Recovery Of Endothelial Function Research Articles

Increasing Physical Tolerance during Cardiac Rehabilitation Helps to Restore Endothelial Function in Patients after Acute Coronary Syndrome

In recent years, many studies have been aimed at exploring the possibilities of cardiac rehabilitation as a tool to improve the prognosis in patients after acute coronary syndrome (ACS). Endothelial dysfunction is one of the initiating mechanisms of cardiovascular diseases, and myocardial infarction in particular, so it is important to assess the dynamics of changes in the number of endothelial progenitor cells (EPCs) in patients during cardiac rehabilitation with the increase in physical activity.
 The aim. To establish the relationship between the level of recovery of exercise tolerance and the recovery of endothelial function by determining the number of EPCs in patients undergoing cardiac rehabilitation after ACS.
 Materials and methods. The study included 44 patients with ST-elevation myocardial infarction who underwent urgent stenting of the infarct-related artery, with a mean age of 59 years (Q1-Q3; 51-64). All the study participants underwent laboratory tests (CD45+/CD34+ cell count before and after the exercise test) and instrumental tests (echocardiography, bicycle ergometry, coronary angiography). Statistical processing was carried out using SPSS Statistics 23 (trial version).
 Results. According to the results of the exercise test at the first examination, the patients were divided into 2 groups: group 1 with low exercise tolerance (≤50 W) and group 2 with high exercise tolerance (>50 W). The data obtained indicate a link between better recovery of exercise tolerance after ACS and recovery of endothelial func-tion in patients with high exercise tolerance during follow-up compared to the patients whose exercise tolerance did not exceed 50 W, as evidenced by a statistically higher number of EPCs after exercise in patients with a favor-able course and high exercise tolerance (3633 vs. 2400 cells/ml) (p=0.006). Patients with low exercise tolerance were more likely to be diagnosed with lesions of left anterior descending coronary artery (96% vs. 70%, p=0.02). More severe coronary vascular lesions with stenosis of 75% of two or more arteries showed lower pre-exercise EPCs, but increased post-exercise EPCs (+228 cells/ml), whereas in the group with stenosis of more than 75% of one vessel, a decrease in post-exercise EPCs (–604 cells/ml) was observed (p=0.004). If patients have more than one stent, there is a 2.5-fold increased risk of decreased exercise tolerance to values of 25-50 W (relative risk = 1.8; 95% confidence interval: 1.3-2.4).
 Conclusions. The data obtained indicate that there is an association between a better recovery of exercise tolerance after ACS and recovery of endothelial function in patients with a favorable course at repeated examination, compared to patients whose level of exercise tolerance did not exceed 50 W (low exercise tolerance), as evidenced by a statistically greater number of EPCs after exercise test in patients with favorable course and high exercise tolerance compared with patients with unfavorable course and low exercise tolerance.

Fat intake impairs the recovery of endothelial function following mental stress in young healthy adults.

Mental stress has been identified as a trigger of cardiovascular events. A single episode of stress can induce acute impairments in endothelial function in healthy adults. Importantly, during stressful periods, individuals often resort to unhealthy behaviors, such as increased consumption of high-fat foods, which is also known to negatively impact endothelial function. Therefore, this study examined whether consumption of a high-fat meal would further exacerbate the negative effect of mental stress on vascular function. In a randomized, counterbalanced, cross- over, postprandial intervention study, 21 healthy males and females ingested a high-fat (56.5 g fat) or a low-fat (11.4 g fat) meal 1.5 h before an 8-min mental stress task (Paced-Auditory-Serial-Addition-Task, PASAT). Plasma triglyceride (TAG) concentration was assessed pre-and post-meal. Forearm blood flow (FBF), blood pressure (BP), and cardiovascular activity were assessed pre-meal at rest and post-meal at rest and during stress. Endothelial function, measured by brachial flow-mediated dilatation (FMD) was assessed pre-meal and 30 and 90 min following mental stress. Plasma TAG concentration was significantly increased following the high-fat meal compared to the low-fat condition. Mental stress induced similar increases in peripheral vasodilation, BP, and cardiovascular activity, and impaired FMD 30 min post-stress, in both conditions. FMD remained significantly impaired 90 min following stress in the high-fat condition only, suggesting that consumption of fat attenuates the recovery of endothelial function following mental stress. Given the prevalence of fat consumption during stressful periods among young adults, these findings have important implications for dietary choices to protect the vasculature during periods of stress.

