Background and objectives: Ocular massage (OM) is used as a treatment option for acute retinal artery occlusion, under the assumption that it induces vessel dilatation and enhances perfusion. Since evidence of ocular perfusion alteration due to OM is lacking, we investigate the impact of OM on the hemodynamics of the posterior pole in healthy eyes in a noninvasive fashion by using optical coherence tomography angiography (OCTA). Materials and Methods: A prospective study was conducted on healthy volunteers, each of whom underwent measurements of intraocular pressure (IOP), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), radial peripapillary capillary perfusion (RPCP), superficial capillary plexus perfusion (SCPP), deep capillary plexus perfusion (DCPP), choriocapillaris perfusion (CCP), Sattler’s layer perfusion (SLP) and Haller’s layer perfusion (HLP) before and after OM. OM was performed for 2 min, consisting of 10-s turns of compression and decompression of the globe. Results: A total of 21 eyes from 21 participants (median age 29) were included. After OM, IOP significantly declined (p < 0.001), while SFCT (p < 0.005), SCPP (p < 0.001), DCPP (p = 0.004) and CCP (p = 0.008) significantly increased. CMT, RPCP, SLP and HLP did not show any significant alteration due to OM. Changes in SCPP correlated positively with changes in CCP and vice versa. Conclusions: OCTA-based analysis in healthy adults following OM demonstrated a significant increase of retinal perfusion values, assumed to be due to failure of autoregulatory mechanisms. These findings may indicate a positive effect of OM as a treatment option for patients with acute retinal artery occlusion. Ocular perfusion mainly depends on the difference between the local arterial blood pressure (BP) and the intraocular pressure (IOP). However, several investigations have revealed that moderate changes in IOP or BP did not significantly affect the retinal blood flow, in contrast to the choroidal vasculature ,2,3,4,5.It has been demonstrated that IOP can be significantly affected by any contact that touches or indents the ocular surface ,9,10. ThIn the present study, we take advantage of this noninvasive imaging technique to investigate structural and functional vascular alterations of the retina and the choroidal sublayers in healthy eyes after undergoing OM.Participants for this prospective observational study were enrolled from the medical staff of the Department of Ophthalmology at the University of Lübeck between August 2019 and January 2020. The study was approved by the institutional review board  and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained individually before enrolment. Exclusion criteria were: (1) any history of ocular disease or ocular surgery; (2) evidence or history of systemic disorders, including cardiovascular disease, antihypertensive drug use and diabetes mellitus. At baseline, all included participants underwent an examination including BP, refraction, best-corrected visual acuity (BCVA) in Snellen, axial length (AL) measurement, slit-lamp biomicroscopy and IOP. IOP measurements were obtained using the TONOREF III  noncontact tonometer. Imaging was performed on all subjects without prior pupil dilatation using the Zeiss Cirrus HD-OCT  by a single, trained operator (F.R.). Each imaging session included Enhanced Depth Imaging (EDI)-OCT scans (10 × 10 mm²) and optical coherence tomography angiography (OCTA) volumetric scans (6 × 6 mm²) of the posterior pole, as well as OCTA scans of the radial peripapillary capillaries (RPC). OCTA scans with a signal strength ≥7 and without motion, segmentation or projection artifacts were utilized to avoid misinterpretation ,19. TotaEach acquired en face image was exported into ImageJ  and binarized using the Otsu method, an automatic threshold selection from gray-level histograms, by using the command path Image > Adjust > Threshold > Auto in order to determine the percentage of white and black pixels . As in pAfter baseline examination, participants were asked to perform OM simultaneously on both eyes. Gentle pressure was applied through the closed eyelids to the globe with the index finger and middle finger for 10 s, followed by a 10 s release. This procedure was performed for a period of 2 min. Immediately after the OM, participants underwent another examination of both eyes including noncontact IOP, EDI-OCT and OCTA. The follow-up examination had to be done within 3 min after completed OM. For further analysis only one eye of each participant was included and laterality was assigned by chance, resulting in 12 of the studied eyes being right and 9 being left.p < 0.05 was considered statistically significant.Statistical calculations were performed using IBM SPSS . Power calculation was performed using G*Power  and a sample size of 19 was calculated to achieve a power of at least >90%. BCVA in decimal Snellen was converted to the logarithm of the minimum angle of resolution (logMAR). Mean arterial pressure (MAP) was calculated based on the formula 2/3 diastolic BP + 1/3 systolic BP. The Shapiro–Wilk test was used to check the normality of the obtained data. As the data were found to be distributed non-normally, variables were summarized in terms of median and range. The nonparametric Wilcoxon signed-rank test was used to compare baseline and follow-up values of the same