selected from diabetes and ophthalmology outpatient clinics of Ain Shams University Hospitals for 7 months in a period from July 2022 to January 2023 with matched age and sex . fasting and post prandial blood glucose, hemoglobin A1c (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DBP),serum creatnine, LDL, HDL, TG,TC and serum zinc levels were measured among groups. Results The study shows statistically significant difference between DM type II subgroups regarding duration of disease (yrs) being higher in DM II with retinopathy 12.5 (10.5 – 16.5) than DM II without retinopathy 9 (6 – 12) with p &amp;lt; 0.001. serum Zn levels were significantly lower in the DR group than the controls and diabetic without retinopathy.in whole DM type II group, there was statistically significant negative correlation found between zinc level and duration of diabetes, HbA1c, LDL, TC, FBS, 2PP and serum creatinine level, while in DM II without retinopathy there was statistically significant negative correlation found between zinc level and duration of diabetes, LDL, TC and FBS and also in DM type II retinopathy there was statistically significant negative correlation found between zinc level and duration of diabetes, HbA1c, FBS, 2PP and serum cretainine level .There is no statistically significant difference found between control group and DM type II group regarding weight, height and BMI of the studied patients with p-value = 0.108, 0.198 and 0.343; respectively. There is no statistically significant difference found between control group and DM type II group regarding systolic and diastolic blood pressure of the studied patients with p- value = 0.554 and 0.405; respectively. Conclusion Our study suggested that lower serum zinc level in T2D patients was related to higher prevalence of diabetic microvascular complications. Patients with lower serum zinc level were more likely to have a longer duration of diabetes, poorer glucose control, and worse β-cell function. Older age, higher HbA1c level, and the prevalence of DN were risk factors related to the lower serum zinc level.

The association of microvascular disease and endothelial dysfunction with vertebral trabecular bone mineral density : The MESA study.

Microvascular diseases of the eye, kidney, and brain are associated with endothelial dysfunction and increased hip fracture risk. To explore the basis for higher hip fracture risk, we comprehensively examined whether markers of microvascular disease and/or endothelial dysfunction are related to trabecular bone mineral density (BMD), a proximate risk factor for osteoporotic fractures. Among 6814 participants in the Multi-Ethnic Study of Atherosclerosis study (MESA), we derived thoracic vertebral trabecular BMD from computed tomography of the chest and measured urine albumin to creatinine ratios (UACR), retinal arteriolar and venular widths, flow mediated dilation (FMD) of the brachial artery after 5min of ischemia; and levels of five soluble endothelial adhesion markers (ICAM-1, VCAM-1, L-selectin, P-selectin, and E-selectin). Linear regression models were used to examine the association of trabecular BMD with markers of microvascular disease and with markers of endothelial dysfunction. We observed no significant associations of UACR, retinal arteriolar or venular widths, or FMD with BMD. We also observed no statistically significant association of spine trabecular BMD with levels of endothelial adhesion markers. Men and women had largely similar results. We conclude that there is little evidence to connect thoracic spine trabecular BMD to microvascular disorders or to endothelial dysfunction among multi-ethnic middle-aged and older adults. Other factors beyond trabecular BMD (e.g., bone quality or predisposition to falling) may be responsible for the associations of microvascular disease with osteoporotic fractures.

#1189 Сorrelations between laser doppler flowmetry spectral indicators and glycated hemoglobin level in patients with diabetic nephropathy

