Arteriolar Wall Research Articles

In vivo biomarkers of arteriolosclerosis are associated with ADRD biomarkers

AbstractBackgroundBrain arteriolosclerosis, which involves thickening of the vessel wall and stenosis of arterioles, is one of the main pathologies of cerebral small vessel disease, and often co‐occurs with other pathology indicative of Alzheimer’s disease and related disorders (ADRD). A novel classifier of arteriolosclerosis, ARTS, was recently developed by the MarkVCID consortium for in vivo studies of arteriolosclerosis. We hypothesized that higher levels of arteriolosclerosis are associated with worse ADRD biomarker levels.Method109 participants from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core underwent clinical and cognitive evaluation, 3T brain MRI, and PiB (amyloid) PET (n=92). Participants were adjudicated by NIA‐AA criteria as having normal cognition (n=69), mild cognitive impairment (n=25), or dementia (n=15). Raw T1, FLAIR, and TOPUP and Eddy Current Corrected DTI images along with age and sex were inputs to a machine learning based classifier generating ARTS scores; higher ARTS indicates higher likelihood of arteriolosclerosis. For variables of interest, T1 MRI were processed (FreeSurfer v5.3) to calculate cortical gray matter (GM), hippocampal, and intracranial (ICV) volumes, and temporal meta‐ROI cortical thickness. White matter hyperintensity (WMH) volumes were calculated on FLAIR with LST in SPM12. NODDI were processed using AMICO to generate mean Free Water (FW) in hippocampus and global GM and white matter (WM). A set of AD‐sensitive cortical ROIs were used to extract mean PET SUVr signal. Separate multivariable general linear models (GLM) examined relationships between ARTS and variables of interest adjusted initially for age and total ICV (Table 1), and then again after adjusting for additional covariates (sex, race, education, APOE‐e4 carrier status, and clinical diagnosis).ResultAmong 109 participants (71±7 years, 60% women), ARTS ranged from ‐.80 to .29 (mean±SD = ‐.37±.20), suggesting a low overall likelihood of arteriolosclerosis in our sample. Higher ARTS was significantly associated with lower cortical thickness, higher WMH, higher WM FW, and greater amyloid deposition (Table 1). When adjusting for additional covariates, only amyloid no longer significantly associated with ARTS (p=0.19).ConclusionHigher ARTS scores are cross‐sectionally associated with other abnormalities in ADRD biomarkers. Future directions will examine the relationship between ARTS and Flortaucipir (tau) uptake.

In vivo biomarkers of arteriolosclerosis are associated with ADRD biomarkers

AbstractBackgroundBrain arteriolosclerosis, which involves thickening of the vessel wall and stenosis of arterioles, is one of the main pathologies of cerebral small vessel disease, and often co‐occurs with other pathology indicative of Alzheimer’s disease and related disorders (ADRD). A novel classifier of arteriolosclerosis, ARTS, was recently developed by the MarkVCID consortium for in vivo studies of arteriolosclerosis. We hypothesized that higher levels of arteriolosclerosis are associated with worse ADRD biomarker levels.Method109 participants from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core underwent clinical and cognitive evaluation, 3T brain MRI, and PiB (amyloid) PET (n=92). Participants were adjudicated by NIA‐AA criteria as having normal cognition (n=69), mild cognitive impairment (n=25), or dementia (n=15). Raw T1, FLAIR, and TOPUP and Eddy Current Corrected DTI images along with age and sex were inputs to a machine learning based classifier generating ARTS scores; higher ARTS indicates higher likelihood of arteriolosclerosis. For variables of interest, T1 MRI were processed (FreeSurfer v5.3) to calculate cortical gray matter (GM), hippocampal, and intracranial (ICV) volumes, and temporal meta‐ROI cortical thickness. White matter hyperintensity (WMH) volumes were calculated on FLAIR with LST in SPM12. NODDI were processed using AMICO to generate mean Free Water (FW) in hippocampus and global GM and white matter (WM). A set of AD‐sensitive cortical ROIs were used to extract mean PET SUVr signal. Separate multivariable general linear models (GLM) examined relationships between ARTS and variables of interest adjusted initially for age and total ICV (Table 1), and then again after adjusting for additional covariates (sex, race, education, APOE‐e4 carrier status, and clinical diagnosis).ResultAmong 109 participants (71±7 years, 60% women), ARTS ranged from ‐.80 to .29 (mean±SD = ‐.37±.20), suggesting a low overall likelihood of arteriolosclerosis in our sample. Higher ARTS was significantly associated with lower cortical thickness, higher WMH, higher WM FW, and greater amyloid deposition (Table 1). When adjusting for additional covariates, only amyloid no longer significantly associated with ARTS (p=0.19).ConclusionHigher ARTS scores are cross‐sectionally associated with other abnormalities in ADRD biomarkers. Future directions will examine the relationship between ARTS and Flortaucipir (tau) uptake.

