Reactive Hyperemia Peripheral Arterial Tonometry Research Articles

Association between protein arginine N-methyltransferase 1 polymorphism and overt diabetic nephropathy: Role of asymmetric dimethylarginine in vascular tone

Backgroundω-NG,NG-asymmetric dimethylarginine (ADMA) regulates vascular tone and may participate in the pathogenesis of diabetic nephropathy (DN). ObjectiveTo investigate whether single-nucleotide polymorphisms (SNPs) around the protein arginine N-methyltransferase 1 gene (PRMT1) influence ADMA dynamics and DN incidence and severity. MethodsThis study utilized a hospital-based database containing 310 Japanese patients with type 2 diabetes mellitus (T2DM). The association of PRMT1-related tagged SNPs with DN stage distribution was examined using a dominant model of minor alleles. PRMT1 mRNA, serum ADMA, reactive hyperemia-peripheral arterial tonometry index (RHI), and brachial-ankle pulse wave velocity (baPWV) were compared between the genotype-based subgroups of causal SNP, and correlations between these variables were evaluated. ResultsThe composition of DN stages significantly differed between the GG and GA + AA subgroups of rs892151 (p = 0.026). In a propensity-matching cohort of rs892151, the GA + AA subgroup had an increased incidence of overt DN (odds ratio 2.92, 95 % confidence interval 1.12–7.62, p = 0.028), along with higher PRMT1 mRNA, serum ADMA levels, and baPWV than the GG subgroup (p < 0.001, p = 0.023 and 0.047, respectively). There were correlations between PRMT1 mRNA and serum ADMA levels, between serum ADMA levels and RHI, and between baPWV and urinary albumin excretion (r = 0.335, p < 0.001, r = -0.221, p = 0.029, and r = 0.254, p = 0.004, respectively). ConclusionsT2DM patients carrying the PRMT1-related variant rs892151 were susceptible to overt DN. ADMA-mediated endothelial dysfunction and arterial stiffness may be involved in the variant-related pathogenesis of overt DN.

Endothelial function in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors is not related to cardiovascular risk assessed by SCORE2 algorithm.

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML) but are endowed with negative effects on endothelial function. To characterize endothelial function in patients with CML treated with various TKIs. Forty-eight patients diagnosed with chronic phase CML treated with TKIs, such as imatinib, bosutinib, nilotinib, ponatinib, and asciminib were included. Endothelial function was assessed in the brachial artery and microcirculation based on flow-mediated dilation (FMD), reactive hyperemia peripheral arterial tonometry (RH-PAT) and Flow Mediated Skin Fluorescence (FMSF). Reactive Hyperemia Index (RHI), FMD [%], Reactive Hyperemia Response (RHR [%]), Normoxia Oscillatory index (NOI [%]) and Hyperemic Response index (HR index [%]) did not differentiate between the group of patients with low / moderate risk in the Systemic Coronary Risk Estimation 2 (SCORE2), SCORE2-Older Persons (SCORE2-OP) and those with high / very high-risk scores. Among patients with low/intermediate risk based on the SCORE2 algorithms, some had lower (<Q1) values of endothelial parameters, reflecting impaired endothelial function, when compared with the whole population. Lower values of endothelial function parameters were associated with overall long-term treatment with TKIs or ponatinib treatment. Importantly, endothelial function assessed by FMSF (RHR [%]) negatively correlated with the total duration of TKI treatment, also after adjustment for age. Endothelial function in CML patients treated with TKIs was not related to cardiovascular risk based on SCORE2/SCORE2-OP algorithms but CML-specific factors, including duration of TKI treatment. FMSF-based assessment of skin microcirculation was a sensitive method for detecting the vascular effects of TKIs.

PS-C05-6: EFFECT OF CORONARY RISK FACTORS AND PRESENCE OF CORONARY ARTERY DISEASE ON DIURNAL VARIATION IN VASCULAR ENDOTHELIAL FUNCTION