Abstract Background and Aims Diabetic microangiopathy is a specific vascular complication of diabetes mellitus type 2, which matters to patients' mortality and individual prognosis. Therefore, an important problem is the development of non-invasive methods for the diagnosis of diabetic microangiopathy, such as laser Doppler flowmetry (LDF). This work aimed to analyze some correlations between LDF spectral indicators and the level of glycated hemoglobin in patients with chronic kidney disease and type 2 diabetes. Method The study included 55 patients (26 men and 29 women) with type 2 diabetes mellitus. The age of patients was 58-77 years. The duration of diabetes was more than 5 years. All patients had chronic kidney disease (stage C3-C4) caused by diabetic nephropathy. For Laser Doppler flowmetry we used the “LDF 100C” system (“Biopac Instruments”, USA). Each patient had a 10-minute LDF registration on the skin of the rear of the foot. Using the special software, we have assessed slow, respiratory and pulse flux motion contribution and flux motion index. The next step was a correlation analysis with the glycated hemoglobin level. Results There were several correlations of the spectral LDF indicators with the level of glycated hemoglobin (Table 1). Thus, a negative correlation with the level of glycated hemoglobin was observed for the flux motion index (p=0.04) and the contribution of slow flux motion (p=0.03). On the contrary, for the contribution of pulse flux motion, there was detected a positive correlation with the level of glycated hemoglobin (p&amp;lt;0.01) (Fig. 1). Conclusion Correlations of LDF indicators with the level of glycated hemoglobin can be explained with the correlation of the diabetic microangiopathy progression with the effectiveness of glycemic control. Hyperglycemia is a key pathogenic factor of type 2 diabetes mellitus and its complications. Consequently, in patients with ineffective or less effective glycemic control, a more significant development of diabetic microangiopathy should be expected. An increase in the contribution of pulse flux motion in the laser Doppler flowmetry use guidelines is regarded as an increase in the role of the pulse wave in microcirculatory blood flow modulation. The cause of the latter is most likely a more intensive remodeling of the walls of arterioles against the background of a higher frequency of hyperglycemia episodes. The negative correlation of the contribution of slow flux motion can be explained by a violation of the local mechanisms of microcirculation modulation. The cause of this disorder is the morphofunctional restructuring of the microvessels themselves, the defeat of smooth myocytes in the wall of arterioles and venules, including pacemaker cells, with a violation of the automatic contractile activity of smooth myocytes, as well as endothelial. These factors lead to a shift in the balance of regulation towards systemic factors, which is reflected in the decrease of the flux motion index. A decrease in the flux motion index is regarded as a microcirculation deficiency, which was detected in all patients with type 2 diabetes mellitus. Thus, correlations of the spectral LDF indicators with the level of glycated hemoglobin corresponds to modern ideas about the pathogenesis of diabetic microangiopathy in type 2 diabetes mellitus. These data can be an additional argument in favor of the further development of improving laser Doppler flowmetry using for the tasks of non-invasive diagnosis of microvascular disorders in patients with type 2 diabetes mellitus. The reported study was funded by RFBR, project number 19-315-90080.

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1

Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.

Machine learning techniques for predicting microvascular network hemodynamics

Existing techniques to image microvascular networks in vivo do not allow a direct and accurate measurement of several hemodynamic variables such as the wall shear stress (WSS). They cannot also provide a full 3D characterization of blood velocity and red blood cell (RBC) concentration profiles in every vessel in a microvascular network. Such physiological parameters however play critical roles in blood flow regulation, disease progression, angiogenesis, and hemostasis. Theoretical models of network blood flow, often used for hemodynamic predictions in experimentally acquired images of the microvascular network, cannot provide the full 3D blood velocity, RBC concentration and WSS profiles as these models assume one-dimensional flow governed by Poiseuille’s law. In contrast, high-fidelity computational models that simulate flow of blood as a suspension of deformable RBCs and model the 3D vessel geometry can readily predict such physiological variables with high accuracy. Such high-fidelity computational models have recently been applied to predict hemodynamic variables in microvascular networks in silico composed of many vessels and vascular junctions. Such models, however, tend to become computationally expensive with increasing size of the network; therefore, they are not feasible for use in large networks at organ scale. To overcome this limitation, we developed a machine learning (ML) approach that can predict hemodynamic variables in 3D and with high accuracy. The ML models are based on artificial neural network and convolution-based U-net models. Using experimentally acquired images of the microvascular networks, inputs at a few inlets, and a “bank” of database that we have developed, these ML models can predict flow and RBC distribution in all vessels in the network, 3D blood velocity and RBC concentration profiles over the cross-section of every vessel, 3D WSS profiles, and time-dependent variations in blood flow in any vessel. The prediction from the ML models compare very well against the true data. Also, the prediction time using ML is significantly less than that of the high-fidelity models. The current ML models, which to our knowledge are the first of their kind, are highly promising for image-based predictions of sub-cellular resolved capillary hemodynamics in organ-scale networks. This study paves the way for AI to make hemodynamic predictions in organ-scale capillary vessel networks while retaining the sub-cellular scale details and overcoming the limitations of the in vivo imaging techniques, with potential applications in hematological and microvascular disorders, angiogenesis, and vascular-mediated drug delivery. Funded by NIH (R01-EY033003) and NSF (CBET 2302212). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evaluating the Effect of Childhood Obesity on Choroidal Structures

