Age-Related Progression of Microvascular Dysfunction in Cystic Fibrosis: New Detection Ways and Clinical Outcomes

There are concerns about altered vascular functions that could play an important role in the pathogenesis and influence the severity of chronic disease, however, increased cardiovascular risk in paediatric cystic fibrosis (CF) has not been yet fully understood. Aim was to analyse vascular disease risk and investigate changes over times in CF and controls. We prospectively enrolled 22 CF subjects (a median age of 16.07 years), and 22 healthy demographically matched controls (a median age of 17.28 years) and determined endothelial function. We utilised a combined diagnostic approach by measuring the plethysmographic Reactive Hyperemia Index (RHI) as the post-to preocclusive endothelium-dependent changes of vascular tone, and biomarkers that are known to be related to endothelial dysfunction (ED): asymmetric dimethyl arginine (ADMA), high-sensitive CRP (hsCRP), VCAM-1 and E-selectin. RHI values were significantly lower in CF young adults (p<0.005). HsCRP (p<0.005), E-selectin (p<0.001) and VCAM-1 (p<0.001) were significantly increased in CF patients since childhood. The findings have provided a detailed account of the ongoing process of microvascular dysfunction with gradual progression with the age of CF patients, making them further at risk of advanced vascular disease. Elevations of biomarkers in CF children with not yet demonstrated RHI changes but with significantly reduced RHI in adulthood and lipid profile changes indicate the possible occurrence of ED with CF-related specific risk factors over time and will enable us to provide the best possible support.

Endothelial Dysfunction is Associated With Early‐Onset Cryptogenic Ischemic Stroke in Men and With Increasing Age

Background The aim of this study was to assess the association between endothelial function and early‐onset cryptogenic ischemic stroke (CIS), with subgroup analyses stratified by sex and age groups. Methods and Results We prospectively enrolled 136 consecutive patients aged 18 to 49 years (median age, 41 years; 44% women) with a recent CIS and 136 age‐ and sex‐matched (±5 years) stroke‐free controls. Endothelial function was measured with an EndoPAT 2000 device and analyzed as tertiles of natural logarithm of reactive hyperemia index with lower values reflecting dysfunction. We used conditional logistic regression adjusting for age, education, hypertension, diabetes mellitus, dyslipidemia, current smoking, heavy drinking, obesity, and diet score to assess the independent association between endothelial function and CIS. Patients in the lowest tertile of natural logarithm of reactive hyperemia index were more often men and they more frequently had a history of dyslipidemia; they were also more often obese, had a lower diet score, and lower high‐density lipoprotein cholesterol. In the entire cohort, we found no association in patients with endothelial function and CIS compared with stroke‐free controls. In sex‐ and age‐specific analyses, endothelial dysfunction was associated with CIS in men (adjusted odds ratio [OR], 3.50 for lowest versus highest natural logarithm of reactive hyperemia index tertile; 95% CI, 1.22–10.07) and in patients ≥41 years (OR, 5.78; 95% CI, 1.52–21.95). These associations remained significant when dyslipidemia was replaced with the ratio of total to high‐density lipoprotein cholesterol. Conclusions Endothelial dysfunction appears to be an independent player in early‐onset CIS in men and patients approaching middle age.

Endothelial Dysfunction Is Associated with Cerebrovascular Events in Pre-Dialysis CKD Patients: A Prospective Study

Background: Patients with chronic kidney disease (CKD) have markedly increased rates of end stage renal disease, major adverse cardiovascular/cerebrovascular events (MACCEs), and mortality. Endothelial dysfunction (ED) is an early marker of atherosclerosis that is emerging as an increasingly important non-traditional cardiovascular risk factor in CKD. There is a lack of clinical studies examining the association between ED and both cardiovascular and renal endpoints in patients with CKD. Aims: We examined the association between reactive hyperemia index (RHI), a validated measure of endothelial function measured by peripheral arterial tonometry (PAT), with traditional cardiovascular risk factors in pre-dialysis CKD patients and prospectively evaluated the role of RHI as predictor of renal and cardiovascular outcomes in this population. Methods: One hundred and twenty pre-dialysis patients with CKD stages 1 to 5 (CKD group) and 18 healthy kidney donor candidates (control group) were recruited and had a successful RHI measurement by PAT. General demographic and clinical information including traditional cardiovascular risk factors were registered from all participants. Thereafter, patients were prospectively followed-up for a median time of 47 (IQR 19–66) months to determine associations of RHI with renal outcomes, MACCEs, hospitalizations or mortality. Results: In the CKD patient population, the mean age was 57.7 ± 15.5 years, the mean eGFR was 54.9 ± 36.7 mL/min/1.73 m2 (CKD-EPI) and 57 were males (47.5%). At baseline, in univariate analysis, RHI in the CKD group correlated positively with eGFR (r = 0.332, p < 0.0001) and correlated negatively with age (r = −0.469, p < 0.0001), Charlson index (r = −0.399, p < 0.0001), systolic blood pressure (r = −0.256, p = 0.005), and proteinuria (r = 0.211, p = 0.027). Reactive hyperemia index in the control group did not significantly differ from RHI observed in patients with CKD stages 1 to 5 (2.09 ± 0.40 vs. 2.01 ± 0.06, p = 0.493). In adjusted analysis, only age (β = −0.014, p = 0.003) remained independently associated with RHI at baseline. During follow-up, 8 patients suffered a MACCEs, 33 patients experienced renal function deterioration, 17 patients were hospitalized for medical reasons and 6 patients died. RHI at baseline was not significantly associated with CKD progression (1.94 vs. 2.02, p = 0.584), hospitalizations (1.90 vs. 2.04, p = 0.334), and all-cause mortality (1.65 vs. 2.01, p = 0.208) or MACCEs (1.77 vs. 2.01, p = 0.356), but was significantly associated with cerebrovascular events (1.27 vs. 2.02, p = 0.004) and with a composite cardiovascular outcome (MACCEs, hospital admissions and death; 1.73 vs. 2.07, p = 0.035). Conclusion: Our results suggest that RHI may be a predictor for the development of cerebrovascular events in pre-dialysis CKD patients who may benefit from more aggressive preventive measures.