eye. Possible interaction between the morphological and functional retinal parameters was analyzed using Spearman’s correlation analysis. A value of A total of 21 eyes from 21 healthy participants enrolled in this study were included in the analysis. Demographic and clinical data are reported in p < 0.001) after OM. While CMT (p = 0.114) and TMV (p = 0.323) did not change, SFCT increased significantly from 342.7 µm to 367 µm (p = 0.005). The RPCP did not change significantly after OM (p = 0.407), while both the SCPP and DCPP significantly increased from 27.7% to 30.4% (p < 0.001) and from 38.6% to 38.7% (p = 0.004), respectively. Likewise, CCP rose from 47.4% to 48.2% (p = 0.008), while SLP (p = 0.304) and HLP (p = 0.554) did not change significantly.Changes in IOP as well as anatomical and functional retinal values at baseline and after OM are reported in p <0.001). Furthermore, changes in SCPP negatively correlated with changes in SLP . Statistically significant negative correlation was also found between changes in CCP and HLP  and positive correlation between SLP and HLP .Differences in IOP and perfusion metrics due to OM are correlated in In this prospective OCTA-based study, we investigated retinal and choroidal vascular alterations in healthy eyes after 2 min of OM with alternating 10-s turns of compression and decompression. To the best of our knowledge, this is the first study demonstrating statistically significant increases of SCPP, DCPP and CCP after digital massage of the globe. Furthermore, we were able to demonstrate a significant thickening of SFCT, while SLP and HLP stayed steady.OM is believed to be a simple procedure to temporary reduce IOP and induce retinal arterial vasodilatation . FurtherDue to its potential to lower IOP through increasing retinal artery perfusion pressure and possibly mechanically facilitate the disintegration of a thrombus, OM is used as an acute treatment option for retinal artery occlusion. However, it is unclear to what extent the compression and decompression of OM can give rise to retinal capillary blood flow. In this study, we were able to demonstrate a statistically significant improved perfusion of the central SCP as well as the DCP following OM by using OCTA. However, RPCP stayed steady after performing OM. One explanation is the fact that the retinal blood flow is mainly determined by autoregulatory mechanisms and local factors with insensitivity to systemic perfusion changes and changes in IOP ,30,31. TIn contrast to the retinal vascular network, choroidal vessels have a rich supply of autonomic vasoactive innervation with a poor autoregulatory capability ,19. ImmeCC showed a significant higher perfusion after OM, correlating positively with SCPP, while SLP and HLP did not change. As pointed out previously, choroidal vessel perfusion is mostly determined by autonomic innervation, making systemic BP the main influencing factor on choroidal perfusion . As OM sThe present study has some limitations. Since there is currently no way of measuring IOP simultaneously with the OM, we do not know the maximum IOP induced by globe compression. Furthermore, participants performed OM by themselves after detailed instruction. Indeed, a standardized procedure cannot be guaranteed since we are unable to measure the applied force. To reduce this possible confounding factor, only participants with a medical background and who were familiar with OM were recruited. It should be noted that we only used the Otsu image processing algorithm and that another algorithm might have led to a divergent outcome, as it has been shown that algorithms do have different discriminatory abilities. Furthermore, the manual recording of SFCT may represent a potential bias. However, all manual measurements were performed by two experienced graders (F.R. and M.P.) and the average values were used for statistical analysis. Furthermore, we cannot suggest global impairment of the choroid from only evaluating SFCT. A wider range of the choroidal examination area, or rather measuring the total choroidal volume, may be more conclusive. As a simple correlation analysis was used, we may have missed out on physiological interactions between the examined tissues. Finally, the relatively small sample size may represent a limiting factor leading to a mainly exploratory data analysis. Nevertheless, strong significant diurnal variations were found. To corroborate our findings, further studies with a larger number of participants and especially with an older study cohort will be necessary, since the young healthy adults included here are not the typical risk group for retinal artery occlusions. Furthermore, future studies should focus on subanalysis of the different vessel types to investigate whether the larger vessels or small capillaries react to OM with perfusion changes.In conclusion, this prospective observational study demonstrated a significant perfusion increase in both the retinal capillary plexus as well as the CC after performing OM in healthy eyes, presumed to be due to failure of autoregulatory mechanisms. These results may indicate a positive effect of OM as a treatment option in patients with acute retinal artery occlusion by improving the retinal perfusion. However, to confirm this hypothesis further OCTA studies should focus on OM in diseased patients as well as age-matched healthy controls.