Purpose: Vascular endothelial dysfunction, an early change in atherosclerosis, is an independent risk factor for cardiovascular disease and is known to be reversible; RH-PAT (Reactive Hyperemia Peripheral Arterial Tonometry) can noninvasively measure vascular endothelial function. However, it is difficult to interpret the pathological significance of a single measurement because of many modifying factors such as diet, temperature, and medications. In this study, we aimed to investigate the effects of coronary risk factors and the presence of coronary artery disease on the diurnal variation of vascular endothelial function. Methods: Between May 2013 and May 2015, 498 patients (31% female, 19–94 years old, mean 66.7 ± 12.5 years) who were admitted to our hospital for cardiac catheterization, percutaneous coronary angioplasty, catheter ablation, or lower extremity peripheral angioplasty underwent RH-PAT examination (The Endo PAT 2000 system, Itamar Medical Ltd, Caesarea, Israel). The correlation between coronary risk factors and RH-PAT results was investigated. Correlations between coronary risk factors and RH-PAT results were also examined in patients who underwent coronary angiography. Results: The Reactive Hyperemia Index (RHI) was significantly lower in the group with smoking habit than in the nonsmoking group. Neither the number of coronary artery branches involved, the presence or absence of atrial fibrillation, nor the responsiveness to coronary spasm induction tests correlated significantly with the RHI. On the other hand, there was a significant difference between the morning and afternoon measurements in the group without coronary artery lesions, but no significant difference between the morning and afternoon measurements in the group with coronary artery lesions, regardless of the number of lesioned branches. Conclusions: Patients with a history of smoking, coronary artery lesions, and coronary spasms may have impaired diurnal variation in vascular endothelial function, suggesting that RH-PAT may be useful as an early indicator of coronary artery disease when measured at different time points.

Increased soluble endoglin levels in newly-diagnosed type 2 diabetic patients are associated with endothelial dysfunction.

Endothelial dysfunction (ED) contributes to the pathologic process underlying macrovascular complications, a common complication of type 2 diabetes mellitus (T2DM). Soluble endoglin (sEng) shed from the extracellular domain of the entire endoglin molecule blocks endothelial protection mediated by transforming growth factor-beta 1 (TGF-β1). The reactive hyperemia index (RHI), which is determined by reactive hyperemia peripheral arterial tonometry (RH-PAT), is a new index with which to evaluate ED. This study determined the changes in serum sEng levels in newly-diagnosed (untreated) T2DM patients and the correlation with the RHI. The T2DM group included 34 newly-diagnosed T2DM patients, while the control group included 53 healthy adults. The clinical data from the two groups were evaluated retrospectively. The intima-media thickness (IMT) of the common carotid artery (CCA) and the ankle-brachial index (ABI) of both legs were used to assess structural vascular changes. The serum sEng level was determined using an ELISA kit. Endothelial function was assessed using RH-PAT and the RHI was computed. The serum sEng level in the T2DM group was significantly greater than the control group, although the RHI was significantly lower in the T2DM group (p < 0.05). The serum sEng level was negatively correlated with the RHI in T2DM patents (r = 0.354, p = 0.041). The serum sEng level, CCA-IMT, and ABI were not significantly correlated with T2DM (p > 0.05). In summary, among newly-diagnosed T2DM patients, the serum sEng levels were inversely correlated with the RHI, and an elevated sEng level may be associated with ED.

Optimal uric acid reduction to improve vascular endothelial function in patients with chronic heart failure complicated by hyperuricemia.

Although an association of serum uric acid levels with endothelial function has been shown in various clinical settings, the optimal treatment target that would benefit vascular endothelial function has not been established. We, therefore, conducted a post hoc analysis of the Excited-UA study to identify an optimal target. Patients (N = 133) with chronic heart failure and comorbid hyperuricemia who enrolled in the Excited-UA study were divided into three tertiles based on their serum uric acid level 24 weeks after initiating xanthine oxidase inhibitor treatment with topiroxostat or allopurinol (i.e., groups with low, moderate, and high uric acid levels). Flow-mediated dilation (FMD) and reactive hyperemia index (RHI) values measured by reactive hyperemia peripheral arterial tonometry (RH-PAT) were compared among groups. The change from baseline in the FMD value 24 weeks after treatment was comparable among the three groups. In contrast, the change from baseline in the RHI was significantly different among the three groups (-0.153 ± 0.073, 0.141 ± 0.081 and -0.103 ± 0.104 in the low, moderate, and high uric acid level groups, respectively, P = 0.032). After adjustment for age, body mass index, and concomitant use of diuretics, which differed among the three groups, the change in the RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group (P = 0.057) and was significantly higher than that in the low uric acid level group (P = 0.020). These results indicate that targeting excessively low uric acid levels by treatment with xanthine oxidase inhibitors might be less beneficial for improving microvascular endothelial function in patients with chronic heart failure. Comparisons of the changes from baseline in vascular endothelial function parameters at 24 weeks among the 3 groups of low, moderae and high uric acid levels achieved with xanthine oxidase inhibitors. After adjustment for confounding factors, such as age, body mass index and concomitant diuretic use, which showed differences among the 3 groups, the change in RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group and was significantly higher than that in the low uric acid level group.