Liposomal nanocarriers of preassembled glycocalyx expeditiously restore endothelial glycocalyx in endotoxemia.

The endothelial glycocalyx (EG) is degraded early during sepsis, and currently available treatments are not effective in promptly restoring it. Here, we created liposomal nanocarriers of preassembled glycocalyx (LNPG) by synthesizing glycosylated syndecan-1 and inserting it into the lipid membrane of unilamellar liposomes. We hypothesized that LNPG would fuse with the endothelial cells where EG is degraded and restore EG in sepsis. We induced endotoxemia in C57BL/6J mice using lipopolysaccharides (LPS) and treated them with LNPG, saline, syndecan-1, or liposomes. LNPG significantly prolonged the survival time of LPS-treated mice compared with the other treatments. Immunostaining of en face mesenteric arteries of LPS-treated mice showed that syndecan-1 was fully restored after LNPG administration. In addition, EG height in microvasculature of mouse cremaster muscle was monitored using sidestream dark field imaging. LNPG restored the perfused boundary region (PBR), which is inversely related to EG dimensions, to the control level after LPS administration. Furthermore, flow-induced dilation in isolated mouse mesenteric arterioles was fully recovered after LNPG treatment in LPS-treated mice. In summary, our findings provide evidence of the therapeutic efficacy of LNPG in the LPS-induced mouse model of sepsis, achieved by expeditiously restoring EG through fusion of LNPG with the endothelial plasma membrane and recovery of endothelial function.NEW & NOTEWORTHY Vascular endothelial cells represent the first line of exposure to bacterial endotoxins. Here, we propose a novel therapeutic strategy using liposomes to deliver preassembled glycocalyx to vascular endothelial cell surface and consequently restore endothelial glycocalyx (EG). We tested liposomal nanocarriers of preassembled glycocalyx (LNPG) in vivo and ex vivo to establish for the first time their expeditious therapeutic efficacy in improving survival of lipopolysaccharides (LPS)-treated mice, as achieved by the restoration of EG and recovery of endothelial function.

KCNJ5 mutation is a predictor for recovery of endothelial function after adrenalectomy in patients with aldosterone-producing adenoma.

The relationship of KCNJ5 mutation with vascular function and vascular structure in aldosterone-producing adenoma (APA) patients before and after adrenalectomy remains unclear. The purpose of this study was to evaluate the influence of KCNJ5 mutation on vascular function and vascular structure in APA and the effects of adrenalectomy on vascular function and vascular structure in APA patients with and those without KCNJ5 mutation. Flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), brachial artery intima-media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) were measured to assess vascular function and vascular structure in 46 APA patients with KCNJ5 mutation and 23 APA patients without KCNJ5 mutation and in 69 matched pairs of patients with essential hypertension (EHT). FMD, NID, brachial IMT and baPVW were evacuated before adrenalectomy and at 12 weeks after adrenalectomy in APA patients with KCNJ5 mutation and APA patients without KCNJ5 mutation. FMD and NID were significantly lower in APA patients than in patients with EHT. There was no significant difference in FMD or NID between patients with and those without KCNJ5 mutation. In APA patients with KCNJ5 mutation, FMD and NID after adrenalectomy were significantly higher than those before adrenalectomy. In APA patients without KCNJ5 mutation, only NID after adrenalectomy was significantly higher than that before adrenalectomy. Endothelial function in APA patients with KCNJ5 mutation was improved by adrenalectomy in the early postoperative period. KCNJ5 mutation is a predictor for early resolution of endothelial function by adrenalectomy. This study was approved by principal authorities and ethical issues in Japan (URL for Clinical Trial: http://www.umin.ac.jp/ctr/index.htm Registration Number for Clinical Trial: UMIN000003409).

Protective effects and molecular mechanisms of tea polyphenols on cardiovascular diseases.

Aging is the most important factor contributing to cardiovascular diseases (CVDs), and the incidence and severity of cardiovascular events tend to increase with age. Currently, CVD is the leading cause of death in the global population. In-depth analysis of the mechanisms and interventions of cardiovascular aging and related diseases is an important basis for achieving healthy aging. Tea polyphenols (TPs) are the general term for the polyhydroxy compounds contained in tea leaves, whose main components are catechins, flavonoids, flavonols, anthocyanins, phenolic acids, condensed phenolic acids and polymeric phenols. Among them, catechins are the main components of TPs. In this article, we provide a detailed review of the classification and composition of teas, as well as an overview of the causes of aging-related CVDs. Then, we focus on ten aspects of the effects of TPs, including anti-hypertension, lipid-lowering effects, anti-oxidation, anti-inflammation, anti-proliferation, anti-angiogenesis, anti-atherosclerosis, recovery of endothelial function, anti-thrombosis, myocardial protective effect, to improve CVDs and the detailed molecular mechanisms.