Global Initiative for Asthma 2019 guidelines recommend to avoid strengthening patients’ reliance on relievers since they increase exacerbation risk. Our aim was to examine the association between reliever inhalers overuse and all-cause healthcare utilization (HCU). A retrospective study among Clalit Health Services (CHS) adult enrollees (n = 977) for 2012–2017. Reliever inhalers overuse was defined as consistent prescription refills of ≥ 3 canisters annually. Adherence to controllers was calculated using the proportion of days covered. HCU included: hospitalizations, diagnostic and surgical procedures, medications, emergency room (ER) visits, and clinic visits. 27% of the study population (n = 264) consistently refilled ≥ 3 relievers prescriptions annually, and had higher adherence to controllers . Their total 6-year HCU costs were not higher than that of others . Most HCU components [including hospitalization (p = 0.405) and ER visits (p = 0.884)] were comparable; however, medication costs were higher . A multivariable ordered-logit model revealed that frequent and regular use of relievers was not associated with higher HCU costs . Higher adherence to maintenance and reliever therapy , other controllers , and nebulized SABAs and SAMAs  was associated with higher costs. Overuse of reliever inhalers was prevalent and associated with higher adherence to controllers, yet not associated with higher all-cause HCU. This highlights the need to examine the sources of elevated usage in order to develop intervention strategies to optimize pharmaceutical therapy of asthma patients. In addition, adherence rates to controllers are suboptimal, ranging from 15 to 54%2. Suboptimal adherence to inhaled therapy stems from treatment-related, patient-related and disease-related factors3.Controlling asthma and reducing exacerbations requires a balance between controller and reliever medications; however, there is a gap between real-world practice and evidence-based guidelines4 signal a paradigm shift with respect to use of relievers for asthma management and recommend avoiding traditional algorithms of care that strengthen patients’ reliance on the short-acting β2-agonist (SABA) since its regular and frequent use increases the risk of exacerbations. This paradigm shift triggered our interest in examining the association between elevated use of reliever inhalers and healthcare utilization (HCU).The Global Initiative for Asthma (GINA) 2019 guidelines14. In most of these studies, improved adherence to controllers was associated with decreased hospitalizations and emergency room (ER) visits13. However, this trend was inconclusive10 or not observed14 in others. In addition, all of these studies analyzed data of short-term follow-up periods14, and most analyzed asthma-related HCU14. Half of the studies12 did include the use of SABAs in their analyses, but as an outcome variable; thus, they did not draw conclusions with regard to the association between elevated SABA use and HCU. To the best of our knowledge, the study of Piecoro et al.15 is the only one that examined whether overuse of inhaled SABA in the absence of concurrent inhaled corticosteroid use was associated with an increased risk of ER visits and hospitalizations. The study revealed that daily use of an inhaled SABA was associated with an increase in asthma-related hospitalizations when compared to patients who did not use inhaled SABA on a daily basis or received inhaled steroids on a continuous basis. However, this result was based on one-year follow-up; thus, it could not address the issue of long-term regular and frequent use of reliever inhalers and its corresponding effect on HCU.Most of the studies that examined the association between adherence to asthma therapy and HCU have focused on adherence to controllersThe goal of this study was to examine the association between elevated and consistent use of reliever inhalers in six years of follow-up and the corresponding HCU. This information may highlight the actual long-term economic burden associated with inappropriate and excessive use of relievers. The Israeli single-payer setting enabled us to provide reliable and comprehensive measures of HCU data for a representative cohort of patients.A retrospective cohort study was conducted among enrollees of the Southern District of Clalit Health Services (CHS), the largest HMO in Israel. The study was conducted in accordance with the amended Declaration of Helsinki. The CHS Internal Review Board—Helsinki Committee for Community Medicine approved the study protocol and participants’ informed consent was waived by this committee since it was a secondary analysis of de-identified dataset (#0061-18-COM2).The inclusion criteria were enrollees: (1) of the Southern District of CHS, (2) aged 18–65 in 2012, (3) diagnosed with asthma (ICD-9 codes 493.xx) before 2012, (4) with active diagnosis of asthma during the entire follow-up period, and (5) who refilled an average of ≥ 1 prescription of inhaled relievers (SABAs and short-acting muscarinic antagonists (SAMAs)) annually during the follow-up period. Exclusion criteria were: (1) concomitant diagnosis of at least one of the following diseases: AIDS, thalassemia, hemophilia, Gaucher disease, COPD, malignancy, or (2) consumption of Omalizumab injections (that implies severe asthma).4, consumption of ≥ three 200-puff canisters of SABA annually increases the risk of severe exacerbation. Thus, regular and frequent use of reliever inhalers was defined as consistent prescription refills of ≥ 3 canisters in each of the follow-up years. In addition, we calculated the annual average number of packages of nebulized SABAs and SAMAs. Adherence to controllers was calculated using the proportion of days covered (PDC) for each of the