The new landscape of differentially expression proteins in placenta tissues of gestational diabetes based on iTRAQ proteomics

IntroductionGestational diabetes mellitus (GDM) refers to abnormal glucose tolerance that occurs or is firstly diagnosed during pregnancy. GDM is related to various adverse pregnancy outcomes, but GDM pathogeny has not been fully elucidated. Nevertheless, previous studies have observed that many proteins in the placentas of patients with GDM are dysregulated. The present study aimed to establish a novel differentially expressed protein (DEP) landscape of GDM and normal maternal placentas and to explore the possible connection between DEPs and GDM pathogenesis. This study provides new insights into the mechanism of GDM and should make an important contribution to the development of biomarkers. MethodsThe morphological characteristics of the placenta were observed on 30 GDM and normal maternal placental tissues stained with haematoxylin and eosin. Isobaric tags for relative and absolute quantitation (iTRAQ) was used in the proteomics screening of the DEPs of the normal and GDM maternal placentas. Bioinformatics analysis was performed on the DEPs, and parallel reaction monitoring (PRM) was performed to verify the DEPs. Finally, the quantitative analysis of iTRAQ and PRM was verified by immunohistochemical assay. ResultsA total of 68 DEPs in the GDM placenta were identified with iTRAQ proteomics experiment, comprising 21 up-regulated and 47 down-regulated DEPs. Bioinformatics analysis showed that the regulation of transport, catabolic process of non-coding RNA, cytoskeleton and cell binding were the most abundant Gene Ontology terms, and RNA degradation was an important pathway for significant enrichment. Protein–protein interaction network analysis showed that heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1), heterogeneous nuclear ribonucleoprotein A/B (HNRNPAB), heterogeneous nuclear ribonucleoprotein L (HNRNPL) and heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) were the cores of the up-regulated proteins. Band 3 anion transport protein (SLC4A1), spectrin beta chain erythrocytic (SPTB), ankyrin-1 (ANK1), spectrin beta chain non-erythrocytic 2 (SPTBN2), D-3-phosphoglycerate dehydrogenase (PHGDH) and exosome complex component RRP42 (EXOSC7) were the cores of the down-regulated proteins. These proteins are involved in the binding, splicing, processing, transport and degradation of RNA and in the formation and maintenance of the cytoskeleton. PRM verification results showed that seven proteins, namely, epiplakin (EPPK1), cold-inducible RNA-binding protein (CIRBP), HNRNPA2B1, HNRNPAB, HNRNPL, Ras-related protein Rab-21 (RAB21) and Ras-related protein Rab-3B (RAB3B), were up-regulated, whereas SPTB and SLC4A1 were down-regulated. The results of immunohistochemical assay also showed that the expression of five proteins, namely EPPK1, HNRNPA2B1, HNRNPAB, CIRBP and RAB21, were significantly higher in GDM placental tissues (P < 0.01). The GDM placentas showed changes in the morphological evaluation, including poor villous maturation, obvious increase in the number of syncytiotrophoblast nodules, thickening of the wall of dry villous arterioles with lumen stenosis, increased fibrinous exudation and excessive filling of villous interstitial vessels. DiscussionDifferentially expressed proteins related to a variety of biological processes in the GDM placenta were found. Fourteen proteins, namely, HNRNPA2B1, HNRNPAB, HNRNPL, HNRNPA3, EPPK1, CIRBP, RAB21, RAB3B, SLC4A1, SPTB, ANK1, SPTBN2, PHGDH and EXOSC7, which were differentially expressed in the placenta, may play an important role in regulating the occurrence and development of gestational diabetes through multi-channel and multi-link regulation.