Aim: To evaluate the effect of childhood obesity on choroidal structures with spectral-domain optical coherence tomography (SD-OCT). Material and Methods: A total of 80 children (20 children per each group; healthy, overweight, obese, and morbid-obese) were included in the study. Accompanying comorbidities such as insulin resistance, dyslipidemia, and metabolic syndrome were recorded. The subfoveal choroidal thickness (SFCT) and choroidal vascularity index (CVI) measurements were obtained from SD-OCT images and compared between groups. Results: No notable differences were found between groups regarding the means of age and axial length (p=0.504, and p=0.805, respectively). The SFCT medians (min-max) of healthy, overweight, obese, and morbid-obese children were 398.5 (319.0-453.5) μm, 299.0 (274.7-387.0) μm, 295.5 (257.0-385.0) μm, and 304.5 (272.2-386.0) μm respectively. Overweight and obese children had thinner choroid than non-obese healthy children (p=0.032). Besides, no significant correlation was observed between the severity of obesity and SFCT (p=0.722). In terms of CVI, total choroidal area, luminal area, and stromal area; no significant differences were found between groups (p=0.710, p=0.452, p=0.221, and p=0.863, respectively). Obese children with dyslipidemia had thinner SFCT than those not have dyslipidemia (292.0 (166-431)μm vs 348.0(173-491)μm, p=0.003), while insulin resistance and metabolic syndrome had no effect on SFCT (p=0.336, and p=0.211, respectively). Conclusion: Childhood obesity and accompanying dyslipidemia led to a decrease in SFCT without any significant change in the CVI. However, the severity of obesity and having insulin resistance or metabolic syndrome had no effect on either SFCT or CVI. The thinning in the SFCT may be related to microvascular disorders due to childhood obesity and dyslipidemia

Risk factors for diabetic retinopathy: a case-control study

Purpose To emphasize the severity of the issue, it is crucial to recognize that diabetic retinopathy (DR) is not only the biggest contributor to blindness in India, but it is also becoming increasingly prevalent with each passing day. This study offers information from a matched case-control study conducted in an Indian tertiary care hospital on several risk factors for DR. The objective of the investigation is to identify the primary diabetes mellitus (DM) risk factors and the amount by which they influence diabetes pathogenesis. Methods The outpatient and inpatient departments participated in a matched research study. Diabetics with DR were included among the patients, while diabetics without DR were included in the controls. Before performing structured interviews, a total of 252 people (126 cases and 126 controls) were recruited and matched for age (±2 years) and sex. Results The average age in the DR and non-DR categories was 63.7 9.5 years and 63.3 10.4 years, respectively. Smoke (OR=1.92, P=0.02), alcoholism (OR=2.62, P=0.03), a poor diet (OR=2.72, P=0.0008), nonadherence to dietary advice (OR=4.41, P=0.0001), other microvascular disorders (OR=3.79, P=0.0001), dyslipidaemia (OR=1.85, P=0.0), and hypertension (OR=5.91, P=0.0001). Drug abnormalities (adjusted odds ratio (AOR)=7.89, P=0.0001) and hypertension (AOR=1.16, P=0.0001) were indicated as risk factors for the development of DR in multivariate regression research. Conclusion According to our findings, DM with inconsistent anti-diabetic drug use and hypertension are more likely to acquire DR. Modifiable risk factors for DR include insulin, physical inactivity, dyslipidemia, alcoholism, and smoking. With the increasing frequency of DR educating DM about lifestyle changes that may minimize their risk of developing DR is more critical than ever.

TGF-β Signaling Pathways in the Development of Diabetic Retinopathy.

Diabetic retinopathy (DR), a prevalent complication of diabetes mellitus affecting a significant portion of the global population, has long been viewed primarily as a microvascular disorder. However, emerging evidence suggests that it should be redefined as a neurovascular disease with multifaceted pathogenesis rooted in oxidative stress and advanced glycation end products. The transforming growth factor-β (TGF-β) signaling family has emerged as a major contributor to DR pathogenesis due to its pivotal role in retinal vascular homeostasis, endothelial cell barrier function, and pericyte differentiation. However, the precise roles of TGF-β signaling in DR remain incompletely understood, with conflicting reports on its impact in different stages of the disease. Additionally, the BMP subfamily within the TGF-β superfamily introduces further complexity, with BMPs exhibiting both pro- and anti-angiogenic properties. Furthermore, TGF-β signaling extends beyond the vascular realm, encompassing immune regulation, neuronal survival, and maintenance. The intricate interactions between TGF-β and reactive oxygen species (ROS), non-coding RNAs, and inflammatory mediators have been implicated in the pathogenesis of DR. This review delves into the complex web of signaling pathways orchestrated by the TGF-β superfamily and their involvement in DR. A comprehensive understanding of these pathways may hold the key to developing targeted therapies to halt or mitigate the progression of DR and its devastating consequences.

