Structural Vascular Changes Research Articles

Endostar Rebuilding Vascular Homeostasis and Enhancing Chemotherapy Efficacy in Cervical Cancer Treatment.

BackgroundThe incidence rate of cervical cancer is the highest in the reproductive tract and is not sensitive to chemotherapy. An appropriate amount of anti-angiogenic agents can reconstruct tumor blood vessels in a short period of time and form vascular homeostasis, increase the function of blood vessel perfusion and reverse the multidrug resistance of chemotherapy, which is also called “vascular normalization.” Endostar (a recombinant human endostatin) was developed by China and as a multi-target anti-angiogenesis agent. Many reports about endostar involved the treatment of non-small cell lung cancer, fewer reports are on cervical cancer.PurposeTo determine whether endostar can rebuild tumor vascular homeostasis and enhance chemotherapy effects for patients with cervical cancer.MethodsIn this study, the patients with cervical cancer within stage IIB2 were selected, endostar combined with cisplatin+paclitaxel neoadjuvant chemotherapy (NACT) before radical surgical operation was adopted, patients outcome and adverse reaction were followed up. The changes of tumor vascular structure and perfusion function before and after endostar given were evaluated by histopathology and dynamic contrast-enhanced magnetic resonance imaging (DEC-MRI). VEGF-Notch signal pathway was detected for the regulating mechanism of vascular proliferation in different groups. GraphPad Prism 6 software was used for statistical analysis of the study results.ResultsEndostar enhanced the short-term (2 year) overall survival (OS), progression-free survival (PFS) rates for cervical cancer patients. All the same, endostar increased long-term (5 year) OS for cervical cancer patients. Endostar therapy exhibited with mild adverse reaction. MRI showed endostar+NACT further reduce tumor volume than NACT alone. The parameters of Ktrans, Ve for DEC-MRI in endostar group exhibited obviously increase than NACT group. Tumor vascular maturation index α-SMA/CD31 in endostar group increased obviously than NACT group, correspondingly Ki67 staining for tumor proliferative rates, lymphovascular space invasion in endostar group further declined than NACT group. The genes and proteins expression of VEGFR2, Notch1, Notch4, Dll4, Jag1 were obviously downregulated in endostar group comparing to NACT group.ConclusionEndostar restored vascular homeostasis in cervical cancer temporarily, enhanced chemotherapeutic agents effects in cervical cancer, increased patient OS ratio. Endostar+NACT treatment may provide a new target therapy for cervical cancer.

The Effect of Exercise During Pregnancy on Maternal and Offspring Vascular Outcomes: a Pilot Study

The aim of this pilot study is to obtain estimates for the change in maternal cerebrovascular (primary) and offspring vascular structure (secondary) during healthy pregnancy that includes structured exercise. Eighteen pregnant women self-assigned to a moderate-intensity aerobic exercise intervention or a control group. Maternal cerebral blood flow (CBF) at the middle cerebral artery, cerebro- and peripheral-vascular function was assessed at the end of each trimester. Offspring carotid artery intima-media thickness (IMT) was measured within 12 weeks of birth. For exploratory purposes, we performed statistical analysis to provide estimates of the change for primary and secondary outcome variables. Maternal CBF reduced (− 8 cm s−1 [− 14 to − 2]) with evidence of change to cerebral autoregulation (normalised gain: 0.12 %cm s−1% mmHg−1mmHg/% [− 0.18 to 0.40]) during pregnancy. Offspring carotid IMT was smaller in the exercise group (− 0.04 mm [− 0.12–0.03]) compared with controls. Based upon this data, a sample size of 33 and 57 in each group is required for low-frequency normalised gain and offspring IMT, respectively. This would provide 90% power to detect statistically significant (P < 0.05) between group differences in a randomised controlled trial. CBF is reduced in pregnancy, possibly due to reduced vascular resistance and altered maternal cerebral autoregulation. Maternal exercise had negligible effects on cerebrovascular adaptation to pregnancy, but we observed lower offspring carotid artery wall thickness following maternal exercise. Our directional findings and sample size estimations should be explored in a fully powered randomised control trial.Clinical trial registration: The trial was registered on March 14th at https://register.clinicaltrials.gov (NCT03079258). Participant enrolment began on 3rd April 2016.