A Case of ALECT2 Renal Amyloidosis Associated with IgG4 Related Kidney Disease, Membranous Nephropathy and Early Diabetic Kidney Injury

Abstract Introduction/Objective ALECT-2 amyloidosis is a rare type of amyloidosis that mostly involves kidneys with other organs rarely affected. It has a high prevalence among patients of Hispanic descent. Membranous nephropathy is one of the most common causes of proteinuria in adults. IgG4-related disease is a systemic disease, which commonly involves the pancreas, but occasionally affects the kidney and manifests as chronic renal insufficiency. Here we describe a very unusual case of concurrence of membranous nephropathy, IgG4 disease involving the kidney, ALECT2 amyloidosis, and early diabetic kidney injury. Methods/Case Report A 49-year-old Hispanic male patient with a history of diabetes and IgG4-related autoimmune pancreatitis and primary sclerosing cholangitis presented with abrupt onset of proteinuria and hypoalbuminemia. A kidney biopsy was performed and showed severe interstitial plasma cell-rich inflammatory infiltrates and interstitial fibrosis which had a storiform pattern. The glomerular basement membranes (GBM) showed focal pinpoint holes but no spikes by silver stain. Immunofluorescence microscopy (IF) showed diffuse and finely granular capillary loop staining for IgG, with Kappa and lambda light chains of equal intensity. IF for Anti-phospholipase A2 receptor (PLA2R) was negative. Immunohistochemical (IHC) stain showed IgG4 positivity in about 60% of IgG-positive plasma cells. Congo red was positive for birefringent deposits predominantly in the interstitium and arteriolar walls with focal deposits in the glomerular mesangium and capillary wall. IHC stain for Amyloid AA and DNAJB9 were negative. Electron microscopy showed scattered subepithelial immune complex-type electron dense deposits consistent with membranous nephropathy, randomly oriented fibrils in interstitium, mesangium and GBM, consistent with amyloidosis, and thickening of GBM (average 559 nm), consistent with early diabetic kidney change. The tissue was sent for mass spectrometry which showed a peptide profile consistent with ALECT-2 (Leukocyte chemotactic factor 2) type amyloidosis. Results (if a Case Study enter NA) NA Conclusion In up to a third of cases reported in the literature, a concomitant renal pathology was present. Diabetic nephropathy was the most common concurrent pathology, to be followed by IgA nephropathy and membranous nephropathy. However, the concurrence of membranous nephropathy, IgG4 disease involving the kidney, ALECT2 amyloidosis, and early diabetic kidney injury has never been described before.

Plasticity of cerebral microvascular structure and mechanics during hypertension and following recovery of arterial pressure.

Changes in vascular structure contribute to vascular events and loss of brain health. We examined changes in cerebral arterioles at the onset of hypertension and the hypothesis that alterations during hypertension would recover with the return of mean arterial pressure (MAP) to normal. MAP was measured with radiotelemetry in awake male C57BL/6J mice at baseline and during infusion of vehicle or angiotensin II (ANG II, 1.4 mg/kg/day using osmotic pumps) for 28 days, followed by a 28-day recovery. With ANG II treatment, MAP increased through day 28. On day 30, MAP began to recover, reaching levels not different from vehicle on day 37. We measured intravascular pressure, diameter, wall thickness (WT), wall:lumen ratio (W:L), cross-sectional area (CSA), and slope of the tangential elastic modulus (ET) in maximally dilated arterioles. Variables were similar in both groups at day 1, with no significant change with vehicle treatment. With ANG II treatment, CSA, WT, and W:L increased on days 7-28. Internal and external diameter was reduced at 14 and 28 days. ET versus wall stress was reduced on days 7-28. During recovery, the diameter remained at days 14 and 28 values, whereas other variables returned partly or completely to normal. Thus, CSA, WT, W:L, and ET versus wall stress changed rapidly during hypertension and recovered with MAP. In contrast, inward remodeling developed slowly and did not recover. This lack of recovery has mechanistic implications for the long-term impact of hypertension on vascular determinants of brain health.NEW & NOTEWORTHY Changes in vascular structure contribute to vascular events and loss of brain health. We examined the inherent structural plasticity of cerebral arterioles during and after a period of hypertension. Arteriolar wall thickness, diameter, wall-to-lumen ratio, and biological stiffness changed rapidly during hypertension and recovered with blood pressure. In contrast, inward remodeling developed slowly and did not recover. This lack of recovery of arteriolar diameter has implications for the long-term impact of hypertension on vascular determinants of brain health.