GLYCOSYLATED HEMOGLOBIN HBA1C AS A BIOMARKER FOR DIABETIC RETINOPATHY

: Diabetes Mellitus (DM) is a long-term metabolic disorder marked by hyperglycemia. Diabetes may lead to various complications like retinopathy. Diabetic retinopathy is a microvascular disorder that may lead to vision loss. It was a hospital-based study to determine the prevalence of diabetic retinopathy in chronic diabetic patients. Patients who visited DHQ and Al Sheikh Hospital Sialkot with blurry or poor vision were taken as samples. The sample size for this study was 100. The demographic and medical history of patients were taken through a questionnaire. These patients were checked by an experienced ophthalmologist after the pupil dilation. After the proper examination, it was suggested that a patient have an HbA1c test to monitor diabetic control. The HbA1c test is one of the most effective techniques to monitor diabetic control. Out of the 100 patients, 60% were diagnosed with diabetic retinopathy. Out of these, 36% were diagnosed with non-proliferative diabetic retinopathy, and 24% were diagnosed with proliferative retinopathy. The results were quite alarming, as 60 out of 100 were suffering from diabetic retinopathy. This study provided the prevalence of diabetic retinopathy in the district of Sialkot. This study also helps to understand the severity of hyperglycemia that may lead to vision loss due to diabetic retinopathy.

Anti-Anginal Efficacy of Zibotentan in the Coronary Slow-Flow Phenomenon.

Patients with coronary microvascular disorders often experience recurrent angina for which there are limited evidence-based therapies. These patients have been found to exhibit increased plasma levels of endothelin; thus, selective endothelin-A (Et-A) receptor blockers such as zibotentan may be an effective anti-anginal therapy in these patients. The study evaluated the impact of a 10 mg daily dose of zibotentan on spontaneous angina episodes in patients with the coronary slow-flow phenomenon who had refractory angina (i.e., experiencing angina at least three times/week despite current anti-anginal therapy). Using a randomized, double-blind, placebo-controlled, crossover trial design with 4-week treatment periods, 18 patients (63.2 ± 9.9 years, 33% females) were recruited. The primary endpoint was angina frequency as measured by an angina diary, with secondary endpoints including nitrate consumption, angina duration/severity and the Seattle Angina Questionnaire (SAQ) domains. During the 4 weeks of therapy, angina frequency significantly improved with zibotentan therapy (placebo 41.4 (58.5) vs. zibotentan 29.2 (31.6), p < 0.05), and sublingual nitrate consumption significantly reduced (placebo 11.8 (15.2) vs. zibotentan 8.8 (12.9), p < 0.05. Zibotentan improved the frequency of spontaneous angina episodes and reduced sublingual nitrate consumption in patients unresponsive to standard anti-anginal therapy.

Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip

Diabetic retinopathy (DR) is a microvascular disorder characterized by inner blood-retinal barrier (iBRB) breakdown and irreversible vision loss. While the symptoms of DR are known, disease mechanisms including basement membrane thickening, pericyte dropout and capillary damage remain poorly understood and interventions to repair diseased iBRB microvascular networks have not been developed. In addition, current approaches using animal models and in vitro systems lack translatability and predictivity to finding new target pathways. Here, we develop a diabetic iBRB-on-a-chip that produces pathophysiological phenotypes and disease pathways in vitro that are representative of clinical diagnoses. We show that diabetic stimulation of the iBRB-on-a-chip mirrors DR features, including pericyte loss, vascular regression, ghost vessels, and production of pro-inflammatory factors. We also report transcriptomic data from diabetic iBRB microvascular networks that may reveal drug targets, and examine pericyte-endothelial cell stabilizing strategies. In summary, our model recapitulates key features of disease, and may inform future therapies for DR.