Endothelial function improvement associated with the new European Society of Cardiology LDL target levels in STEMI patients

Abstract Funding Acknowledgements Type of funding sources: None. According to current guidelines, statin therapy is indicated for all ACS patients regardless of the initial cholesterol level. However, the effects of different lipid-lowering regimes on endothelial function in patients after STEMI have been insufficiently studied. Methods The study involved 135 STEMI patients admitted an average of 4.5 hours after symptoms onset and treated with primary PCI. Lipid-lowering treatment was prescribed immediately after admittance. Patients were randomly assigned to one of two patients groups – 50 pts with intermediate (atorvastatin 10 mg /ezetimibe 10 mg or atorvastatin 40 mg), and 85 pts with high intensity treatment (atorvastatin 40 mg/ ezetimibe 10 mg or atorvastatin 80 mg). Endothelial function assessment by flow-dependent vasodilation (FDV) was performed on the 1st, 10th days of the hospital period and within the 90th day of onset of the disease. Results The average level of low-density lipoprotein cholesterol (LDL) on the 90th day in patients was 1,66 ± 0.11 mmol /l. On that time frame the growth of the diameter of the brachial artery and FDV were increased by 66.2% in patients who reached LDL cholesterol <1.8 mmol/l and 85% in patients with LDL cholesterol <1.4 mmol/l versus 26.8% in patients with LDL cholesterol ≥1.8 mmol/l, p<0.05. Growth in the diameter of the brachial artery according to the results of the test with FDV more than 10% was statistically significant and more frequently observed in patients who reached the level of LDL less than 1.4 mmol /l on the 90th day (Fig.1). Conclusions Patients with STEMI who achieved a reduction in LDL cholesterol <1.4 mmol/l on the 90th day of follow-up were more likely to have a complete recovery of endothelial function. It may be dependent on early initiation of high intensity lipid-lowering treatment.

The recovery of endothelial function in novel coronavirus infection COVID-19 (review)

Endothelial dysfunction is a valued part in the pathogenesis of many diseases and conditions including the active phase of COVID-19 and postcovid syndrome. The review presents both the viral and autoimmune pathways for endothelial and glycocalyx lesions and the clinical impacts of such a lesion in comorbid patients. Both endothelium and glycocalyx affected by the SARS-CoV-2 virus are considered as the main goal for therapy in outpatient patients and patients with postcovid syndrome. The glycosaminoglycans belonged natural components of vascular wall seem appropriate pathogenetically in order to recovery the endothelial barrier. The review demonstrates the advantages and limitations of using sulodexide in patients with COVID-19. This article presents a clinical case of a patient with confirmed COVID-19 of moderate severity, with the presence of risk factors for thrombosis, who developed a post-covid syndrome, a heterogeneous symptom complex that developed after the acute phase of COVID-19 infection. The post-covid period was marked by symptoms of rapid fatigue, tachycardia, shortness of breath. By day 25-26, itching and red rash appeared, and there was moderate swelling of the shins and feet of both lower extremities. Taking into account the clinical picture and laboratory findings, a decision was made to cancel the previously prescribed low-molecularweight heparin and prescribe sulodexide at a dose of 500 LU 2 times a day for a course of 28 days. On the 4th-5th day after the start of treatment there was a decrease in the area of skin rash, cessation of itching, almost complete disappearance of the cutaneous vascular pattern and reduction in the severity of edema. This clinical case demonstrates endothelial damage caused by COVID-19, which makes it advisable to use angioprotective drugs.