Endothelial function testing before conditioning therapy is useful for predicting transplant-related complications after allogeneic hematopoietic cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is a useful tool for the treatment of hematologic malignancies. However, transplantation-related complications are the main cause of non-relapse mortality. Previous reports suggest that endothelial damage is related to early complications after HSCT. Non-invasive reactive hyperemia peripheral arterial tonometry (RH-PAT) was performed to evaluate endothelial function as a predictive marker for these complications. The reactive hyperemia index (RHI) obtained from RH-PAT was evaluated before the conditioning regimen. The relationship between the RHI and the appearance of engraftment syndrome, thrombotic microangiopathy, and acute graft-versus-host disease (aGVHD) was assessed. Receiver operating characteristic curve analysis showed that an RHI value of 1.58 was the optimal cut-off for predicting transplantation-related complications. In total, 49 patients (22 acute myelogenous leukemia, 7 acute lymphocytic leukemia, 6 myelodysplastic syndrome, 6 adult T-cell leukemia, 6 non-Hodgkin lymphoma, and 2 others) were enrolled; 34 had a normal RHI (≥ 1.59), and 15 had an abnormally low RHI (≤ 1.58). Thrombotic microangiopathy (20.2% vs 0.0%, P = 0.025) and aGVHD (80.0% vs 41.2%, P = 0.015) were significantly more frequent in patients with a low RHI. Endothelial dysfunction assessed by RH-PAT before HSCT was able to predict transplantation-related complications.

Abstract 14141: A Novel Endothelial Function Test in Predicting Late Coronary In-Stent Restenosis

Introduction: Endothelial dysfunction is related with in-stent restenosis (ISR) of prior drug-eluting stents (DES) implanted more than 1 year ago (late ISR). EndoPAT is a novel non-invasive test quantifying endothelial function as reactive hyperemia peripheral arterial tonometry index (RHI). Hypothesis: EndoPAT is a potential predicting test for late ISR. Methods: We conducted a case control study on 186 patients with coronary DES implanted more than 1 year ago in a single medical center. Those who had contraindications to EndoPAT test, acute myocardial infarction, coronary artery bypass graft (CABG), chronic kidney disease (CKD) stage III and above, active infection and rheumatologic disease or acute decompensated heart failure were excluded. Patients were divided into ISR and non-ISR group based on coronary angiography. EndoPAT test was done at 24 to 48 hours prior to catherization. LnRHI is an index after natural log transformation of RHI. A receiver operative characteristic (ROC) curve analysis was used to determine the sensitivity and specificity of LnRHI for predicting late ISR. Results: ISR group had significantly more patients with history of ISR or triple-vessel disease, longer stent length and fewer totally occlusive lesions than non-ISR group. LnRHI was significantly lower in ISR group than in non-ISR group (0.66 vs 0.50, p&lt;0.01). Patients with diffuse ISR had lower LnRHI than those with focal ISR (0.40 vs 0.55, p=0.03). Patients without ISR but undergoing revascularization had lower LnRHI than those with patent coronary arteries (0.56 vs 0.70, p=0.02). Endothelial function quantified by LnRHI was an independent risk factor for ISR (LnRHI/0.1, OR=0.79, 95% CI 0.64-0.97, p=0.03). The ROC curve analysis showed LnRHI of 0.44 had a sensitivity of 81.7% and specificity of 53.8% for predicting late ISR. Conclusions: Endothelial dysfunction measured by EndoPAT had a clinical potential for predicting the development of late ISR.

Abstract 13368: Effect of Peripheral Endothelial Function Assessment in Improving the Risk Stratification of Major Cardiovascular Events Beyond CHA2DS2-Vasc