Microvascular retinal alterations in rhegmatogenous retinal detachment after pneumatic retinopexy

To evaluate the macular microvascularity with optical coherence tomography angiography (OCTA) in rhegmatogenous retinal detachment (RRD) which were successfully treated with pneumatic retinopexy (PR). Thirty eyes of thirty patients who were treated with PR (12 eyes with macula-off RRD and 18 eyes with macula-on RRD) were included in this prospective study. OCTA was used to evaluate the macular perfusion changes postoperatively at 1 and 3months. The fellow eyes (30 eyes) were used as control for comparison. Parafoveal retinal thickness (RT) and best-corrected visual acuity (BCVA) were evaluated. Vessel density (VD) in SCP, DCP and choriocapillaris plexus (CCP) flow area was significantly lower in the macula-off group one month after the PR (p<0.001). In the macula-off group, VD in SCP, DCP and CCP flow area significantly increased at months 3 (p<0.001, p<0.001, p=0.009). The inner RT, RT and FAZ decreased three months after PR (p<0.001, p=0.001, <0.001). The FAZ was significantly larger in the macula-off group at third months after PR (p<0.001). The inner RT was higher in the macula-off group at third month (p=0.012). There was no significant difference between the groups in means of final VD, CCP flow area and RT. There was also a negative correlation between the final BCVA (logMAR) and FAZ at month 3 (r=0.776, p=0.003). Optical coherence tomography angiography evaluation of macular capillary plexuses may be useful for predicting vascular structural changes in patients undergoing PR.

Imaging Mass Cytometry Reveals the Spatial Architecture of Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemias

Histologic review of bone marrow trephine biopsies is a central component of the diagnostic and treatment response evaluation of hematologic malignancies. Well-validated antibody reagents are routinely used for immunohistochemistry of these samples to provide additional insight into abnormal antigen expression. However, current immunohistochemistry staining protocols are typically limited to only one or two markers simultaneously. Dysplastic changes in cellular morphology and dyssynchronous expression of lineage markers are common features of myelodysplastic syndromes, myeloproliferative neoplasms and secondary acute leukemias. We have integrated the use of multiple diagnostic validated antibody clones with additional antibodies for hematologic lineages and structural proteins to create a 30-marker panel for imaging mass cytometry (IMC). Antibodies included in this panel identify myeloid, lymphoid, erythroid, macrophage, vascular, megakaryocyte and stromal markers as well as markers of cellular proliferation and apoptosis. Through conjugation to elemental metal tags, the entire panel is stained simultaneously on the tissue sample, then acquired by time-of-flight mass spectrometry on a Hyperion instrument (Fluidigm). Antibody staining concentrations and antigen retrieval conditions were optimized for formalin-fixed paraffin-embedded (FFPE) bone marrow to obtain consistent staining for all markers on the panel. Redundant markers for cell populations were selected to provide further internal validation of the observed staining patterns. After data acquisition, cell segmentation algorithms using CellProfiler and ilastik were applied to quantify marker expression in single cells and Phenograph in HistoCAT was used for cell population clustering. Cluster identities for all cells are associated with the original image location in order to plot the spatial arrangement of populations. Using this highly multiplexed panel, we have imaged sets of bone marrow specimens from patients with normal bone marrow morphology and those with myeloid malignancies. We initially confirmed the staining patterns expected for each antibody patterns of co-expression of lineage markers in normal bone marrow samples. We then extended this panel to examine biopsies from patients with myelodysplastic syndrome, myelofibrosis, and secondary acute myeloid leukemia. We found a clear population of CD71+ CD235a+ erythroid cells with strong expression of the proliferative marker Ki67 located within erythroid islands in normal bone marrow samples and MDS. Cell markers of apoptosis and DNA damage are scattered at low frequency throughout the bone marrow in samples with normal bone marrow morphology, but increased clusters of the DNA damage marker phospho-H2AX are observed in selected cases of myelodysplastic syndromes. Overall, this IMC imaging approach is able to extend the current clinical immunostaining for myeloid malignancies by identifying all major bone marrow cell populations. Through highly multiplexed analysis of bone marrow cell populations, the spatial architecture of cell populations and stromal structures can be elucidated, including erythroid islands, lymphoid aggregates and changes in vascular structures with increasing severity of myelofibrosis. In ongoing studies, the development of these imaging techniques for analysis of archived FFPE bone marrow samples is being applied to translational research on hematologic diseases. Disclosures Oh: Kartos Therapeutics: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; Constellation: Consultancy; CTI Biopharma: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Novartis: Consultancy; Gilead Sciences: Consultancy; Incyte Corporation: Consultancy.