MON-701 Uncontrolled Diabetes Presenting as Isolated Sixth Nerve Palsy

BACKGROUND Our case report demonstrates acute onset of diplopia due to Isolated Sixth Nerve Palsy (ISNP) secondary to uncontrolled T2DM, presenting as an ophthalmoplegia. The most frequent one, is ISNP with an incidence of 11.3/100.000 1. Vasculopathic ISNP is associated with atherosclerosis in patients older than 50 years 1.CASE PRESENTATION A 63 year-old male with history of T2DM, HTN, HL, came for evaluation of acute onset double vision 3 days prior. He noted diplopia while attempting to park his car; he saw that tracking to the left with his eyes would elicit double vision. Denied recent travel, trauma, headache or dizziness. He was awake and alert, BP 200/110mmHg, BMI 33. No pathologic murmur. He had PERRLA bilaterally but impaired lateral rectus muscle movement on the left side. Otherwise, EOMI on the right side. No facial asymmetry or ptosis. Overall, findings positive for ISNP. BMP only remarkable for a glucose of 297, HA1c was 10.0. Head CT was negative for any acute intracranial abnormality. Orbital MRI did not show acute infarction or masses. Patient was admitted for acute diplopia due to ISNP. Differential diagnoses were neoplasm, migraine, MS and diabetic neuropathy. Based on the aforementioned data, we suggested that T2DM was the probable cause. Counseling on improving glycemic control was given. Unfortunately, patient was lost to follow up. DISCUSSION ISNP remains an elusive entity; atherosclerotic risk factors such as DM, HTN, HL, hyperhomocysteinemia 2 or viral infections 3 have been reported in association. This type of palsy seems to be more frequent in children and can be recurrent in nature.In adults, the most likely cause of ISNP seems to be ischemic mononeuropathy or more aggressive etiologies such as temporal arteritis 4. Inconclusive images prove even a higher diagnostic challenge 3. Of note, we found a case demonstrating evidence for Eicosapentaenoic Acid in the improvement of ISNP with recovery in as shortly as 8 weeks. The basis of this treatment lies in the recovery of endothelial function focusing on the anti-platelet and anti-inflammatory effects of the drug2,4. REFERENCES (1). Elder, Christopher, et al. “Isolated abducens nerve palsy: update on evaluation and diagnosis.” Current neurology and neuroscience reports 16.8 (2016): 69. (2). Takenouchi, Yasuhiro, et al. “Eicosapentaenoic acid ethyl ester improves endothelial dysfunction in type 2 diabetic mice.” Lipids in health and disease 17.1 (2018): 118. (3). Azarmina, Mohsen, and Hossein Azarmina. “The six syndromes of the sixth cranial nerve.” Journal of ophthalmic & vision research 8.2 (2013): 160. (4). Yanai, Hidekatsu, and Mariko Hakoshima. “Eicosapentaenoic Acid for Diabetic Abducens Nerve Palsy.” Journal of Endocrinology and Metabolism 7.4 (2017): 131–132.

Evaluation of radial artery endothelial functions in transradial coronary angiography according to different radial access sites.

Radial endothelial dysfunction may occur after transradial coronary angiography (CAG). This study aimed to make a comparative evaluation of the radial endothelial functions before and after catheterization between three different radial access sites: left radial (LR) artery, left distal radial (LDR) artery, and right radial (RR) artery. Seventy patients scheduled for elective transradial CAG and intervention from September 6, 2017 to March 6, 2018 were consecutively enrolled. Radial artery endothelial functions of the catheterization arm were measured by flow-mediated vasodilation (FMD) upon admission, at 24 hours, and 2 months following the procedure. LR access was used in 17 patients, whereas the LDR and the RR access were used in 27 and 26 patients, respectively. Basal radial diameters and FMD median values measured on the intervention arm were found to be similar between groups (LR 3.04±0.29 mm, 13.33%; LDR 2.79±0.31 mm; 13.64%; RR 2.74±0.29 mm; 12.52%, p=0.952). The radial vasodilation percentage change expressed as median decreased in all groups 24 hours after the procedure; however, the one with the LDR access was found to be significantly higher than with the LR (9.7% vs. 6.25% p=0.013) and the RR access (9.7% vs. 3.39 p<0.001). A partial recovery of endothelial functions was seen at 2 months after the procedure, approximating to basal values (11.11%; 12%; 10.62%, p=0.079, respectively). Radial artery functions deteriorate early after transradial catheterization. The LDR access seems safer than the other conventional radial access sites in terms of preservation of radial endothelial functions.

Analysis of Vascular Mechanical Characteristics after Coronary Degradable Stent Implantation.