Introduction: Peripheral microvascular endothelial dysfunction (PMED) is a marker and precursor of atherosclerosis and is associated with an increased risk of cardiovascular events. The present study aims to identify the best cut-off value of PMED, assessed by the reactive hyperemia index, in predicting major adverse cardiovascular events (MACE). Additionally, we investigate whether integrating PMED to CHA2DS2-Vasc score improves the predicting accuracy of cardiovascular disease. Methods: this is a retrospective study of patients who underwent reactive hyperemia peripheral arterial tonometry (PAT). The optimal cut-off value of reactive hyperemia index associated with MACE was calculated using the area under the receiver-operating curve and the maximum Youden index. Traditional cardiovascular risk factors such as age, sex, congestive heart failure, hypertension, diabetes, stroke, vascular disease were determined to calculate the CHA2DS2-VASc score. MACE was defined as myocardial infarction, heart failure hospitalization, and cerebrovascular events. Results: 1,690 patients were enrolled (average age 51.1±13.9, 64.1% female). The optimal cut-off value of the reactive hyperemia index was 2.0 in the overall population and females and 2.17 in males. The risk of MACE during 10 (Interquartile range: 4,16) years of follow-up was 15.3%. Multivariable logistic regression revealed that PMED as an independent predictor of MACE (PMED: OR, 3.6, 95% CI, 2.6-4.9, p&lt;0.001) (Table1). Furthermore, integrating PMED to CHA2DS2-VASc significantly improved the predictive accuracy (area under the curve, 0.747 vs. 0.708, p&lt;0.001). Conclusion: PMED is a strong predictor of cardiovascular events. Non-invasive assessment of peripheral endothelial function may be useful in early detection and improving the stratification of high-risk patients for cardiovascular events.

Abstract 11957: Physical Training Augmented With Whole Body Electronic Muscle Stimulation is Superior to Conventional Training Alone in Healthy Subjects, a Pilot Randomized Controlled Trial

Introduction: Physical activity is protective against cardiovascular (CV) disease and mortality, yet more than 25% of adults do not perform any regular exercise. Whole body electronic muscle stimulation (WB-EMS) is a novel FDA-approved device used for physical training that simultaneously stimulates all major muscle groups using percutaneous electrical impulse transmission during exercise. Preliminary studies demonstrated increased muscle mass, reduced fat mass, and improved functional capacity in elderly individuals who trained with WB-EMS. We evaluated the effects of training with WB-EMS on measures of CV health. Methods: Healthy adults were randomized to physical training with versus without WB-EMS for one 20-minute session each week for 16 weeks. Participants wore a specifically designed vest and arm and leg straps connected to the WB-EMS device (Miha Bodytec, Germany). Biphasic electrical stimulation was delivered through the vest and straps (4 sec on, 4 sec off) at a frequency that elicited a score of 5-6 on the Borg perceived exertion scale when each major muscle group was stimulated. Individuals randomized to no WB-EMS wore the same equipment but received no stimulation. Sessions were provided by trainers certified in WB-EMS training and consisted of a fixed protocol of simple exercises such as squats and lunges. Temporal changes in measures of CV health were compared between groups. Results: Forty-one individuals were recruited between 02/2021 and 02/2022 (n=24 WB-EMS, n=17 no WB-EMS; mean age 35.9±11.2 yrs; 61.3% females; median BMI 24.3 (21.8, 28.1) kg/m 2 . After 16 weeks there were significant and favorable differences in the intervention group compared to controls in waist: hip ratio (-1.2 cm vs. 0.9, p=0.05); total cholesterol (-1.1 mg/kg vs. 14.2 mg/kg, p=0.02); anaerobic threshold (68.2% vs. 30.8%, p=0.03); breathing efficiency (VE/VCO2: -10.36 vs -7.38, p=0.01); and peripheral endothelial function, measured with reactive hyperemia peripheral arterial tonometry (-0.009 vs. -0.29, p=0.06). Conclusions: Once weekly training with WB-EMS yielded more favorable changes in CV biomarkers compared to conventional training alone in healthy adults, and thus may offer an effective and time-efficient method of physical training.

Effects of fructose restriction on blood pressure: Secondary analysis of a double-blind randomized controlled trial

Despite convincing animal data, there is an ongoing debate on whether and how fructose affects blood pressure in humans. The aim of this study was to investigate the effects of fructose restriction on blood pressure, and the role of endothelial function herein. forty-four overweight individuals were asked to follow a fructose-restricted diet (<7.5g/meal and <10g/day) for 6 weeks. They were randomly assigned to double-blind supplementation with glucose (=intervention group) or fructose (=control group) powder three times daily. Office blood pressure was measured with an automated device, and endothelial function was assessed by reactive hyperemia peripheral arterial tonometry, skin laser doppler flowmetry, and serum sE-selectin. Thirty-seven participants completed the study. Systolic blood pressure decreased significantly in the intervention group (change from baseline:-3.3mmHg; 95%CI:-8.8,- 0.3), but this change was not statistically different from the control group. In contrast, diastolic blood pressure decreased significantly in the intervention group in comparison to controls (difference:-4.0mmHg; 95%CI:-9.5,-0.5). Furthermore, the change in fructose intake was associated with the change in diastolic blood pressure (beta: 0.085mmHg; 95% CI: 0.032;0.138). The endothelial markers were not affected by the intervention. Finally, the effects of the intervention on diastolic blood pressure appeared to be higher in individuals consuming high amounts of salt at baseline (difference:-9.0mmHg; 95%CI:-14.5,-2.5). Six-week fructose restriction per se results in a dose-dependent decrease in diastolic blood pressure. Further studies are warranted to elucidate the effects of fructose restriction on salt-sensitive hypertension in humans. www. gov; NCT03067428.