The Relationship Between Klotho and SIRT1 Expression in Renal Aging Related Disease.

BackgroundThis study focused on renal arteriosclerosis and aimed to explore the relationship between Klotho and SIRT1 by morphological staining, which will help to provide new ideas for the treatment of renal-aging-related diseases and a theoretical basis for the development of new drugs.MethodsKidney tissue samples were collected from patients who underwent nephrectomy. HK-2 cells were cultured. The Hematoxylin-eosin (HE) staining, Periodic Acid-Schiff (PAS) staining, Masson’s Trichrome staining, Immunohistochemistry (IHC) staining, Immunofluorescence (ICC) and bioinformatics means were used for this study.ResultsHE staining showed that glomerulosclerosis was atrophic and cast was significantly increased luminal narrowing of renal arterioles in aging group. PAS staining showed that the number of podocytes was reduced, the mesangial matrix expansion and the intimal fibrosis of renal arterioles. Masson’s trichrome staining showed that there was massive collagen proliferation in the tubulointerstitial in aging group, as well as intimal thickening and fibrin deposition in the tubular walls of arterioles. IHC staining showed that the expression of Klotho and SIRT1 protein was downregulated in aging group and the trend of the two was positively correlated (P < 0.01). Klotho and SIRT1 co-localized in HK-2 cells and kidney tissue. The GEPIA database analysis showed a significant positive correlation between Klotho and SIRT1 in multiple human tissues and tumors.ConclusionGlomerulosclerosis in aging group is accompanied by low expression of Klotho and SIRT1 in renal tissue, and Klotho is positively correlated with SIRT1. Klotho-SIRT1 pathway may be involved in the occurrence and development of renal-aging-related diseases.

Abstract 011: Epigenetic Determinants Of Renin Cell Identity

Renin secreting cells are restricted in adult mammals within the walls of renal arterioles near the entrance to the glomeruli and are therefore known as juxtaglomerular (JG) cells. These JG cells are critical for survival through the maintenance of homeostasis via the release of the peptide hormone renin in response to changes in blood pressure. By performing independently paired scATAC-seq and scRNA-seq during mouse kidney development, we sought to identify epigenetic markers of renin cell identity. While we lack spatial information, we identified putative JG cells through the identification of cells enriched in canonical markers (Ren1 and Akr1b7) of JG cell identity using both expression and accessibility derived measures of gene activity. We constructed a pseudotime trajectory of cells that lead to the mature JG population and performed pairwise comparisons of cell populations to identify the genomic regions and transcription factors (TFs) contributing to JG cell identity. As JG cells form along this trajectory, significantly different (Log2FC&gt;0.5 and FDR&lt;0.1) regions of accessible chromatin define the JG cell population. Within these open regions, the MEF2 family of TF motifs are significantly enriched (log10Padj &gt; 20). We further identify a specific region of accessible chromatin (chr1:133345385-133345885) unique to the initial population of JG cells located within a Ren1 super enhancer previously identified by our group. This region is co-accessible with several regions of open chromatin within the greater Ren1 gene region (correlation &gt; 0.75) where we identify putative binding sites for Mef2b, 2c, and 2d at these co-accessible regions. As the mature renin-expressing cells further differentiate into terminally differentiated cell populations including pericytes and mesangial cells, we continue to see significant enrichment of the MEF2 TF family within the JG cell population compared to downstream populations (log10Padj &gt; 646.6891). Overall, we have presented the first investigation and finding using single-cell -omics of the JG cell population and uncover the importance of the MEF2 family of TFs as significant drivers of JG cell formation and identity.