Purpose To explore the effect of vascular stress changes on endothelial function recovery and vascular restenosis inhibition, under the condition of dynamic degradation process of the degradable stent. Methods Fitting the material parameters of the hyperelastic vascular constitutive relationship, the stress distribution of the intima of the blood vessel before the stent was implanted and during the dynamic degradation was calculated by numerical simulation. In vitro culture experiments were carried out, and the stretch ratios of the silicone chamber were set to 0%, 5%, 10%, and 15%, respectively, to simulate the effects of different degradation stages on the growth state of endothelial cells. Results After the stent was completely degraded, the circumferential intimal stress (strain) of the vessel was recovered to 0.137 MPa, 5.5%, which was close to the physiological parameters (0.122 MPa, 4.8%) before stent implantation. In vitro experiments showed that the endothelial cell survival rate was the highest under the condition of circumferential stress (strain) of 0.1 MPa, 5%, and all adhesion growth could be achieved. Conclusions With the occurrence of degradation process of the stent, the circumferential stress (strain) of the intima was recovered to a range close to physiological parameters, which promotes the growth of endothelial cells. The recovery of intimal function can effectively inhibit the process of vascular restenosis. The results can provide a theoretical basis and experimental platform for the study of coronary intervention for the treatment of vascular restenosis.

Empagliflozin's Ameliorating Effect on Plasma Triglycerides: Association with Endothelial Function Recovery in Diabetic Patients with Coronary Artery Disease.

Aim: So far, the mechanisms behind the cardiovascular benefits of sodium/glucose cotransporter 2 (SGLT2) inhibitors have not been fully clarified.Methods: In order to evaluate the effects of SGLT2 inhibitors on systemic hemodynamics, glucose metabolism, lipid profile, and endothelial function, 50 diabetic patients with established coronary artery disease (CAD) were included in this analysis and were given empagliflozin 10 mg/d. Cookie meal testing (carbohydrates: 75 g, fats: 28.5 g), endothelial function testing using flow-mediated dilatation (FMD), and body composition evaluation were performed before and after six months of treatment. Changes in %FMD between the treatment periods and its association with metabolic biomarkers were evaluated.Results: After six months of treatment, the body weight and body fat percentage decreased significantly, while the body muscle percentage increased significantly. The hemoglobin A1c level and fasting and postprandial plasma glucose levels were significantly decreased with treatment. Postprandial insulin secretion was also significantly suppressed and the insulin resistance index was significantly decreased. Furthermore, the fasting and postprandial triglyceride (TG) levels decreased significantly, while total ketone bodies increased significantly after the six-month treatment. While the plasma brain natriuretic peptide level was not changed, the C-reactive protein level was decreased and FMD was significantly improved after the six-month treatment. Multiple regression analysis showed that the strongest predictive factor of FMD improvement is change in the plasma TG levels.Conclusion: SGLT2 inhibitors improve multiple metabolic parameters. Of these, a reduction in plasma TGs was strongly associated with endothelial function recovery in diabetic patients with CAD, and this reduction may be related to the cardiovascular benefits of SGLT2 inhibitors.

P3581Periinterventional cocoa flavanol supplementation prevents functional and structural damage to the arterial wall after transradial catheter intervention

Abstract Background The transradial approach is commonly preferred over the femoral approach for coronary angiography to reduce vascular complications like bleeding, aneurysm formation and all-cause mortality ensuring early ambulation after coronary procedures. However, there is growing evidence that damage to the radial artery endothelium elicits intimal hyperplasia, vascular remodeling and might ultimately lead to total vessel occlusion. Objective Our study aimed to investigate the effects of dietary flavanol intervention on (a) early endothelial functional recovery and (b) late structural changes i.e. intimal hyperplasia after mechanical vascular wall injury in the human forearm model during coronary angiography. Methods Radial artery flow-mediated vasodilation (RA-FMD), local stiffness (fractional diameter change, Fdc), intima-media thickness (IMT), luminal and external arterial diameter at the site of intervention and the contralateral control artery were measured in 38 male patients (19 flavanol intervention, 19 placebo control) undergoing transradial coronary angiography (TCA) at baseline, after 7 days of 450mg flavanol supplementation BID, directly after TCA and 6 months after TCA. Circulating levels of endothelial microparticle (EMP) subpopulations CD31+/41-, CD62e+and CD144+were analyzed simultaneously as a surrogate for endothelial functional integrity and activation. Results One week of flavanol supplementation, not placebo, significantly increased RA-FMD (8.88±2.03% vs. 11.17±2.89%, p&lt;0.01 in flavanol and 8.64±1.87% vs. 8.32±1.63%, p=n.s. in placebo). RA-FMD significantly decreased in the intervention artery directly after TCA, which was partly mitigated by flavanol supplementation (delta to baseline: −2.61±0.82% in flavanol vs. −4.91±0.63% in placebo, p=0.034). TCA induced significant intimal hyperplasia in the radial artery (0.36±0.02mm vs. 0.44±0.04mm, p&lt;0.01) in placebo, but not in the flavanol group (0.36±0.02mm vs. 0.37±0.02mm, p=n.s.) after 6 month. One week of flavanol supplementation increased Fdc (1.94±0.99 vs. 3.07±1.31, p&lt;0.01). No changes occurred in the placebo group (1.99±1.29 vs. 1.96±1.17, p=n.s.). On the contralateral arm, the decrease in RA-FMD was blunted by flavanols (delta to baseline: +0.42±1.05% in flavanol vs. −0.61±1.55% in placebo) along with decreased circulating levels of EMPs. Conclusions TCA impairs endothelial function (RA-FMD), vascular physicomechanics (Fdc) and induces intimal hyperplasia (IMT). Periinterventional flavanol supplementation blunts the acute decreases in endothelial function and physicomechanics and prevents chronic negative vascular remodeling.