follow-up years and as an annual average for the entire period. The PDC was calculated by dividing the number of months that canisters/tablets were available to the patient (numerator) by 12 months (denominator). The PDC was calculated as the annual average PDC for maintenance and reliever therapy (MART), and as the annual average of the maximum PDC level of the following controllers: (a) inhaled corticosteroid (ICS) inhalers, (b) leukotriene receptor antagonists (LTRA), (c) ICS + long-acting β2-agonists (LABA) combinations excluding MARTs, and (d) Theophylline. This analysis excluded prescription refills of controllers’ therapy administered by nebulizers since this was negligible in our cohort and since estimation of PDC is not applicable for nebulized therapy.All study variables were obtained from the computerized database of CHS. We estimated adherence to relievers and controllers separately. Adherence to relievers  was calculated as the number of canisters used. This measure was calculated for each of the follow-up years (2012–2017) and as an average for the entire period. As stated in the 2019 GINA guidelinesCHS enrollees, like all Israeli citizens, are covered by generous and quite uniform universal health insurance that provides access to various healthcare services with no or relatively low co-payments. HCU cost estimates analyzed in our study included: hospitalizations, diagnostic procedures, medications, surgical procedures, ER visits, and outpatient clinic visits. Total cost was calculated as the sum of all these estimates. Cost estimates were adjusted to June 2018 prices and converted to US dollars (USD) using the June 2018 exchange rate of 3.65 Israeli shekels per 1 USD. The quantity of primary care physician visits  was estimated as well, yet not included in the total HCU costs. HCU data were calculated for the entire follow-up period (2012–2017).Data were analyzed using Stata software . The Mann–Whitney U test was used to determine between-group differences in HCU and adherence to controllers and nebulized SABAs and SAMAs. A multivariable ordered-logit model was specified to analyze predictors of HCU costs. The core independent variable was consumption of reliever inhalers . This association was analyzed in the presence of: adherence to MART, adherence to other controllers (excluding MART), and consumption of nebulized SABAs and SAMAs. In addition, the model was adjusted for potential confounders including: age, gender, ownership of voluntary supplementary health insurance, disease duration, the Charlson Comorbidity Index (CCI), and comorbidities . P-values of < 0.05 determined statistical significance in all analyses.Our cohort consisted of 977 asthma patients Table . Of thosHCU of the study groups during 2012–2017 is presented in Table The multivariable model Table  shows thThis study revealed that, counter to our expectations, regular and frequent use of reliever inhalers was not found to be an independent determinant of increased HCU. However, this inappropriate use of reliever inhalers was associated with higher adherence to controllers (excluding MART), and this higher adherence to controllers, in turn, was indeed associated with increased HCU. These results imply that regular and frequent use of reliever inhalers, observed in our study among more than one fourth of the study population, may be a proxy of a more comprehensive phenomenon of inappropriate use of pharmaceutical therapy for asthma management that may indicate uncontrolled asthma, which is associated with elevated HCU costs.16. In a qualitative study that examined guideline implementation from the patients’ perspective, one interviewee described his tremendous dependence on the reliever therapy by saying that when he noticed he did not have the reliever inhaler with him, he immediately had an asthma attack17. Asthma patients learn quickly that SABA and SAMA use is the fastest way to get symptom relief, and reliever treatment becomes their main way to manage attacks18. In the last decade in Israel, patients have been able to submit an online request for a prescription (instead of scheduling face-to-face appointment with their primary physician). This innovative approach may have led to excessive use of prescription drugs in general and reliever inhalers specifically19. It may be possible to curb overuse of relievers if prescriptions for reliever inhalers can be obtained only through face-to-face visits with the primary care physician, who can estimate the actual need for the medication and ensure correct controller use.Elevated use of relievers indicates poor asthma control and may worsen the disease symptoms due to the fact that the immediate symptomatic relief may delay or even prevent patients from seeking medical help7, there is also evidence of mixed results (depending on the controller therapy)10, or similar to our findings, evidence of a positive association between adherence to controllers and use of relievers6. An additional study that focused on estimating the overuse of MART20 revealed that, despite the clear guidelines, 10% of MART users were concurrently using SABAs. Incorrect use of controllers may underlie these findings. While intake of chronic medications administered as tablets is relatively easy, inhaler use is more complex (requiring synchronized breathing), and necessitates guidance and tailoring to each patient’s needs and abilities in order to minimize inhaler use errors21. A systematic review on errors in inhaler use found that the inhaler technique has not improved in the past 40 years22, and that frequent critical errors in inhaler use are still prevalent23.Reliever overuse is expected to be associated with poor adherence to controllers, but there is inconsistent evidence in this