Cerebral blood flow velocity is associated with endothelial function in men

Background and objective: Reduction in cerebral blood flow with aging leads to cognitive decline and brain atrophy. Cerebrovascular hemodynamics are associated with vascular function. However, little is known about endothelial function in relation to cerebral blood flow at rest. The present study aimed to examine the association between microvascular endothelial function and middle cerebral blood flow. Material and methods: This study involved 60 healthy middle-aged and elderly men. The microvascular endothelial function was measured via digital reactive hyperemia index using pulse amplitude tonometry, and the mean middle cerebral blood flow velocity and cerebrovascular conductance were measured using transcranial Doppler ultrasonography. Results and conclusions: Reactive hyperemia index was significantly correlated with the mean middle cerebral blood flow velocity and cerebrovascular conductance. Multiple regression analysis further indicated that the correlation was significant after adjustment of covariates, such as age, body mass index, smoking status, medication history, blood pressure, and arterial stiffness. Further, Reactive hyperemia index was found to be a significant independent determinant of the mean middle cerebral blood flow velocity and cerebrovascular conductance. The present study demonstrated that vascular endothelial function is associated with cerebral blood flow and is an independent potential confounding factor in healthy middle-aged and older men.

Vascular Effects of ACE (Angiotensin-Converting Enzyme) Inhibitors and Statins in Adolescents With Type 1 Diabetes

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0–7.2] versus 5.3% [4.7–5.9]; P =0.005), whereas no effect was observed following statin use (6.2% [5.5–6.8] versus 5.8% [5.1–6.4]; P =0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8–5.9] versus 6.3% [5.8–6.7] for high-risk versus low-risk groups; P =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment ( P >0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03–0.12]; P =0.001 and 0.5 m/s [0.4–0.6]; P <0.001 for reactive hyperemia index and pulse wave velocity, respectively). ACE inhibitors improve endothelial function in high-risk adolescents as they transition through puberty. The longer-term protective effects of this intervention at this early age remain to be determined. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier NCT01581476.

Effect of drug-coated balloons versus bare-metal stents on endothelial function in patients with severe lower limb peripheral artery disease

Background Research shows impaired endothelial function in patients with vascular diseases and improved endothelial function following revascularization and medical treatment. There is, however, a dearth of data on the effects of different endovascular therapeutic strategies on endothelial function. We sought to compare the effects of two endovascular strategies of drug-coated balloons versus stenting on endothelial function. Methods The reactive hyperemia index, the ankle-brachial index, and the toe-brachial index were measured in patients undergoing endovascular revascularization preprocedurally and on the 90th postprocedural day. After adjusting for baseline line characteristics, reactive hyperemia index were compared between the two groups at baseline and at 90 days. Results Between January 2018 and March 2019, 86 patients were prospectively included in a non-randomized manner. Drug-coated ballooning alone was carried out on 46 patients, and bailout stenting after plain balloon angioplasty was performed on the remaining 40 patients The post-revascularization reactive hyperemia index exhibited a significant rise in both groups (1.58 ± 0.21 vs. 1.43 ± 0.20; P = 0.0001). There was no difference in the postprocedural reactive hyperemia index between the two treatment groups. Additionally, the follow-up reactive hyperemia index showed no significant change compared with the postprocedural reactive hyperemia index (1.58 ± 0.23 vs. 1.57 ± 0.22). The results of subgroup analysis between a group of clinically high-risk patients and a group of patients with complex lesions were similar to the aforementioned results. Conclusions The reactive hyperemia index was significantly improved by endovascular therapy in our study population. However, no difference was observed between drug-coated ballooning and bare-metal stenting, which highlights the effects of vessel patency on endothelial function.