Associations of sodium intake with central hemodynamics and changes in vascular structure and function at high altitude localities

Abstract Objectives To investigate the associations of sodium intake with central hemodynamics and changes in vascular structure and function at high altitude localities. Methods A total of 383 Buddhists were enrolled in four temples with an average elevation of 3,800 meters from December 2018 to January 2019. Estimated 24-hour urinary sodium excretion was measured by the Kawasaki formula using the urinary sodium/creatinine ratio of the second fasting spot urine in the morning. Central hemodynamics, including central systolic blood pressure (CSBP), central diastolic blood pressure (CDBP), central pulse pressure (CPP), central mean arterial pressure (CMAP), augmentation pressure (AP), augmentation index (AI), were evaluated by applanation tonometry using the SphygmoCor analyzer. Vascular structure and function were quantified by carotid intima media thickness (cIMT) and brachial ankle pulse wave velocity (BaPWV), respectively. Pearson correlation and multiple linear regression were used to analyze the associations between 24h urinary sodium with central arterial hemodynamic parameters, cIMT and BaPWV. Results The estimated 24h urinary sodium excretion of the Buddhists in such area was (5.26±1.61)g and the estimated salt intake was (13.36±4.09)g. There was no significant correlation between 24h urinary sodium with CDBP, AP and cIMT (P&amp;gt;0.05). After adjusting for gender, age, CSBP, body mass index (BMI), fasting blood glucose (FBG), estimated glomerular filtration rate (eGFR), triglycerides (TG), high density lipoprotein (HDL) and low density lipoprotein (LDL), the estimated 24h urine sodium was positively correlated with CSBP (β=1.313, P=0.018) and CPP (β=1.311, P&amp;lt;0.001), the estimated 24h urinary sodium was significantly negatively correlated with AIX75 and BaPWV (β=−1.124, P=0.028 and β=−37.530, P&amp;lt;0.001, respectively). The line graph of means across the 24h urinary sodium quartiles and the cubic fitting curve showed that the associations between 24h urinary sodium excretion with AIX75 and BaPWV presented an approximate “J” shape. Conclusions 24h urinary sodium was positively correlated with CSBP and CPP and negatively correlated with AIX75 and BaPWV in the Buddhists in this high altitude area. The associations between 24h urinary sodium with AIX75 and BaPWV resembled a “J” shape. Funding Acknowledgement Type of funding source: None

Exploring functional and structural vascular changes in obesity: are metabolically healthy obese individuals really healthy?

Abstract Purpose Aim of the study is to compare vascular function and structure parameters among middle-aged men with differences in body mass index (BMI) and metabolic status and to investigate whether obese individuals with a normal metabolic profile have a unhealthy vascular profile. Methods We measured carotid-femoral pulse wave velocity (cfPWV), carotid intima media thickness (cIMT) and brachial flow-mediated dilation (bFMD) in 141 obese (BMI≥30 kg/m2) and in 176 aged-matched men with normal BMI (&amp;lt;25 kg/m2) individuals. All participants had no clinical manifestations or a history of atherosclerotic disease. High sensitivity C-reactive protein (hsCRP) and total testosterone (TT) were measured in all patients. Results The two BMI groups were subdivided into subgroups according to presence/absence of abnormal metabolic profile (presence of major cardiovascular risk factors): Metabolically unhealthy obese (MeUO, n=114), metabolically healthy obese (MeHO, n=27), metabolically unhealthy with normal BMI (MeUN, n=122) and metabolically healthy with normal BMI individuals (MeHN, n=54). The four subgroups had similar age. Figure 1 shows the mean cIMT (left plot), cfPWV (middle plot) and bFMD (right plot) of the four subgroups. Carotid IMT and cfPWV is higher and bFMD is lower in metabolically unhealthy compared to individuals with a normal metabolic profile in both patients with obesity and subjects with normal BMI. Interestingly, the MeNO patients had significantly lower cIMT (P&amp;lt;0.05) and cfPWV (P&amp;lt;0.01) and higher bFMD (P&amp;lt;0.01) level compared to MeUN individuals. However, as figure shows all measured vascular parameters were significantly impaired in MeNO patients compared to those of MeHN individuals. MeHO patients had comparable hsCRP and TT levels to those of MeUO and MeUN individuals denoting increased inflammatory activation and endogenous androgen deficiency. Conclusions MeHO which is a obesity phenotype that has created lot of debate is associated with a better vascular profile compared to MeUN status, however patients with MeHO have more impaired vascular function and structure parameters than MeHN individuals. This finding implies that even in the absence of overt metabolic aberrations, the MeHO profile may be associated with endothelial dysfunction, increased aortic stiffness and thickness of the carotid arterial wall. Figure 1. BMI, metabolic status and vascular changes Funding Acknowledgement Type of funding source: None