Hypoglycemia induces vascular endothelial dysfunction in subjects with normal glucose tolerance

This prospective study determined the effects of hypoglycemic stimulation on vascular endothelial function in non-diabetic patients using reactive hyperemia peripheral arterial tonometry (RH-PAT). The study included non-diabetic patients who were hospitalized for an insulin tolerance test (ITT) for the diagnosis of hypoadrenocorticism or hypopituitarism. Vascular endothelial function was assessed using the reactive hyperemia index (RHI) measured by the RH-PAT. We also measured the levels of anterior pituitary hormone, adrenaline, noradrenaline, and dopamine at the time of hypoglycemia. The primary endpoint was a change in the RHI at 120 min after insulin administration. The study included 27 patients. ITT was associated with significant increases in systolic blood pressure, pulse rate, and the blood levels of adrenocorticotropic hormone, cortisol, growth hormone, adrenaline, noradrenaline, and dopamine. RHI significantly decreased after ITT from 2.24 ± 0.51 to 1.71 ± 0.42. A significant inverse correlation was observed between the change in RHI and change in adrenaline (r = − 0.670, p = 0.012). We concluded that hypoglycemic stimulation altered vascular endothelial function, as measured by RH-PAT, even in patients free of glucose intolerance. The observed deterioration in vascular endothelial function correlated with increases in catecholamine levels during hypoglycemia.Trial registration: UMIN000033244.

Long term non-invasive endothelial function assessment in patients with paediatric inflammatory multisystem syndrome temporarily associated with Covid 19 (PIMS TS)

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patients with PIMS-TS present with features of vasculitis (bright coronary arteries and diffuse coronary ectasia on transthoracic echocardiography) and prothrombotic features (e.g. elevated D Dimers) indicating involvement of the endothelial layer in the inflammatory process. Impairment in endothelial function may contribute to the acute but also to possible long-term consequences in patients with PIMS-TS. The aim of this pilot study is to assess non-invasively the endothelial (dys)function using reactive hyperemic peripheral arterial tonometry (RH-PAT) 6 months after the acute inflammatory phase. Methods Ten patients with previous diagnosis of PIMS-TS were compared to age-matched controls. The endothelial function was assessed using the EndoPAT device which provides the reactive hyperemic index (RHI) of endothelial function in a 15-min test. Cardiac function indices by means of LV fractional shortening (FS) was also assessed. Results There were no significant differences regarding age (11.2 ± 3.0 vs 13.6 ± 2.4, p = 0.063), height, weight and body surface area, (BSA: 1.49 ± 0.36 vs 1.52 ± 0.25, p = 0.856) in patients with previous diagnosis of PIMS-TS and controls respectively. The two groups also had similar LV systolic function assessed by FS (36.3 ± 9.1% vs 36.7 ± 7.1%, p = 0.922). The RHI in the PIMS TS group was similar to the control group (1.65 ± 0.43 vs 1.81 ± 0.60, p = 0.533 respectively). Conclusions. Patients with PIMS-TS who may present with features of vasculitis during the acute phase, do not show evidence of endothelial dysfunction during the long term follow-up, suggesting resolution. Further studies are required to accurately determine the endothelial (dys)function during the acute phase of the inflammatory syndrome and course.