SAT-206 EFFECT OF FRUTOOLIGOSACCHARIDE ON ENDOTHELIAL FUNCTION IN CKD PATIENTS: A RANDOMIZED CONTROLLED TRIAL

Microbiota-derived uremic toxins, p-cresyl sulfate (PCS) and indoxyl sulfate (IS), have been associated with increased cardiovascular risk in chronic kidney disease (CKD). This has encouraged the investigation of alternative approaches to modulate gut environment with consequent attenuation of toxin production, inflammation and endothelial dysfunction. This trial aimed to evaluate the effect of the prebiotic fructooligosaccharide (FOS) on endothelial dysfunction markers in CKD non-dialysis patients. The 3-month double-blind randomized controlled trial included 46 non-diabetic CKD patients [52% men; 57.6±14.4 years; eGFR: 21.3±7.3 mL/min/1.73m²]. Intervention and placebo consisted in 12g/day of FOS or maltodextrin, respectively. PCS, and IS were determined by high performance liquid chromatography. Interleukin 6 (IL6) was evaluated by ELISA essay. Endothelial dysfunction was assessed through stroma derived factor 1 alfa (SDF1 alfa), serum nitric oxide (NO) and flow-mediated dilatation (FMD). Aside for the intervention group being older (53.4±16.0 vs 61.9±11.4, p=0.04) the groups were homogeneous. [ME1] During the study, renal function, electrolytes, remained stable in both groups. A downward trend in PCS serum levels (52.86±30.68 vs 43.06±32.43 mg/L, p=0.07) was observed in the treated group. Regarding inflammation, C-reative protein did not change and IL6 decreased in this group (3.14±2.22 vs 2.65±1.37 pg/mL, p = 0.04). There was no difference in NO, SDF1 alfa levels and FMD. In an exploratory analysis, including only patients with less damaged endothelium (FMD ≥ 2.2 % median) we observed that the treated group had significant higher values of FMD after 3 months (group effect p=0.09, time effect p=0.095, interaction p=0.04). There was no effect of FOS on endothelial function in the studied population. Nonetheless, in patients with less damaged endothelium we could observe an improvement of endothelial dilatation in the treated group, which could suggest a potential impact of FOS in the recovery of endothelial function.

Inhaled carbon monoxide increases vasodilation in the microvascular circulation

Preeclampsia (PE) is characterized by systemic maternal endothelial dysfunction. Changes in endothelial reactivity have been reported before the onset of clinical signs of PE, and continuing into the post-partum period. Women who smoke during pregnancy have a 33% reduced risk of developing PE. This reduced risk is hypothesized to be, in part, attributed to carbon monoxide (CO), a by-product of cigarette combustion and a known endogenous vasodilator. Determining the vascular effects of CO in healthy women, may inform how CO can improve endothelial function and have promise as a novel therapeutic for PE. As part of a pilot study to determine the vascular effects of CO, the aim of this study was to measure microvascular vasodilation following low-dose CO inhalation. Non-pregnant women inhaled ambient room air or 250 ppm CO for 24 min during microvascular assessment using laser speckle contrast imaging. Changes in vascular flux were measured in the forearm before, during, and following a three-minute arterial occlusion. CO inhalation increased end-tidal breath CO (EtCO) (9.1 ± 1.9 vs. 1.8 ± 0.7 ppm, p < 0.05) and increased microvascular vasodilation, measured as difference of maximum level/resting level ratio (mean difference 0.476, 95% confidence interval (CI) = 0.149–0.802 vs. 0.118, 95% CI = −0.425–0.662, p < 0.05). Women who inhaled CO had a longer time to half recovery of endothelial function following arterial occlusion, compared to controls (hazard ratio 0.29, 95% CI = 0.10–0.91, p = 0.033). Inhalation of CO moderately increased EtCO and resulted in an increased microvascular response, suggesting that CO may have potential as a therapeutic for PE.