regard. While there is evidence that improved adherence was associated with lower use of SABA21, although in practice only 27% of adult asthma patients receive such plans24. Even so, when an action plan already exists, it is usually not patient-centered, and there is a gap between healthcare provider recommendations and actual use which, in turn, leads to uncontrolled disease and SABA overuse25. A systematic review of the cost-effectiveness of intervention strategies targeted at asthma patients found that patient education and self-management intervention were the most cost-effective measures26; thus, it may be that the combination of the two together with patient-centered care would result in minimal use of relievers, higher adherence to controllers, lower unnecessary HCU costs, and higher quality of life. Pharmacists are the last medical professionals that the patient encounters before he/she uses the inhaler. Community pharmacists who are part of a multidisciplinary team that design continuous educational workshops may increase adherence to controllers, minimize incorrect use of inhalers, and encourage self-management of asthma patients28.Asthma guidelines recommend and encourage asthma patients to be educated for self-management by a personalized asthma action plan14. The current study provides a different angle of the analysis of elevated HCU determinants among asthma patients by analyzing the independent role of regular and frequent use of reliever inhalers. We revealed that this use was not associated with increased HCU, including hospitalizations and ER visits. Reliever inhalers are generally administered through metered dose inhalers, which require patients to synchronize between puffing and inhaling. This may result in many wasted puffs due to retrying to use these inhalers effectively23. In addition, relievers prescription refills may not solely indicate overuse, but rather stem from regular replacement due to expiration dates or for ease of having multiple inhalers in frequented places . Finally, asthma patients may take relievers prophylactically before exercise or exposure to triggers. These three reasons may imply that overconsumption of inhalers may not necessarily indicate an elevated intake of the medication and poor asthma control, and thus may not be reflected in elevated hospitalization and ER visits. Further in-depth exploration of the sources of excess refills of reliever inhalers is still warranted.Together with reliever overuse, suboptimal adherence to controllers and associated HCU is a worldwide concern, and extant research on this topic has not demonstrated unequivocal results14. However, we provide a description of all-cause HCU; thus, all pharmacological groups of pharmaceutical therapy were included. As hypothesized, medication costs were higher among those who consistently refilled ≥ 3 prescriptions of canisters annually compared to others, and mostly due to significantly higher utilization of medication for the respiratory system, which corresponds with the positive association with controllers and may indicate these patients’ inability to manage their disease.Our results reveal that the most dominant component of HCU costs was medication costs, similar to other studies that examined asthma-related HCU costsOur analysis has several limitations. First, a prescription refill does not necessarily mean medication uptake. With asthma, this limitation may be even more salient since only appropriate use of the inhalers (purchased) assures their effectiveness. Second, our analysis relied on financial data that lack clinical information; thus, we could not adjust the multivariable analysis to asthma severity. We acknowledge that asthma-related clinical characteristics might contribute to variability in the HCU estimates. Third, cost estimates of HCU may not be generalizable to other healthcare systems, as practice patterns and tariffs may differ. Even so, this limitation does not weaken our analysis since our objective was to compare patterns of HCU of two groups of patients, rather than to provide the absolute cost estimates of this population.Notwithstanding these limitations, our study contributes to the extant knowledge by examining the effect of consistent and elevated usage of reliever inhalers on HCU, which now may be of great interest following the paradigm shift in asthma pharmaceutical care suggested by the updated GINA guidelines. Our comprehensive analysis of all-cause HCU patterns of asthma patients during a long follow-up period of six years may highlight the actual economic burden associated with inappropriate and excessive use of asthma therapy. Our results emphasize the need for further study to examine the sources of elevated usage of relievers and the low adherence to controllers, as well as incorrect inhaler use. This may enable development of intervention strategies that will optimize pharmaceutical therapy of asthma patients.