Lipid variability and risk of microvascular complications in patients with diabetes: a systematic review and meta-analysis

Background and aimsThe current systematic review aimed to elucidate the effects of lipid variability on microvascular complication risk in diabetic patients. The lipid components studied were as follows: High-density lipoprotein (HDL), High-density lipoprotein (LDL), Triglyceride (TG), Total Cholesterol (TC), and Remnant Cholesterol (RC).MethodWe carried out a systematic search in multiple databases, including PubMed, Web of Science, and SCOPUS, up to October 2nd, 2023. After omitting the duplicates, we screened the title and abstract of the studies. Next, we retrieved and reviewed the full text of the remaining articles and included the ones that met our inclusion criteria in the study.ResultIn this research, we examined seven studies, comprising six cohort studies and one cross-sectional study. This research was conducted in Hong Kong, China, Japan, Taiwan, Finland, and Italy. The publication years of these articles ranged from 2012 to 2022, and the duration of each study ranged from 5 to 14.3 years. The study group consisted of patients with type 2 diabetes aged between 45 and 84 years, with a diabetes history of 7 to 12 years. These studies have demonstrated that higher levels of LDL, HDL, and TG variability can have adverse effects on microvascular complications, especially nephropathy and neuropathic complications. TG and LDL variability were associated with the development of albuminuria and GFR decline.Additionally, reducing HDL levels showed a protective effect against microalbuminuria. However, other studies did not reveal an apparent relationship between lipid variations and microvascular complications, such as retinopathy. Current research lacks geographic and demographic diversity. Increased HDL, TG, and RC variability have been associated with several microvascular difficulties. Still, the pathogenic mechanism is not entirely known, and understanding how lipid variability affects microvascular disorders may lead to novel treatments. Furthermore, the current body of this research is restricted in its coverage. This field's lack of thorough investigations required a more extensive study and comprehensive effort.ConclusionThe relationship between lipid variation (LDL, HDL, and TG) (adverse effects) on microvascular complications, especially nephropathy and neuropathic (and maybe not retinopathy), is proven. Physicians and health policymakers should be highly vigilant to lipid variation in a general population.

The association between the severity of erectile dysfunction and left ventricular diastolic dysfunction in patients with and without cardiovascular disease.

Erectile dysfunction (ED) is considered a microvascular disorder and serves as an indicator for the potential development of cardiovascular disease (CVD). Although left ventricular diastolic dysfunction (LVDD) reflects early myocardial damage caused by microvascular disorders, the association between ED and LVDD remains poorly elucidated. A cross-sectional study was conducted on 123 patients with ED. They underwent RigiScan, and conventional echocardiography, and attempted International Index of Erectile Function (IIEF) questionnaire. ED severity was evaluated by measuring changes in the penile base circumference and duration of penile rigidity (≥70%) during erection. The early diastolic velocity of mitral inflow (E) and early diastolic velocity of the mitral annulus (e') were measured using echocardiography. The patients were grouped based on the presence of CVD. Among 123 patients, 29 had CVD and 94 did not. Patients with CVD exhibited more pronounced ED and more severe LVDD. Associations between increased penile circumference with echocardiographic parameters were more prominent in patients with CVD than in those without CVD (ΔTtop and e' wave, r=0.508 and r=0.282, respectively, p for interaction=0.033; ΔTbase and E/e' ratio, r=-0.338 and r=-0.293, respectively, p for interaction <0.001). In the multivariate linear regression, the increase of penile base circumference was an independent risk factor for LVDD (e', B=0.503; E/e' ratio, B=-1.416, respectively, p<0.001). ED severity correlated well with LV diastolic dysfunction, particularly in the presence of CVD. This study highlighted the potential role of ED assessment as early indicator of CVD development.

Myocardial Ischemia/Reperfusion Injury: Mechanism and Targeted Treatment for Ferroptosis.

Myocardial ischemia/reperfusion injury (MIRI) is a pathophysiological process connected to the onset of numerous heart disorders. The pathogenesis of MIRI is complex, and it mainly involves calcium overload, classic oxidative stress, mitochondrial disorder, inflammation, microvascular disorder, and cell death. The clinical treatment options for MIRI are presently constrained, making it imperative to develop new treatment modalities. Recent studies have demonstrated that ferroptosis is the main cause of MIRI. Ferroptosis is a new type of regulated iron-dependent cell death whose mechanism and targeted therapy are anticipated to be novel therapeutic techniques for MIRI. Herein, the primary mechanism underlying ferroptosis (the 3 major metabolic routes involving iron, amino acids, and lipids, and in MIRI, the specific mechanism and therapeutic target of ferroptosis) are discussed to determine the potential therapeutic approach for MIRI.