LDL-C/HDL-C ratio associated with carotid intima-media thickness and carotid plaques in male but not female patients with type 2 diabetes

BackgroundWe investigated the associations between low-density lipoprotein cholesterol (LDL-C) to high-density cholesterol (HDL-C) ratio (LDL-C/HDL-C) with structural and functional early atherosclerosis vascular changes in patients with type 2 diabetes mellitus (T2DM). MethodsThis hospital-based cross-sectional study included 814 patients with T2DM. Structural atherosclerotic parameters included carotid intima-media thickness (CIMT) and carotid plaque, the cardio-ankle vascular index (CAVI) was considered as the functional parameter. Multiple linear regression and logistic regression models were preformed to identify the associations between LDL-C/HDL-C with atherosclerotic parameters. ResultsIncreased LDL-C/HDL-C corresponded with the increase levels in CIMT and percentage of carotid plaque. LDL-C/HDL-C was found to be positively associated with CIMT both in female and male patients in unadjusted model. This association persisted in male patients but not in female patients after adjusted for other related factors. No association was found between LDL-C/HDL-C with CAVI both in female and male patients. LDL-C/HDL-C was positively associated with the presence of carotid plaque in male patients. However, this association was not found in female patients. ConclusionLDL-C/HDL-C was positively associated with CIMT and presence of carotid plaque though not with CAVI in male T2DM patients. However, these associations were not observed in female patients.

Computer-Aided Diagnosis With Monochromatic Light Endoscopy for Scoring Histologic Remission in Ulcerative Colitis

Computer-Aided Diagnosis With Monochromatic Light Endoscopy for Scoring Histologic Remission in Ulcerative Colitis

Model for type 2 diabetes exhibits changes in vascular function and structure due to vascular oxidative stress and inflammation

ABSTRACT We used a type 2 diabetes rat model produced by a high fat diet (HFD) followed by low dose streptozotocin (STZ) to study diabetic vasculopathy. Animals were evaluated for early vascular structural changes, endothelial function, inflammation, lipid profile and oxidative stress. We used 20 male Sprague-Dawley rats divided equally into control and diabetic groups. Diabetic rats were fed an HFD for 4 weeks, injected intraperitoneally with STZ, then sacrificed at week 15. Aortic endothelial nitric oxide synthase (eNOS), aortic superoxide dismutase (SOD), endothelial-dependent and independent relaxation and contraction, intima-media thickness (IMT), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) were measured. Histopathological characteristics also were assessed. Diabetic rats exhibited higher fasting blood glucose (FBG), low density lipoprotein, total cholesterol and triglycerides compared to the control group. Aortic endothelium-dependent relaxation due to acetylcholine (ACh) was lower, while aortic endothelium-dependent contraction due to calcium ionophore and endothelium-independent contraction due to phenylephrine (PE) were higher for the diabetic group. eNOS expression was lower in the diabetic group compared to controls. IMT and MDA levels were increased, while SOD activity was decreased in the diabetic group compared to controls. TNF-α was higher in the diabetic group than for controls. Our type 2 diabetes model exhibited endothelial dysfunction associated with early vascular structural changes, dyslipidemia, increased vascular oxidative stress, and inflammation. Therefore, the model is suitable for studying diabetic atherosclerosis.

A Window of Vascular Plasticity Coupled to Behavioral Recovery after Stroke.