Validity of flow-mediated dilation and reactive hyperemia index in assessing the risk of coronary artery disease based on the new definition by the Japan Society for Vascular Failure

Background: Flow-mediated dilation (FMD) measurement and reactive hyperemia-peripheral arterial tonometry (RH-PAT) are established methods for assessing vascular endothelial function. Recently, the Japan Society for Vascular Failure proposed a new definition for the values of FMD (≥7.0%, normal; 7.0%> and ≥4.0%, borderline; 4.0%≥, abnormal) and reactive hyperemia index (RHI) measured using RH-PAT (≥2.10, normal; 2.10≥ and >1.67, borderline; 1.67≥, abnormal). This study aimed to assess the clinical significance of FMD and RHI in coronary artery disease (CAD) based on the new definition. Methods: We performed simultaneous FMD and RH-PAT measurements in 131 patients undergoing coronary angiography for suspected CAD. The patients were divided into subgroups according to the normal, borderline, and abnormal values of FMD and RHI in the new definition. Results: No significant correlation was found between the FMD and RHI values in the overall patients. In the normal FMD/normal RHI, normal FMD/abnormal RHI, abnormal FMD/normal RHI, and abnormal FMD/abnormal RHI groups, the prevalence of multivessel CAD was 0%, 25%, 36%, and 56% (P=0.038), respectively. Furthermore, multivessel CAD was observed in 17% of patients in the borderline FMD/borderline RHI group, and the prevalence showed a significant difference among the normal FMD/normal RHI, borderline FMD/borderline RHI, and abnormal FMD/abnormal RHI groups (P=0.006). Multivariate logistic regression analysis showed that abnormal FMD/abnormal RHI was an independent predictor of multivessel CAD (odds ratio: 3.172, 95% confidence interval: 1.012-7.336, P=0.042). Conclusions: The evaluation of simultaneously measured FMD and RHI values based on the new definition would be advantageous for predicting the severity of CAD.

A Case of Vascular Endothelial Dysfunction Detected Using Reactive Hyperemia-Peripheral Arterial Tonometry Contributed to the Development of Coronary Spastic Angina in a 10-Year-Old Boy

冠攣縮性狭心症（Coronary Spastic Angina: CSA）を小児期に発症することは稀であり，その病態も不明な部分が多い．症例は10歳男児で，以前より非運動時に15～30分ほどの胸痛を認めていた．就寝中に突然絞扼感を伴う左前胸部痛が出現し，30～40分で自然軽快した．心電図で広範な誘導におけるSTの上昇を認め，心筋逸脱酵素も有意に上昇していた．心エコーで急性心筋炎や冠動脈の器質的疾患を疑う所見を認めず，CSAを疑い硝酸薬を開始した後は症状再発なく経過した．アセチルコリン負荷試験では冠動脈3枝のびまん性の攣縮とV4–6でのST上昇を認めた．CSAと診断してカルシウム拮抗薬の内服を開始し，以後，狭心症状はみられていない．退院後に施行したReactive Hyperemia-Peripheral Arterial Tonometryでは血管内皮機能の指標である反応性血管指数が1.17と正常下限（1.67）を大きく下回っていた．基礎病態として全身性の血管内皮機能障害の存在が示唆され，小児期発症CSAの病態に関与する可能性があると考えられた．

In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19

BackgroundEndothelial dysfunction is one of the underlying mechanisms to vascular and cardiac complications in patients with COVID-19. We sought to investigate the systemic vascular endothelial function and its temporal changes in COVID-19 patients from a non-invasive approach with reactive hyperemia peripheral arterial tonometry (PAT). MethodsThis is a prospective, observational, case-control and blinded study. The population was comprised by 3 groups: patients investigated during acute COVID-19 (group 1), patients investigated during past COVID-19 (group 2), and controls 1:1 matched to COVID-19 patients by demographics and cardiovascular risk factors (group 3). The natural logarithmic scaled reactive hyperemia index (LnRHI), a measure of endothelium-mediated dilation of peripheral arteries, was obtained in all the participants and compared between study groups. Results144 participants were enrolled (72 COVID-19 patients and 72 matched controls). Median time from COVID-19 symptoms to PAT assessment was 9.5 and 101.5 days in groups 1 and 2, respectively. LnRHI was significantly lower in group 2 compared to both group 1 and controls (0.53 ± 0.23 group 2 vs. 0.72 ± 0.26 group 1, p = 0.0043; and 0.79 ± 0.23 in group 3, p < 0.0001). In addition, within group 1, it was observed a markedly decrease in LnRHI from acute COVID-19 to post infection stage (0.73 ± 0.23 vs. 0.42 ± 0.26, p = 0.0042). ConclusionsThis study suggests a deleterious effect of SARS-CoV-2 infection on systemic vascular endothelial function. These findings open new venues to investigate the clinical implication and prognostic role of vascular endothelial dysfunction in COVID-19 patients and post-COVID syndrome using non-invasive techniques.