Empagliflozin Ameliorating Effect of on Plasma Triglyceride: An Association with Endothelial Function Recovery in Diabetic Patients with Coronary Artery Disease

Introduction: The mechanisms behind the cardiovascular benefits of Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors have not been fully clarified. We aimed to identify potential mechanisms underlying the favorable effects of SGLT2 inhibitors on cardiovascular events. Methods: The 50 diabetic patients with established Coronary Artery Disease (CAD) included in this study analysis were administered 10 mg/day of empagliflozin. Cookie meal testing (carbohydrates: 75 g, fat: 28.5 g), endothelial function testing using Flow-Mediated Dilatation (FMD), and body composition evaluation were performed before and after 6 months treatments. Evaluation of changes in % FMD between treatment periods, and its association with metabolic biomarkers were evaluated. Results: After the 6 month treatment, body weight and body fat percentage decreased significantly, while body muscle percentage increased significantly. HbA1C level and fasting and postprandial plasma glucose levels were significantly decreased by treatment. Postprandial insulin secretion was also significantly suppressed and insulin resistance index was significantly decreased. Furthermore, fasting and postprandial triglyceride levels decreased significantly while total ketone body increased significantly after the 6 months treatment. While plasma brain natriuretic peptide level was not changed, C-reactive protein was decreased, and FMD was significantly improved after the 6 months treatment. Multiple regression analysis showed the strongest predictive factor of FMD improvement to be change in fasting and postprandial plasma triglyceride levels. Conclusion: SGLT2 inhibitors improved multiple metabolic parameters. Of these, reduction in plasma triglyceride was strongly associated with endothelial function recovery in diabetic patients with CAD, and this reduction may be related to the cardiovascular benefit of SGLT2 inhibitors.

Recovery of Endothelial Function after Minor-to-Moderate Surgery Is Impaired by Diabetes Mellitus, Obesity, Hyperuricemia and Sevoflurane-Based Anesthesia.

Endothelial dysfunction is observed in several cardiovascular diseases, where endothelium-dependent vasodilation is impaired by oxidative stress. However, the time course of endothelial function during the perioperative period of a minor-to-moderate surgery, and the effects of atherosclerotic risk factors and employed general anesthetics on recovery of endothelial function, are unknown. Endothelial function of 30 patients was evaluated as the reactive hyperemia index (RHI) of reactive hyperemia peripheral arterial tonometry. RHI was measured on day before surgery (control), immediately after surgery (Day 0), day after surgery (Day 1), and day 4 after surgery (Day 4) in patients with no functional limitations who were scheduled for oral and maxillofacial surgery of around 3 hours. Sevoflurane- or propofol-based anesthesia supplemented with an opioid analgesic remifentanil was employed. The control RHI was 2.26 ± 0.64. The RHI significantly decreased to the lowest level on Day 0 (1.52 ± 0.28), recovered on Day 1 (2.07 ± 0.58), and improved further on Day 4 (2.55 ± 0.83). Multiple linear regression analysis revealed that recovery of the RHI from Day 0 to Day 4 was impaired by diabetes mellitus (P = 0.0313), obesity (BMI ≥ 25; P = 0.0166), hyperuricemia (uric acid ≥ 6.0 mg/dL; P = 0.0416) and sevoflurane-based anesthesia (P = 0.0308). These findings suggest that endothelial function as evaluated by the RHI is severely suppressed on the day of a minor-to-moderate surgery, and that it improves until the 4th postoperative day on average. Recovery of endothelial function is impaired by diabetes mellitus, obesity, hyperuricemia, and sevoflurane-based anesthesia.