Blood-brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-β deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy–related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-β at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood–brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy–related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-β, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood–brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood–brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-β deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-β (Grade 0), and blood–brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2–4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood–brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood–brain barrier leakage as a potential trigger for subsequent perivascular inflammation.

The effect of rehabilitation exercise on the expression of glutaminase and cardiopulmonary remodeling in pulmonary hypertension

Pulmonary hypertension (PH) is featured by pulmonary vascular and cardiac remodeling. Rehabilitation exercise can improve patients’ quality of life. We previously pinpointed a potential glutamine metabolism dysfunction in PH. Hence, we aim to investigate whether rehabilitation exercise could mitigate right ventricular and pulmonary vascular remodeling and its effect on glutaminase (GLS). We collected clinical indicators of PH patients and analyzed their correlation with GLS. Rehabilitation exercise (moderate intensity swimming exercise) was performed in monocrotaline-induced PH (MCT-PH) rats. We found that plasma GLS1 level in patients was lower than healthy subjects, and it was negatively correlated with end-systolic stage eccentricity index, right atrial transverse dimension and right atrial longitudinal dimension. MCT-PH rats displayed pulmonary vascular remodeling and right ventricular hypertrophy. Compared to control rats, higher levels of GLS1 and GLS2 mRNA in lung and lower levels of these two isoforms of GLS in right ventricle (RV) were displayed in MCT-PH rats. After swimming exercise, GLS mRNA levels in the lung and RV were significantly upregulated, and the cross-sectional area of right ventricular cardiomyocytes was significantly decreased although the percentage of pulmonary arteriolar medial wall thickness was not significantly changed. Therefore, we hold the opinion that plasma GLS1 level was decreased in PH. The transcriptional levels of GLS1 and GLS2 were increased in the lung tissues in PH, but were decreased in the RV tissues. Meanwhile, the changes of GLS levels indicated the pulmonary vascular and right ventricular remodeling. Whereas moderate intensity swimming exercise might improve the right ventricular remodeling by regulating the levels of GLS.

HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF‐β/Smad signaling pathway in CARASIL model mice

AimsCerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a life‐threatening, inherited, nonhypertensive arteriole disease of the brain. Therapeutic strategy for CARASIL is limited because its pathogenesis is not clear. We previously reported the first family with CARASIL in China, which involves a high‐temperature requirement serine protease gene mutation (HtrA1L364P). Based on this previous study, we constructed a CARASIL mouse model (Mut‐hHtrA1L364P mouse, hereinafter referred to as Mut). This paper aimed to systematically study the behavior, pathology, and molecular biology of Mut mice and explore the pathogenesis and possible therapeutic strategies of CARASIL.MethodsFood maze and water maze experiments were used in the behavioral studies. Pathological studies were carried out by arteriole labeling staining and electron microscopy. The mRNA and protein expression levels of the key factors of TGF‐β/Smad signaling pathway (TGF‐β, Smad2, Smad3, and Smad4) in the brain of the model mice were detected by immunohistochemistry, real‐time quantitative polymerase chain reaction (RT‐PCR), and Western blot assay.ResultsThe food maze and water maze experiment data showed significant differences between the Mut and wild‐type (WT) mice in the first time to find food, the time to contact the escape table for the first time, and the number of times to travel in the escape table quadrant (p < 0.001). The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure. The results of electron microscopy showed that the cell morphologies in the cortex and hippocampus of Mut mice were abnormal; the number of synapses was reduced; the walls of capillaries, venules, and arterioles thickened; lumen stenosis and other abnormal phenomenon occurred; and lipofuscin deposition and autophagosomes were found in the hippocampus. Immunohistochemistry, RT‐PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF‐β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees.ConclusionsThe most significant innovation of this study is the first study on the pathogenesis of CARASIL disease using model animals. The Mut mice can well simulate the pathogenesis of CARASIL in behavioral and pathological aspects. The TGF‐β/Smad signaling pathway, which is involved in the pathogenesis of CARASIL, is abnormally upregulated in the brain of Mut mice.