Impact of Peripheral Microvascular Endothelial Dysfunction on White Matter Hyperintensity

BackgroundWhite matter hyperintensity (WMH), characterized by hyperintensities on T2‐weighted fluid‐attenuated inversion recovery brain magnetic resonance imaging, has been linked to an increased risk of ischemic stroke (IS). Endothelial dysfunction is an indicator of vascular dysfunction, predicting the risk of IS. This study aimed to investigate the association between endothelial dysfunction and regional WMH, and its impact on future risk of IS.Methods and ResultsWe enrolled 219 patients (mean age, 53.1±14.1 years; 34.7% men) who underwent peripheral endothelial function assessment using reactive hyperemia peripheral arterial tonometry and brain magnetic resonance imaging without any history of IS. Volumetric WMH segmentation was automatically extrapolated using a validated automated digital tool. Total and juxtacortical WMH volume/intracranial volume (%) increased with aging and became more prominent in patients aged >50 years (n=131) than those aged ≤50 years (n=88) (total WMH: ≤50 years, Pearson r=0.24, P=0.03; >50 years, Pearson r=0.62, P<0.0001; juxtacortical WMH: ≤50 years, Pearson r=0.09, P=0.40; >50 years, Pearson r=0.55, P<0.0001). Reactive hyperemia peripheral arterial tonometry index was negatively associated with total and juxtacortical WMH volume/intracranial volume (%) in patients aged >50 years after adjustment for other covariates (reactive hyperemia peripheral arterial tonometry index, standardized β coefficient −0.17, P=0.04). Juxtacortical WMH volume/intracranial volume (%) was associated with an increased risk of IS during median follow‐up of 6.5 years (hazard ratio, 1.47; 95% CI, 1.05–1.92; P=0.03).ConclusionsPeripheral endothelial dysfunction is associated with an increased volume of juxtacortical WMH in patients aged >50 years, which is a potential marker to predict future risk of IS.

A Randomized, Double-Blind Comparison Study of Royal Jelly to Augment Vascular Endothelial Function in Healthy Volunteers.

Aims: Royal jelly, a creamy substance secreted by honeybees, has been reported to have beneficial effects against dyslipidemia and metabolic syndrome. However, the effects of royal jelly on atherogenesis remain unknown. Hence, we prospectively evaluated whether royal jelly augments vascular endothelial function, which can reflect early atherogenesis, in healthy volunteers. Methods: This was a single-center, double-blind, 1:1 randomized placebo-controlled study conducted from October 2018 to December 2019. A total of 100 healthy volunteers were randomly assigned to receive either royal jelly 690 mg or placebo daily for 4 weeks. The primary endpoint was augmentation in vascular endothelial function as assessed using the change in the reactive hyperemia peripheral arterial tonometry index (RH-PAT) index, and the secondary endpoints were the changes in liver function and lipid profiles between baseline and 4 weeks after enrollment. Results: The mean age of the participants was 35.0±9.3 years in the placebo group and 36.1±9.1 years in the royal jelly groups; 45% and 50% of the placebo and the royal jelly groups, respectively, were male. The percentage relative change in the RH-PAT index was significantly higher in the royal jelly group than in the placebo group (21.4%±53.1% vs. 0.05%±40.9%,P=0.037). The percentage relative changes in alanine aminotransferase and γ-glutamyl transpeptidase were significantly lower in the royal jelly group than in the placebo group (alanine aminotransferase: −6.06%±22.2% vs. 11.6%±46.5%,P=0.02; γ-glutamyl transpeptidase: −3.45%±17.8% vs. 4.62%±19.4%,P=0.045). Lipid profiles were not significantly different between the two groups. Conclusions: Royal jelly might have antiatherogenic property by improving vascular endothelial function. It also augmented liver functions in healthy volunteers.

Does overnight duty affect vascular endothelial function?