Анализ состояния микрососудистого русла и планирование реабилитационных мероприятий у детей после перенесенной новой коронавирусной инфекции

Aim: to analyze microcirculation in children who recovered from coronavirus disease 2019 (COVID-19) in order to identify microcirculatory disorders and their association with clinical symptoms and to design rehabilitation measures Patients and Methods: the study included 78 children aged 7–15 years who recovered from COVID-19. All children had negative SARS- CoV-2 RNA tests (oropharyngeal and naso-pharyngeal swabs) by PCR and positive blood SARS-CoV-2 immunoglobulin class G (IgG). The control group included 30 healthy age-matched children who did not experience COVID-19. Microcirculation was evaluated by slit lamp biomicroscopy for imaging bulbar conjunctival microvasculature with further morphometric processing of images. Exclusion criteria included inflammatory eye diseases, acute bronchopulmonary diseases or their exacerbation, arterial hy-pertension, and obesity grades 2 to 4. Results: a decrease in the count of capillaries, pre- and postcapillaries, and 1 st-order ar-terioles, as well as a decrease in the percentage of 1st-order arterioles were identified in indi-viduals who had been asymptomatic or had experienced mild COVID-19 symptoms 3 to 12 months prior. Additionally, an increase in the count of 1st-order venules and arteriolar venular anastomoses, 2nd-order arterioles and venules, and 1st-order arteries and veins was revealed. The coefficient of irregularity in venular caliber in severe cases of COVID-19 was 0.62±0.05, which was significantly (p&lt;0.023) greater than that in asymptomatic cases of COVID-19 (0.43±0.03). This indicates a persistent reduction in venous tone Conclusions: our study demonstrated microvascular disorders in children in the long-term period following COVID-19, indicating a long-term maladaptation of microcirculation These children can be classified as belonging to the risk group for microcirculatory disorders in the post- COVID period. KEYWORDS: children, COVID-19, long COVID, microvasculature, capillaries, venules, arterioles, microcirculation. FOR CITATION: Mikheeva I.G., Kurasova O.B., Milekhina M.Yu., Moiseev A.B., Kuznetsova N.I., Kalinovskaya I.I., Zimina N.A., Vereshchagina T.G. Study of microcirculation and the scheduling of rehabilitation measures in children who have recovered from coronavirus disease 2019. Russian Journal of Woman and Child Health. 2024;7(2):171–176 (in Russ.). DOI: 10.32364/2618-8430-2024-7-2-13.

MECHANISMS OF DEVELOPMENT AND MODERN DIRECTIONS OF TREATMENT OF DIABETIC RETINOPATHY (literature review)

Background. Despite the significant achievements in understanding the mechanisms of diabetic retinopathy (DR), the active search for new approaches and testing directions for its treatment continues today.&#x0D; Aim: To determine the current state of understanding of the mechanisms of development and directions of treatment of diabetic retinopathy.&#x0D; Materials and methods. An information search for the results of scientific research was conducted in the online databases PubMed, Web of Science, Scopus, and Google Scholar using keywords. The search depth is 10 years. The search was performed by two independent authors. 178 sources were selected for analysis, of which 53 that met the search criteria were used.&#x0D; Results. From a pathophysiological point of view, DR is a complex of progressive changes in the microcirculatory channel, which lead to ischemia, neovascularization, increased permeability of the hematoretinal barrier, and macular edema. At the same time, the predominantly inflammatory nature of the damage with a sluggish chronic course and damage to retinal neurons and microvascular disorders was established. The universal mechanism of DR can be considered oxidative stress, which connects all biochemical and molecular pathways induced by hyperglycemia. Important mechanisms are loss of pericytes, changes in gene expression, activation of signaling cascades Ras/Raf-1/MEK/ERK, p38-MAPK, endothelial dysfunction and recruitment of leukocytes and monocytes, activation of NF-κB, HIF-1 and VEGF pathways, activation of apoptosis and pyroptosis. Existing methods of DR treating require significant expansion with the use of targeted therapy aimed at specific pathogenetic pathways.&#x0D; Conclusion. The discovery of new mechanisms of DR and the search for new directions of targeted therapy is an urgent task of modern ophthalmology.