Patients with chronic kidney disease (CKD) experience abnormality of intracardiac blood flow status during early-stages of disease. Left ventricular energy loss (EL) derived from vector flow mapping (VFM) represents fluid energy lost as heat in left ventricle and had been used to detect intracardiac blood flow efficiency. We aimed to evaluate the left ventricular EL in stage 1–3 CKD patients, and explored whether hypertension, a main cardiovascular risk, deteriorate the abnormality of intracardiac blood flow status.Transthoracic echocardiography was performed in 41 controls and 48 patients with stages 1–3 CKD. CKD patients consisted a subgroup with no hypertension, a subgroup with well-controlled hypertension and a subgroup with poorly controlled hypertension. The EL were calculated in the left ventricle using VFM analysis from the apical 3-chamber view. Furthermore, the correlation and stepwise multiple regression analysis were used to explore the potential independent predictors of left ventricular EL.Compared with controls, stage 1–3 CKD patients showed increased left ventricular EL during total diastole, late diastole, total systole, isovolumic contraction and ejection. CKD patients with poorly controlled hypertension had higher left ventricular EL compared to the other CKD subgroups. Additionally, the ratio of mitral early filling wave peak velocity and early mitral annular peak velocity on septal side, mitral early filling wave peak velocity, and left ventricular mass index were independent predictors of the diastolic EL; whereas systolic blood pressure and left ventricular mass index were independent predictors of the systolic EL.Left ventricular EL was a useful echocardiographic parameter to evaluate the impaired intracardiac blood flow efficiency in patients with stages 1–3 CKD. Hypertension was a crucial contributor for intracardiac blood flow abnormality. This study might provide valuable clinical data to discern cardiac dysfunction and reduce the cardiovascular risk in early-stage CKD. Chronic kidney disease (CKD) affects about one in ten adults , and is Cardiac magnetic resonance, contrast particle imaging velocimetry and vector flow mapping (VFM) are mainly techniques for evaluating the intracardiac blood flow status. Compared to the other two techniques, VFM is more suitable for clinical application owing to its convenient, non-invasive and inexpensive characteristics , 10, andLeft ventricular EL bas been shown its efficacy in evaluation of intracardiac fluid dynamics in uremic hearts . Althougn = 10): Without using antihypertensive drugs, blood pressure < 140/90 mmHg  or blood pressure < 130/80 mmHg with overt proteinuria; patients with well-controlled hypertension : Using antihypertensive drugs, blood pressure < 140/90 mmHg  or blood pressure < 130/80 mmHg with overt proteinuria; patients with poorly controlled hypertension : Regardless of whether taking antihypertensive drugs, blood pressure ≥ 140/90 mmHg  or blood pressure ≥ 130/80 mmHg with overt proteinuria. Blood pressure was measured after a rest for at least 10 min in a supine position and averaged from three continuously monitoring on the first 3 days after admission [Patients with CKD (KDOQI stages 1–3) who accepted professional treatment according to CKD clinical guidelines in the Second Hospital of Hebei Medical University from 2016 to 2019 were invited to participate this study. The criteria for enrollment were stable stage 1–3 CKD patients with primary glomerulonephritis (diagnosis with kidney puncture), adequate echocardiograms with sinus rhythm. Exclusion criteria were clinical evidence of heart failure, substantial valvular stenosis or regurgitation, and a history of angina pectoris or myocardial infarction, congenital heart disease, hypertrophic cardiomyopathy, pulmonary heart disease, essential hypertension and diabetes. Overall, this cross-sectional study recruited 48 CKD patients (KDOQI stages 1–3). To explore whether the hypertension have further effect on the blood flow efficiency in CKD stages 1–3. The patients were divided into three subgroups according to the Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure in non-dialysis-dependent CKD : patientdmission . Forty-oTransthoracic echocardiography was performed by experienced sonographers using a Pro-Sound F75 ultrasound device  with a UST-52105 probe (1–5 MHz) in all subjects.The conventional echocardiographic parameters were acquired according to the American Society of Echocardiography guidelines . Left veColor Doppler Images for flow visualization were obtained from an apical three-chamber view in VFM mode, which was available for analyzing offline. The depth, width, angle and spatial-temporal resolution of images were adjusted to obtain the frame rate as high as possible (frame rate > 23 frames/s) while including left ventricle, left ventricular inflow and outflow tract in the color-scan area. Additionally, to mitigate aliasing phenomena, the Nyquist limit about two-dimensional color Doppler imaging should be set high sufficiently. Three cardiac cycles were stored, and the images were analyzed using VFM analysis software  installed in an offline workstation, so as to obtain the velocity vector fields about intraventricular blood flow. In brief, VFM visualizes intraventricular blood flow by velocity vector based on color Doppler imaging and two-dimensional speckle tracking. Color Doppler shows flow velocity in the parallel direction of the echo beam, whereas two-dimensional speckle tracking tracks ventricular wall motion, and blood flow velocity component in the direction perpendicular to the echo beam is calculated by continuity equation, which begins from the vicinity of the cardiac wall .The EL was the amount of fluid energy lost and dissipated as heat in the cardiac cavity. From the velocity vector fields of the intracardiac blood flow, EL for every frame of the cine-loop image was calculated by the formula  as folloμ is the blood viscosity, u is the component of the velocity vector, i and j are the two-dimensional coordinates corresponding to the point, suggesting that EL increases at the point where direction and size of velocity vectors change. Based on the time-flow curve and synchronized electrocardiogram, each cardiac cycle was divided into 5 phases . Normality was evaluated by the Kolmogorov-Smirnov test. Continuous data were expressed as the mean ± Standard Deviation (SD) or median and inter-quartile ranges. Comparisons between two groups were evaluated using Student’s t-test . Comparisons between multiple groups were analyzed by One-way ANOVAs followed