Novel rhynchophylline analogues as microvascular relaxation agents for the treatment of microvascular dysfunction caused by diabetes

Dysfunction in vascular reactivity in the micro- and macrocirculation is well established in cardiovascular disease. However, little is known about methods that may improve vascular reactivity in patients likely to develop microvascular dysfunction. One of the racemic analogues of rhynchophylline (G2) and its stereoisomers (G2-a and G2-b) were synthesized to address this knowledge gap. The preliminary pharmaceutical studies on the relaxation of the rat thoracic aorta showed that G2 and its stereoisomers are more potent (at least 30-fold) than the natural product rhynchophylline, which encouraged us to further investigate their functions and mechanisms as treatments for microvascular dysfunction caused by diabetes. G2-a displayed the best microvascular relaxation activity on rat mesenteric arteries among the three compounds, and G2 or G2-a caused relaxation in an endothelium-dependent manner. In ex vivo tests, G2 and G2-a exhibited a weaker potency in inducing microvascular relaxation in mesenteric arteries from diabetic rats than from normal rats, most likely, due to microvascular endothelium damage caused by diabetes. However, based on the animal studies, G2 ameliorated diabetes-induced endothelial dysfunction in rat mesenteric arteries in vivo. Further investigations of the mechanism showed that G2 mainly induced the recovery of endothelial function by upregulating endothelial nitric oxide synthase (eNOS) expression and further increasing the concentration of nitric oxide (NO), which is required for vascular relaxation.

Role of flavonoids and nitrates in cardiovascular health.

CVD remain the leading cause of death globally. Effective dietary strategies for their reduction are of high priority. Increasing evidence suggests that phytochemicals, particularly dietary flavonoids and nitrates, are key modulators of CVD risk reduction through impact on multiple risk factors. The aim of this review is to explore the evidence for the impact of flavonoid- and nitrate-rich foods and supplements on CVD risk, with specific reference to their importance as mediators of vascular health and platelet function. There is accumulating evidence to support benefits of dietary flavonoids on cardiovascular health. Dose-dependent recovery of endothelial function and lowering of blood pressure have been reported for the flavanol (-)-epicatechin, found in cocoa, apples and tea, through production and availability of endothelial nitric oxide (NO). Furthermore, flavonoids, including quercetin and its metabolites, reduce in vitro and ex vivo platelet function via inhibition of phosphorylation-dependent cellular signalling pathways, although further in vivo studies are required to substantiate these mechanistic effects. Hypotensive effects of dietary nitrates have been consistently reported in healthy subjects in acute and chronic settings, although there is less evidence for these effects in patient groups. Proposed mechanisms of actions include endothelial-independent NO availability, which is dependent on the entro-salivary circulation and microbial conversion of dietary nitrate to nitrite in the mouth. In conclusion, flavonoid- and nitrate-rich foods show promising effects on vascular function, yet further randomly controlled studies are required to confirm these findings and to determine effective doses.

PLEJOTROPOWE DZIAŁANIE INHIBITORÓW 3-HYDROKSY‑3-METYLO-GLUTARYLO-KOENZYMU A (STATYN). POTENCJAŁ LECZNICZY W UKŁADOWYCH CHOROBACH TKANKI ŁĄCZNEJ

3-Hydroxy-3-Methyl-Glutharyl-Coenzyme A reduct- ase inhibitors, known as statins, form a group of chemical compounds that are characterized by the ability to inhibit cholesterol synthesis. Statins have proved their efficacy as potent drugs in the primary and secondary prevention of cardiovascular events. It has also been shown that the thera- peutic effects of statins go beyond reduction of cholesterol level. These properties, which are separate from the influ- ence on cholesterol synthesis, are sometimes called the pleio- tropic effect. This effect comprises immunomodulation, an anti-inflammatory effect, and endothelial function recovery.

Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension.

The impairment of vasodilator nitric oxide (NO) production is well accepted as a typical marker of endothelial dysfunction in vascular diseases, including in the pathophysiology of pulmonary arterial hypertension (PAH), but the molecular mechanisms accounting for loss of NO production are unknown. We hypothesized that low NO production by pulmonary arterial endothelial cells in PAH is due to inactivation of NO synthase (eNOS) by aberrant phosphorylation of the protein. To test the hypothesis, we evaluated eNOS levels, dimerization, and phosphorylation in the vascular endothelial cells and lungs of patients with PAH compared with controls. In mechanistic studies, eNOS activity in endothelial cells in PAH lungs was found to be inhibited due to phosphorylation at T495. Evidence pointed to greater phosphorylation/activation of protein kinase C (PKC) α and its greater association with eNOS as the source of greater phosphorylation at T495. The presence of greater amounts of pT495-eNOS in plexiform lesions in lungs of patients with PAH confirmed the pathobiological mechanism in vivo. Transfection of the activating mutation of eNOS (T495A/S1177D) restored NO production in PAH cells. Pharmacological blockade of PKC activity by β-blocker also restored NO formation by PAH cells, identifying one mechanism by which β-blockers may benefit PAH and cardiovascular diseases through recovery of endothelial functions.