Smoking in pregnancy is associated with increased adiposity and retinal arteriolar wall-to-lumen ratio in adolescence: The Copenhagen Child Cohort Study 2000.

To investigate the association between prenatal exposures and anthropometric data and cardiovascular risk factors including retinal arteriolar wall-to-lumen ratio in adolescence. This longitudinal observational study included all 1445 adolescents from the Copenhagen Child Cohort 2000 who attended the 2016-2017 examination. Outcome measures included retinal arteriolar wall-to-lumen ratio, height, body mass index, waist-to-hip ratio, body composition measured by bioimpedance, and blood pressure. Information on prenatal exposures (birth weight, gestational age, maternal smoking during pregnancy) as well as sex, parental age, household income and parental educational levels were obtained from national registries. Associations between exposures and outcome measures were analyzed using general linear models. Maternal smoking during pregnancy was associated with a higher retinal arteriolar wall-to-lumen ratio (0.004 or 1.9%, P=0.009) at age 16/17years, an association driven exclusively by the female participants (0.008 or 3.7%, P<0.0001). Maternal smoking during pregnancy was also associated to higher body-mass index (1.43kg/m2, P<0.0001), waist-to-hip ratio (0.02, P<0.0001) and fat mass index (0.93kg/m2, P<0.0001). Birth weight, gestational age, and parental age had no detectable impact on retinal arteriolar wall-to-lumen ratios. Prenatal exposure to tobacco smoking is associated with a higher risk of obesity and, predominantly in girls, to a greater retinal arteriolar wall thickness, which suggests that maternal smoking may induce an unfavorable cardiovascular and metabolic risk profile in the child.

Remodeling of Retinal Arterioles and Carotid Arteries in Heart Failure Development-A Preliminary Study.

Current data indicate that heart failure (HF) is associated with inflammation and microvascular dysfunction and remodeling. These mechanisms could be involved in HF development and progression, especially in HF with preserved ejection fraction (HFpEF). We aimed to compare structural changes in retinal arterioles and carotid arteries between HF patients and patients without heart failure. This preliminary, retrospective, case-control study included 28 participants (14 patients with HFpEF and 14 age- and sex-matched healthy controls). Carotid intima-media thickness to lumen ratio (cIMTLR) was assessed using B-mode ultrasonography. Retinal arterioles wall- to-lumen ratio (rWLR) was assessed by adaptive optics camera rtx1. The HF patients had higher IMTLR (Δmedian [HFpEF–control group] 0.07, p = 0.01) and eWLR (Δmedian 0.03, p = 0.001) in comparison to patients without HF. In the whole study group, rWLR correlated significantly with IMTLR (r = 0.739, p = 0.001). Prevalence of arterial hypertension was similar in both groups, however, patients with HF had a significantly lower office, central and 24-h ambulatory blood pressure (systolic Δmedian −21 to −18 mmHg; diastolic Δmedian −23 to −10 mmHg). Our data suggests gradual and simultaneous progression of vascular remodeling in both retinal arterioles and carotid arteries in HFpEF patients. This process could be a marker of HF development. Significantly lower blood pressure values in HF group may indicate that vascular remodeling could be independent of BP control. Nevertheless, further and larger prospective studies allowing to reduce the impact of confounding and address temporality are warranted.

Susac syndrome: A rare presentation

Susac syndrome is an autoimmune microangiopathy characterized by a triad of encephalopathy, sensori-neural hearing loss and varying degrees of branch retinal artery occlusion. A young male patient is described with features of focal neurological lesions and small superficial retinal haemorrhages and areas of retinal arteriolar endothelial inflammation appearing as Gass plaques. Susac syndrome presents with varying features involving brain, inner ear and retina. Fundus Fluorescein angiography should be performed in all patients with an unexplained encephalopathy to look for characteristic arteriolar wall changes.