Stroke causes remodeling of vasculature surrounding the infarct, but whether and how vascular remodeling contributes to recovery are unclear. We established an approach to monitor and compare changes in vascular structure and blood flow with high spatiotemporal precision after photothrombotic infarcts in motor cortex using longitudinal 2-photon and multiexposure speckle imaging in mice of both sexes. A spatially graded pattern of vascular structural remodeling in peri-infarct cortex unfolded over the first 2 weeks after stroke, characterized by vessel loss and formation, and selective stabilization of a subset of new vessels. This vascular structural plasticity was coincident with transient activation of transcriptional programs relevant for vascular remodeling, reestablishment of peri-infarct blood flow, and large improvements in motor performance. Local vascular plasticity was strongly predictive of restoration of blood flow, which was in turn predictive of behavioral recovery. These findings reveal the spatiotemporal evolution of vascular remodeling after stroke and demonstrate that a window of heightened vascular plasticity is coupled to the reestablishment of blood flow and behavioral recovery. Our findings support that neovascularization contributes to behavioral recovery after stroke by restoring blood flow to peri-infarct regions. These findings may inform strategies for enhancing recovery from stroke and other types of brain injury.SIGNIFICANCE STATEMENT An improved understanding of neural repair could inform strategies for enhancing recovery from stroke and other types of brain injury. Stroke causes remodeling of vasculature surrounding the lesion, but whether and how the process of vascular remodeling contributes to recovery of behavioral function have been unclear. Here we used longitudinal in vivo imaging to track vascular structure and blood flow in residual peri-infarct cortex after ischemic stroke in mice. We found that stroke created a restricted period of heightened vascular plasticity that was associated with restoration of blood flow, which was in turn predictive of recovery of motor function. Therefore, our findings support that vascular remodeling facilitates behavioral recovery after stroke by restoring blood flow to peri-infarct cortex.

Effects of angiotensin receptor neprilysin inhibition on pulmonary arterial stiffness in heart failure with reduced ejection fraction.

The sacubitril/valsartan combination is an important agent used in the treatment of heart failure with reduced ejection fraction (HFrEF). Pulmonary artery stiffness (PAS) is an index developed to evaluate the pulmonary vascular bed. Changes in pulmonary vascular structures in HFrEF patients can affect PAS. In this study, we aimed to investigate the effect of sacubitril/valsartan on PAS in HFrEF patients. One hundred fifty HFrEF patients, who received sacubitril/valsartan therapy and continued for at least 6months without interruption, were examined retrospectively. N-terminal pro-B-type natriuretic peptide levels (NT-proBNP), NYHA classes, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) scores, New York Heart Association (NYHA) functional classes and echocardiograpic parameters such as left ventricular ejection fraction (LVEF), mean pulmonary artery pressure (mPAP), right ventricle myocardial performance index (RV-MPI), Tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RV-FAC) and PAS changes were evaluated before and 6months after sacubitril/valsartan treatment. PAS was calculated by using the maximal frequency shift and acceleration time of the pulmonary artery flow trace measured in the echocardiogram. PAS values were significantly reduced (23.8 ± 2.8 vs 19.1 ± 3.1kHz/ms, p < 0.001) after the sacubitril/valsartan treatment. Sacubitril/valsartan treatment was associated with significant improvements in NYHA class and MLWHFQ scores; significant reductions in the NT-proBNP levels, mPAP, and RV-MPI, and significant increases in LVEF, TAPSE, and RV-FAC (p < 0.05). The significant reduction in the PAS value was significantly correlated with the improvements in the MLWFQ scores, NT-proBNP levels, mPAP, RV-MPI, TAPSE and RV-FAC. In HFrEF patients, switching from angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to sacubitril/valsartan may result in reduction in PAS.

Impact of the Vulnerable Preterm Heart and Circulation on Adult Cardiovascular Disease Risk.

Preterm birth accounts for over 15 million global births per year. Perinatal interventions introduced since the early 1980s, such as antenatal glucocorticoids, surfactant, and invasive ventilation strategies, have dramatically improved survival of even the smallest, most vulnerable neonates. As a result, a new generation of preterm-born individuals has now reached early adulthood, and they are at increased risk of cardiovascular diseases. To better understand the sequelae of preterm birth, cardiovascular follow-up studies in adolescents and young adults born preterm have focused on characterizing changes in cardiac, vascular, and pulmonary structure and function. Being born preterm associates with a reduced cardiac reserve and smaller left and right ventricular volumes, as well as decreased vascularity, increased vascular stiffness, and higher pressure of both the pulmonary and systemic vasculature. The purpose of this review is to present major epidemiological evidence linking preterm birth with cardiovascular disease; to discuss findings from clinical studies showing a long-term impact of preterm birth on cardiac remodeling, as well as the systemic and pulmonary vascular systems; to discuss differences across gestational ages; and to consider possible driving mechanisms and therapeutic approaches for reducing cardiovascular burden in individuals born preterm.