BackgroundThe reactive hyperemia index (RHI), which is obtained from the measurement of peripheral arterial tonometry (PAT), is highly associated with the percentage change in the end-diastolic arterial diameter (%flow-mediated dilatation) at reactive hyperemia. Low RHI is reported to be a mortality risk in patients with a high risk of cardiovascular (CV) disease. CV events are thought to be induced by physical and mental stress, including long-term fatigue and lack of sleep. However, the relationship between fatigue, lack of sleep, and endothelial function has not yet been established.MethodsHealthy hospital workers (n = 13, 6 men and 7 women) with an average age of 31.6 years were assigned to this study after they provided written informed consent. During the study period, we conducted 72 measurements of reactive hyperemia-peripheral arterial tonometry (RH-PAT) in the morning before or after their duty. At each measurement of the RH-PAT, we recorded the participants’ hours of sleep and evaluated their degree of fatigue using a visual analog scale (VAS).ResultsAlthough the VAS was significantly less (36 ± 16% and 64 ± 12%, p < 0.001) and the hours of sleep were longer (6.0 ± 1.1 h and 2.3 ± 1.0 h, p < 0.001) before duty compared to those after duty, the RHI was comparable between them (2.12 ± 0.53 vs. 1.97 ± 0.50, p = 0.21). The VAS score was significantly higher in participants with low RHI (< 1.67) than in those with normal RHI (≥ 2.07) (59 ± 13% and 46 ± 21%, respectively, p < 0.05). However, binary logistic regression showed no significant association between low RHI and the VAS when adjusted for systemic blood pressure (SBP) and heart rate variability (HRV). In a simple regression analysis, the RHI was significantly correlated with the VAS score but not with sleep duration. A multiple linear regression analysis also showed no significant association between the RHI and VAS scores after adjustment for SBP and HRV.ConclusionsVascular endothelial function was not associated with overnight duty, hours of sleep, or degree of fatigue in healthy young adults. Since the RHI may be decreased in severe fatigue conditions through autonomic nerve activity, one should consider the physical and mental conditions of the examinee when evaluating the RH-PAT results.

Vascular Protective Effects of New Oral Anticoagulants in Patients with Atrial Fibrillation.

This study was designed to determine the efficacy of a new oral anticoagulant (NOAC) therapy for the prevention of endothelial dysfunction and atherosclerosis progression in patients with atrial fibrillation (AF). Sixty-five AF patients with a CHA2DS2-VASc score ≥2 without previous history of cardiovascular disease were registered and randomly assigned to either an NOAC group (dabigatran or rivaroxaban) or the warfarin group. Reactive hyperemia peripheral arterial tonometry (RH-PAT) measurements reflecting endothelial function were taken using Endo-PAT2000. Carotid intima–media thickness (IMT) was measured at baseline, 12 months, and 24 months, and several biomarkers were also analyzed. For the primary end point, the reactive hyperemia index (RHI) for the NOAC group was 1.5 ± 0.4 and that for the warfarin group was 1.6 ± 0.5. The left and right carotid IMT was 0.7 mm in the NOAC groups and 0.8 mm in the warfarin group. At 12 months, RHI was 1.6 ± 0.3 for the dabigatran group, 1.6 ± 0.5 for the rivaroxaban group, and 1.6 ± 0.3 for the warfarin group. The three groups did not differ statistically with respect to change in left and right carotid IMT at 12 and 24 months, respectively. The biomarkers for endothelial function and atherosclerosis were not significantly different. There was a trend of reduced P-selectin levels in the NOAC group compared to the warfarin group. In patients with AF, there were no significant differences in the prevention of endothelial dysfunction and atherosclerosis progression between the NOAC and warfarin groups.

Peripheral microvascular dysfunction is associated with plaque progression and adverse long-term outcomes in heart transplant patients.

AimsCardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non‐heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation.Methods and resultsWe included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index < 2. The primary endpoint of the study was to investigate the association of PED with CAV progression assessed by intravascular ultrasound (IVUS). CAV progression was assessed as the change (Δ) in plaque volume divided by segment length, and Δ plaque index (plaque volume/vessel volume), adjusted for the time between IVUS measurements (median 3.0 [2.2, 3.1] years). The secondary endpoint was to investigate the association between PED and future MACE, which was defined as any incident of revascularization, heart failure hospitalization, stroke, myocardial infarction, re‐transplantation, and death. Patients with PED (n = 27) had more yearly plaque progression (0.50 ± 0.66 vs. 0.15 ± 0.50 mm3/mm/year, P = 0.02) and a higher Δ plaque index (2.41 ± 2.53% vs. 0.69 ± 2.22%, P = 0.01). Patients with PED were more likely to experience MACE during a median follow‐up of 8.2 years (interquartile range [7.6, 8.4]), after adjustment for potential cofounders such as age, high‐density lipoprotein cholesterol levels, total rejection score, baseline International Society for Heart & Lung Transplantation CAV grade, and indication of transplantation. (hazard ratio 2.15, 95% confidence interval [1.09, 4.23], P = 0.03).ConclusionsPeripheral endothelial dysfunction is associated with increased plaque progression and adverse long‐term cardiovascular outcomes in transplant patients. PED assessment might be a useful clinical tool for risk stratification after heart transplantation.