Age-related Changes in Renal Arterio-Arteriolosclerosis in Kidney Disease: Renal Biopsy-based Study

Age-related Changes in Renal Arterio-Arteriolosclerosis in Kidney Disease: Renal Biopsy-based Study

PHARMACOLOGIC NEUROMODULATION TARGETING NEUROINFLAMMATION AS A NOVEL THERAPEUTIC STRATEGY FOR PULMONARY HYPERTENSION AND RIGHT HEART FAILURE

TYPE: Late Breaking Abstract TOPIC: Pulmonary Vascular Disease PURPOSE: Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to right ventricular failure (RVF). Neuroinflammation has been implicated in sympathoexcitation in experimental PH. Here we hypothesize that pharmacologic neuromodulation targeting TSC neuroinflammation may serve as a novel therapy for PH and RVF. METHODS: Adult male Sprague Dawley rats received either Monocrotaline (MCT, 60mg/kg, subcutaneous, n=10) and were followed for 4-weeks or Sugen (SuHx, 20mg/kg, subcutaneous, n=10) and kept in hypoxia (10% O2) for 3-weeks followed by 2-weeks of normoxia. Saline treated rats served as controls (CTRL, n=10). Next, MCT-rats received either daily intrathecal specific NOS1-inhibitor S-Methyl-L-thiocitrulline (SMTC; 0.5mg/kg, n=7) or PBS (n=7) from day 14-28. Echo and RV-catheterization were performed terminally. TSC, lung and RV RNASeq, RT-qPCR, NOS1 activity and immunolocalization, and catecholamine ELISA were performed. RESULTS: MCT and SuHx rats highlighted similar degree of PH, RVF and TSC-specific neuroinflammation and apoptosis. TSC transcriptome showed common genes and pathways linked to neuroinflammation, nitrosative stress and apoptosis. NOS1 was one of the top-most upregulated genes in TSC. NOS1-specific inhibition rescued PH, RV-hypertrophy, and RVF (all p<0.05). SMTC significantly decreased pulmonary arteriolar wall thickness, TSC NOS activity, microglia and astrocyte activation, apoptosis, plasma catecholamines and QTc prolongation (all p<0.05). This rescue was associated with reversal of RV and lung transcriptome and sympathoexcitation. CONCLUSIONS: Pharmacologic neuromodulation via intrathecal NOS1-specific inhibition rescues PH and RVF by reducing TSC neuroinflammation, apoptosis and sympathoexcitation in rats. CLINICAL IMPLICATIONS: Targeting NOS1 in TSC may serve as a novel therapeutic strategy for clinical PH and RVF. DISCLOSURE: No significant relationships. KEYWORD: Pulmonary Hypertension

2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association.

2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association.

Effects of YM155 on the proliferation and apoptosis of pulmonary artery smooth muscle cells in a rat model of high pulmonary blood flow-induced pulmonary arterial hypertension

ABSTRACT Introduction Proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) play an important role in the occurrence and development of pulmonary arterial hypertension (PAH). The purpose of this study was to investigate the effects of survivin inhibitor YM155 on the proliferation and apoptosis of PASMCs in rats with PAH induced by high pulmonary blood flow. Methods Thirty male Sprague-Dawley (SD) rats were randomly divided into control, model, and YM155 intervention groups. A rat model of PAH induced by high pulmonary blood flow was established, and it was confirmed by assessments of right-ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI). Immunohistochemical staining and western blot analysis were used to detect the expression of survivin, and the proliferation and apoptosis of PASMCs. Lastly, the effects of in vivo treatment of YM155 were tested. Results The increased expression of survivin mRNA and protein were observed in the model group, accompanied by pulmonary arteriolar wall thickening, lumen stenosis, and perivascular inflammatory cell infiltration. Elevated expression of survivin and pulmonary vascular remodeling were significantly mitigated after YM155 treatment. Specifically, the YM155 intervention group had a significantly lower PASMC proliferation rate and a higher PASMC apoptotic rate. Conclusion YM155 suppressed PASMC proliferation and promoted PASMC apoptosis by inhibiting survivin expression and thereby reducing pulmonary vascular remodeling in high pulmonary blood flow-induced PAH in vivo.