Tukey’s post hoc test  Additionally, the Spearman correlation test and Multiple linear regression analysis (stepwise method) were used to estimate the potential variables that were associated with the diastolic EL or systole EL of CKD patients. All analyses were two-tailed, and P <  0.001), diastolic blood pressure , serum creatinine (P <  0.001), creatinine clearance rate (P <  0.001), Triglycerides (P <  0.001), high-density lipoprotein (P <  0.001), albumin (P <  0.001), hemoglobin (P = 0.010) and body mass index (P = 0.004) were increased in early CKD patients compared to that in control participants. The above indices between CKD subgroups were comparable, except for SBP and DBP. The stage 1–3 CKD patients with poorly controlled hypertension (P-HTN) had higher SBP (P <  0.001) and DBP (P = 0.003) than that in the stage 1–3 CKD patients without hypertension (N-THN). Moreover, the stage 1–3 CKD patients with poorly controlled hypertension had raised SBP (P <  0.001) and DBP (P <  0.001) compared to the stage 1–3 CKD patients with well-controlled hypertension (W-HTN). In present study, the poorly controlled hypertension was found in 41.67% (20 / 48) of early CKD patients. Patients with stages 1–3 CKD had similar LVEDd, LVEDV and LVEF as control participants. Compared with the controls, stage 1–3 CKD patients had enhanced LVPW (P <  0.001), this change was particularly significant in stage 1–3 CKD patients with poorly controlled hypertension . Likewise, stage 1–3 CKD patients had higher LVMI than that in controls (P = 0.001), the highest LVMI was found in early CKD patients with poorly controlled hypertension among the CKD subgroups . The data of LVPW and LVMI suggested heart configuration changed more obviously in stage 1–3 CKD patients with poorly controlled hypertension. Furthermore, A wave and E/e’ increased in patients with stages 1–3 CKD compared to control participants , but had no statistical significance among the CKD subgroups . We also found that there was no difference between CKD patients and control groups about E-wave, but the CKD patients with poorly controlled hypertension had increased E-wave compared the other two subgroups .Baseline clinical characteristics and conventional echocardiographic were shown in Table P < 0.001) and raised EL during total systole phase (EL-TS) (P < 0.001). Those data suggested patients with stages 1–3 CKD had more intraventricular energy dissipation than healthy participants. Similarly, EL during late diastole phase (EL-LD), EL during isovolumic contraction phase (EL-IVC) and EL during ejection phase (EL-EJE) were found increased in patients with stages 1–3 CKD compared to control participants . However EL during isovolumic relaxation phase (EL-IVR) and EL during the early diastole phase (EL-ED) had no significant difference between patients with stages 1–3 CKD and control participants (P > 0.05). The analysis of left ventricular EL between CKD and control participants was illustrated in Fig. The date of left ventricular EL were shown in Table P = 0.041; P-HTN vs. W-HTN, P = 0.020). Similarly, EL-LD raised more significantly in the patients with poorly controlled hypertension  and the increased EL-ED was also found in patients with poorly controlled hypertension . However, EL-IVR had no significant difference between the subgroups . Next, we explored EL-IVC had a similar statistical result to EL-TS between the three subgroups , and the higher level of EL-EJE was also detected in patients with poorly controlled hypertension . Together, those data suggested patients with stages 1–3 CKD had increased EL during diastole and systole, this hemodynamic abnormality was more significant in CKD patients with poorly controlled hypertension.Interestingly, EL-IVR, EL-ED, EL-LD, EL-IVC and EL-EJE all presented increased trend in CKD subgroups , E-wave , A-wave , LVMI  and LVPW , whereas systolic EL was significantly associated with LVMI  and SBP .The results of stepwise multiple regression analysis were shown in Table 2 0.693, P < 0.001), EL-TS = − 10.420 + 0.090LVMI + 0.081SBP .The results of correlation analysis were shown in Table The Bland-Altman analysis illustrated that measurements of left ventricular EL-TD and EL-TS exhibit good reproducibility Fig. Fig. 5BlIntracardiac blood flow status has not been investigated in stage 1–3 CKD. In current study, the left ventricular EL in CKD stages 1–3 with primary glomerulonephritis were quantitatively analyzed using VFM technology. We found that patients with stages 1–3 CKD had increased left ventricular EL during diastole and systole, this hemodynamic abnormality was more significant in CKD patients with poorly controlled hypertension. Using correlation and multivariate regression analysis, we indicated blood pressure might play some role in the increased EL.VFM, as a novel echocardiographic technology, has been shown to be capable to quantitatively evaluate EL derived from the velocity vector field of the blood flow in ventricle . EL valuSince the cardiac cycle is continuous, abnormality in blood flow can last from diastole to systole. It had been confirmed by VFM in patients with a reduced LVEF , in whomPatients with stages 1–3 CKD generally have no serious complications and frequently experience hypertension, edema, proteinuria and anemia, leading to hypoproteinemia and increased BMI. Using correlation and stepwise multiple regression analysis, we found only the SBP was the predictor of systolic EL in patients with stages 1–3 CKD, suggesting that the clinical presentation had little bearing on the result of assessment of left ventricular EL. Hypertension, as a main cardiovascular risk factor, is a main clinical symptom in patients with stages 1–3 CKD. However, it does not get enough attention in real-world. In