Inhibition of Aquaporin 4 Decreases Amyloid A\u03b240 Drainage Around Cerebral Vessels

Aquaporin-4 (AQP4) is located mainly in the astrocytic end-feet around cerebral blood vessels and regulates ion and water homeostasis in the brain. While deletion of AQP4 is shown to reduce amyloid-β (Aβ) clearance and exacerbate Aβ peptide accumulation in plaques and vessels of Alzheimer’s disease mouse models, the mechanism and clearing pathways involved are debated. Here, we investigated how inhibiting the function of AQP4 in healthy male C57BL/6 J mice impacts clearance of Aβ40, the more soluble Aβ isoform. Using two-photon in vivo imaging and visualizing vessels with Sulfurodamine 101 (SR101), we first showed that Aβ40 injected as a ≤ 0.5-μl volume in the cerebral cortex diffused rapidly in parenchyma and accumulated around blood vessels. In animals treated with the AQP4 inhibitor TGN-020, the perivascular Aβ40 accumulation was significantly (P < 0.001) intensified by involving four times more vessels, thus suggesting a generalized clearance defect associated with vessels. Increasing the injecting volume to ≥ 0.5 ≤ 1 μl decreased the difference of Aβ40-positive vessels observed in non-treated and AQP4 inhibitor-treated animals, although the difference was still significant (P = 0.001), suggesting that larger injection volumes could overwhelm intramural vascular clearance mechanisms. While both small and large vessels accumulated Aβ40, for the ≤ 0.5-μl volume group, the average diameter of the Aβ40-positive vessels tended to be larger in control animals compared with TGN-020-treated animals, although the difference was non-significant (P = 0.066). Using histopathology and ultrastructural microscopy, no vascular structural change was observed after a single massive dose of TGN-020. These data suggest that AQP4 deficiency is directly involved in impaired Aβ brain clearance via the peri-/para-vascular routes, and AQP4-mediated vascular clearance might counteract blood-brain barrier abnormalities and age-related vascular amyloidopathy.

Cratoxylum Formosum extract exhibits antihypertensive effects via suppressing the renin-angiotensin cascade in hypertensive rats

Abstract The effect of Cratoxylum Formosum (CF) extract on blood pressure and changes in vascular structure and function in hypertensive rats was studied. Rats received 40 mg/kg L-NAME and treated with CF extract or captopril or captopril + CF extract (n = 8). CF extract attenuated hypertension, enhancement of nerve-mediated contractile responses, endothelial dysfunction and oxidative stress markers and raised concentrations of nitric oxide metabolites (NOx) in L-NAME treated rats. Aortic hypertrophy associated with increases in serum ACE activity, plasma angiotensin II level, and AT1R/Akt/STAT3 protein expression in hypertensive rats were alleviated by CF extract. In hypertensive rats, captopril + CF extract administration showed greater effects on reducing blood pressure and vascular hypertrophy. Data of this study suggested that an antihypertensive effect of CF extract is linked to its antioxidant effect to enhance NO bioavailability and an inhibitory effect on RAS cascade.

Effects of exercise on blood pressure and arterial stiffness in patients with type 2 diabetes mellitus: a literature review

Introduction: Diabetes mellitus type 2 increases the mortality and the risk of premature morbidity related to cardiovascular disease. High blood pressure stands out as the main morbidity in this diabetic patient and arterial stiffness by one of the common complications associated with the disease, both of which can precipitate the occurrence of vascular disorders. In this context, the physical exercise is considered an important component in the treatment of these patients, as it helps in the control of cardiovascular risk factors. Objective: To investigate the effects of the physical exercise on pressure and arterial stiffness in patients with type 2 Diabetes mellitus. Methods: This is a literature review conducted in the period March-April 2015 in MEDLINE, LILACS, SciELO, PubMed and Cochrane databases. The keywords used were “Type 2 Diabetes Mellitus”, “Exercise”, “Arterial Stiffness” and “Arterial Pressure”, combined by the boolean operator “and” being considered for this review only studies published between 2009 and 2015. Results: A total of 146 publications, were select 8 studies that investigated the effects of physical exercise on blood pressure and arterial stiffness in patients with type 2 Diabetes mellitus. Of these, 6 studies investigated the effects of physical exercise on blood pressure, which was completed in 4 of them, that it was effective in promoting protective effects of blood pressure. With respect to arterial stiffness, analyzed in four studies, it was found that aerobic training was able to generate reductions in their values after 3 months of intervention, which however were not maintained after longer periods. Conclusion: The physical exercise can be appointed as a promising strategy for arterial pressure control in patients with diabetes mellitus type 2. With regard to arterial stiffness, it is assumed that structural vascular changes manifested in the disease process present irreversible characteristics and therefore can not be modified even after long periods of intervention.