Modeling of vasomotion in arterioles

We consider the flow of blood, treated as an incompressible Newtonian fluid, through vessels undergoing periodic oscillations. As remarked by many authors, in the absence of valves oscillations hinder the flow because of the lumen reduction. The underlying biological mechanism is the so-called vasomotion, observed long ago in small blood vessels. Here, we study the vasomotion in arterioles and provide its theoretical justification by analyzing the effect when the network of vessels downstream of the arterioles is considered. We thus explain both quantitatively and qualitatively, why the oscillations of the arteriole walls, a phenomenon that undoubtedly reduces blood flow at the level of the single arteriole, play a fundamental role in microcirculation. In “large” arterioles we analyze also the coupling between the vasomotion and the Fåhræus-Lindqvist effect (the tendency of the erythrocytes to accumulate towards the center). In particular, we prove that the presence of a cell depleted layer close to the vessel walls mitigates the disadvantage caused by the lumen reduction.

Susac Syndrome: A Case Series.

Susac syndrome (SS) is an autoimmune disorder that involves the eyes, the brain, and the ears. It is a rare cause of recurrent branch retinal artery occlusion. The purpose of this study was to report cases of SS, highlighting the clinical presentations, therapeutic options, and their outcome. Retrospective case series of patients seen at our institution for SS between 2005 and 2020. Demographics, clinical characteristics, treatment, and outcome were studied. Four patients (3 females, mean age 29 years old) were included in the study. According to the recently revised diagnostic criteria, three patients had definite and one patient had probable SS (distinctive ophthalmological and brain involvement without ear involvement). Initial visual acuity (VA) was normal in all eyes, but two patients had unilateral visual field impairment. Gass plaques (defined as yellow-white plaques found in the arteriolar wall away from arterial bifurcations) were observed on fundus examination in all patients. Fluorescein angiography revealed arteriolar wall hyperfluorescence and branch retinal arterial occlusions (BRAOs) in the absence of other signs of intraocular inflammation in all patients. Initial treatment consisted of a high-dose corticosteroid (intravenous or oral) with additional immunosuppressive therapy (azathioprine, intravenous immunoglobulins, mycophenolate mofetil, and/or cyclophosphamide). Residual symptoms were present in all patients and included scotoma (n = 2) and hearing loss (n = 3). SS is a rare disease with characteristic ophthalmological manifestation. The majority of patients present a crude form of the triad, and retinal findings may be the first initial manifestation. Ophthalmologists should consider the possibility of an SS in all young patients presenting with BRAOs.

The Inflammatory Cytokine Imbalance for Miscarriage, Pregnancy Loss and COVID-19 Pneumonia.

Pregnancy can be defined a vascular event upon endocrine control. In the human hemo-chorial placentation the chorionic villi penetrate the wall of the uterine spiral arteries, to provide increasing amounts of nutrients and oxygen for optimal fetal growth. In any physiological pregnancy the natural maternal response is of a Th1 inflammatory type, aimed at avoiding blood loss through the arteriolar wall openings. The control of the vascular function, during gestation as in any other condition, is achieved through the action of two main types of prostanoids: prostaglandin E2 and thromboxane on the one hand (for vasoconstriction and coagulation), prostacyclin on the other (for vasodilation and blood fluidification). The control of the maternal immune response is upon the responsibility of the fetus itself. Indeed, the chorionic villi are able to counteract the natural maternal response, thus changing the inflammatory Th1 type into the anti-inflammatory Th2. Clinical and experimental research in the past half century address to inflammation as the leading cause of abortion, pregnancy loss, premature delivery and related pulmonary, cerebral, intestinal fetal syndromes. Increased level of Interleukin 6, Interleukin 1-beta, Tumor Necrosis Factor-alfa, Interferon-gamma, are some among the well-known markers of gestational inflammation. On the other side, COVID-19 pneumonia is a result of extensive inflammation induced by viral replication within the cells of the respiratory tract. As it may happen in the uterine arteries in the absence of an effective fetal control, viral pneumonia triggers pulmonary vascular coagulation. The cytokines involved in the process are the same as those in gestational inflammation. As the fetus breathes throughout the placenta, fetal death from placental thrombosis is similar to adult death from pulmonary thrombosis. Preventing and counteracting inflammation is mandatory in both conditions. The most relevant literature dealing with the above-mentioned concepts is reviewed in the present article.