Vascular function and cardiovascular risk in a HIV infected and HIV free cohort of African ancestry: baseline profile, rationale and methods of the longitudinal EndoAfrica-NWU study

BackgroundPeople living with the Human Immunodeficiency Virus (PLHIV) have an increased susceptibility to develop non-communicable diseases such as cardiovascular disease (CVD). Infection with HIV contributes to the development of CVD independent of traditional risk factors, with endothelial dysfunction being the central physiological mechanism. While HIV-related mortality is declining due to antiretroviral treatment (ART), the number of deaths due to CVD is rising in South Africa - the country with the highest number of PLHIV and the world’s largest ART programme.The EndoAfrica study was developed to determine whether HIV infection and ART are associated with cardiovascular risk markers and changes in vascular structure and function over 18 months in adults from different provinces of South Africa. This paper describes the rationale, methodology and baseline cohort profile of the EndoAfrica study conducted in the North West Province, South Africa.MethodsIn this case-control study, conducted between August 2017 and June 2018, 382 volunteers of African descent (276 women; 106 men), comprising of 278 HIV infected and 104 HIV free individuals were included. We measured health behaviours, a detailed cardiovascular profile, and performed biomarker analyses. We compared baseline characteristics, blood pressure, vascular function and biochemical markers between those infected and HIV free.ResultsAt baseline, the HIV infected participants were older (43 vs 39 years), less were employed (21% vs 40%), less had a tertiary education (7% vs 16%) and their body mass index was lower (26 vs 29 kg/m2) than that of the HIV free participants. While the cardiovascular profile, flow-mediated dilation and pulse wave velocity did not differ, glycated haemoglobin was lower (p = 0.017) and total cholesterol, high density lipoprotein cholesterol, triglycerides, gamma-glutamyltransferase and tobacco use were higher (all p < 0.047) in PLHIV.ConclusionDespite PLHIV being older, preliminary cross-sectional analysis suggests that PLHIV being treated with ART do not have poorer endothelial or vascular function compared to the HIV free participants. More detailed analyses on the baseline and follow-up data will provide further clarity regarding the cardiovascular profile of South Africans living with HIV.

Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction.

Hypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)-dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown. A mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance. By 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice. 5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.

P0295IMPROVED LEFT VENTRICULAR FUNCTION EVALUATION AFTER KIDNEY TRANSPLANT

Abstract Background and Aims Chronic kidney disease (CKD) represents a major risk factor for cardiovascular (CV) disease. CKD pro inflammatory state evokes structural and functional cardiac and vascular changes, such as chronic dysregulation of nitric oxide in vascular muscle, results in left ventricular hypertrophy (LVH), LV dilatation, LV systolic and diastolic dysfunction, endothelial dysfunction and atherosclerosis. Recent advances in echocardiographic methods allows to evaluate changes in cardiac structure and function after KT. The aim of this study was to assess changes in LV structure and function after renal transplantation in patients with end-stage renal disease (ESRD). Method All subjects were prospectively recruited prior to kidney transplantation in our center at Centro Medico Nacional de Occidente, Jalisco, Mexico. Demographics, echocardiographic evaluation, clinical and biochemical studies were performed before and after KT. Patients with transplant failure after KT were excluded. Thirty patients were included in the final analysis. Statistical analysis: Results are expressed as means and standard deviation (SD). Accordingly, paired T test or Wilcoxon test were used for comparison of paired observations. Categorical variables were compared using chi-square test or Fisher’s exact probability test, as appropriate. Multivariate logistic regression models including the variables changes in LVEF, LV systolic and diastolic function and LV mass index. Statistical analyses were performed using SPSS v26.0 (IBM Corporation, NY, USA); p &amp;lt; 0.05 was considered statistically significant. Results Mean age was 31.99 ± 11.28 years, and 65% were women. Before transplant, LVEF was 58% and pulmonary arterial pressure was 32 mmHg. Ventricular dysfunction was associated with unclamping donor renal vessels at 107.8 ± 7.96mmHg, and lower perioperative hemodynamics values. The LVEF group increased from 25% to 72.5%, and serum creatinine decrease from 2.25 ± 3.76 mg/dl to 1.98± 2.65 mg/dl (p&amp;lt;0.001) by 6 months after kidney transplant. The best set of predictors in multiple regression analysis of renal function were the onset of diuresis and the use of diuretics (R2 = 0.4; p &amp;lt; 0.001). Conclusion We observed a significant reversal of LV dysfunction. This was accompanied by a significant improvement on kidney graft function. These findings highlight the dynamics between cardiac and renal function, and support the application of adequate echocardiographic evaluation on CKD patients with low LVEF undergoing KT.

Potential Molecular Mechanisms and Drugs for Aconitine-Induced Cardiotoxicity in Zebrafish through RNA Sequencing and Bioinformatics Analysis.

BackgroundAccumulating evidence suggests that cardiotoxicity is one of the main manifestations of aconitine (AC) poisoning. However, the molecular mechanism of AC-induced cardiotoxicity remains unclear, there is little direct evidence for therapeutic targets and drugs of AC-induced cardiotoxicity.Material/MethodsZebrafish were exposed to AC to evaluate cardiotoxicity by calculating the heart rates and observing the changes of cardiac and vascular structure. RNA-seq (RNA sequencing) and bioinformatics analysis were used to obtain differentially expressed genes (DEGs). The anti-AC cardiotoxicity compound was identified via connectivity map (CMAP) analysis and molecular docking.ResultsAC-induced cardiotoxicity in zebrafish predominantly included arrhythmias, extended sinus venous and bulbus arteriosus (SV-BA) distance, and larger pericardial edema aera. A total of 1380 DEGs were identified by RNA-seq and bioinformatics analysis. cyclin-dependent kinase-1 (CDK1) was screened as the hub gene and the most potential therapeutic target due to its significant downregulation in cardiotoxicity based on protein-protein interaction (PPI) and drug-gene interaction (DGIdb) network analysis. Cell cycle signal pathway was the most significant pathways identified in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Furthermore, the expression of CDK1 was validated in the Gene Expression Omnibus (GEO) database GSE71906, GSE65705, and GSE95140. Finally, heptaminol was identified as a novel anti-AC cardiotoxicity compound via CMAP analysis and molecular docking.ConclusionsTotally, hub genes and key pathways identified in this study can aid in the understanding of the molecular changes in AC-induced cardiotoxicity. Meanwhile, we provide a systematic method to explore drug toxicity prevention and treatment.

Maternal Glycemia During Pregnancy and Child Carotid Intima Media Thickness, Pulse Wave Velocity, and Augmentation Index.

In women without diabetes, little is known about the consequences of hyperglycemia during pregnancy for the offspring's cardiovascular structure and function. To investigate the association of maternal glycemia during pregnancy with cardiovascular risk markers in their children in GUSTO, a Singaporean birth cohort study. Around 26 weeks' gestation, a 75 g oral glucose tolerance test was performed and fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPPG) concentrations were measured. Gestational diabetes mellitus (GDM) was defined using WHO 1999 diagnostic criteria. At 6 years of age, we measured the child's carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), and blood pressure (BP). Association of maternal glycemia during pregnancy with cardiovascular risk markers in their children were analyzed using multiple linear and logistic regressions. Analysis were performed on 479 mother-child dyads. Higher maternal FPG was associated with higher cIMT and, in males, with a higher cfPWV in the offspring (adjusted β [CI 95%], cIMT: 0.08 per 10mm increase [0.02; 0.15], cfPWV: 0.36 m/s [0.01; 0.70]). Higher 2-hour PPPG was associated with higher cfPWV and AIx. Gestational diabetes mellitus was associated with higher AIx. No association was found between maternal glycemia and their offspring blood pressure. among mothers without pre-existing diabetes, higher glycemia during pregnancy was associated with mild structural and functional vascular changes in their children at 6 years of age across a continuum. These results support the necessity to monitor maternal glycemia during pregnancy even in the absence of pre-existing diabetes or diagnosed GDM.