present study, 41.67% of patients had poorly controlled hypertension, suggesting a poor condition of blood pressure management in CKD during the early stages. Unexpectedly, our data confirmed stage 1–3 CKD patients with poorly controlled hypertension had higher left ventricular EL compared to those patients with well-controlled hypertension or with no hypertension, indicating hypertension was a crucial contributor for intracardiac blood flow abnormality in early-stage CKD. Hypertension can increase cardiac afterload and damage cardiac configuration in the background of CKD, then further deteriorate hemodynamic abnormalities. Blood pressure management, is considered as the main target of CKD treatment. Our date revealed the importance of hypertension control from the perspective of hemodynamics in early-stage CKD when the best treatment time window exists. Considering the harmfulness of cardiovascular complications and the high prevalence of poorly controlled hypertension, Patients with CKD stage 1–3 are supposed to pay more attention to their blood pressure level.The present research has several limitations. Although CKD related to diabetes has become more prevalent than CKD related to glomerulonephritis in China, the recruited CKD participants in current study were only patients with primary glomerulonephritis. This relatively single patient population may hinder the universalization of our findings in all CKD patients. Additionally, this work was a single-center cross-sectional study with a relatively small sample size, which might contribute to the result  of left ventricular EL during isovolumic diastole. The changes in left ventricular EL values in patients with stages 1–3 CKD should be validated by further multi-center, large-scale longitudinal studies. Furthermore, Although the recruited CKD participants all accepted professional treatment according to CKD clinical guidelines, we did not evaluate the influence of the treatment protocols on the results in this cross-sectional study without therapeutic intervention.In conclusion, left ventricular EL was a practical echocardiographic parameter to evaluate the impaired ventricular blood flow efficiency exists in patients with early-stage CKD. Poorly controlled hypertension was a crucial contributor for intracardiac blood flow abnormality. We expected that this study provides hemodynamic evidence to reduce the disproportionately risk of cardiovascular disease and slow, or halt the progression of CKD during the early stages.


Moreover, a new model with h3/h1 had a higher AUC than the reference model without it . And the NRI and IDI for the new model was 50.0% (P=0.017) and 3.16% (P=0.044), respectively. In addition to Ba-PWV, we found that the decrease of t4, t5, and h5 might be associated with higher FPG, TC, LDL-C, and UA and lower HDL-C. This research might provide a valuable additional tool for remote wearable monitoring of radial artery pulse wave signals in hypertension risk evaluation and management.Our aim was to study whether radial pulse wave signals can improve the risk prediction of incident hypertension and are associated with its concomitant metabolic risk factors beyond the traditional cardiovascular risk factor Ba-PWV. By enrolling 523 Chinese subjects in this study, linear and stepwise regression analysis was performed to assess the association of radial artery pulse wave signals and Ba-PWV with blood pressure and its related metabolic risk factors such as fasting plasma glucose (FPG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and uric acid (UA). The area under the receiver-operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated by risk assessment plot to compare the discriminative ability among models with and without radial artery pulse wave signals. After adjusting related confounding factors, radial artery pulse wave variable  Hypertension, as an important risk factor responsible for 19% of global deaths , 3, has From the perspective of modern medicine, arterial vessel is one of the main target organs in hypertension injury. Initially, its structural changes are adaptive, but it becomes maladaptive in chronic hypertension, leading to vascular remodeling and arterial stiffness , 8. In pt1, t5, t3, h5 and increase of h1, h3/h1 were independently associated with arterial stiffness, while the height of dicrotic wave indicated by h5 was the most relevant pulse wave variable to the echocardiographic parameters [Although from the perspective of traditional Chinese Medicine (TCM), as we know, hypertension belongs to “vertigo” or “headache,” the main disease location in hypertension is liver, just like the saying in Huang Di's Canon of Internal Medicine: “all wind and dizziness disorders belong to the liver.” According to the TCM theory, liver controls the function of storing blood; that is to say, the liver is capable of retaining blood and regulating the amount of blood in the body. However, in TCM, it is also said that the pulse is the mansion of blood; therefore, we speculate that the pulse diagnosis might play a role in hypertension prediction. The pulse state of radial artery, as one part of the arterial system, has been described in traditional Chinese medicine (TCM) and other related oriental medicine systems. In order to overcome the subjectivity and ambiguity of the traditional description, considerable researches on varying pulse waveform acquisition sensors –21, pulsrameters . Furtherrameters –33.Thus, both arterial stiffness and radial artery pulse wave parameters could predict hypertension. However, it is not yet clear whether the BP-increasing effects of arterial stiffness and radial artery pulse wave parameters are related. No study has investigated the role of radial pulse wave signals combined with Ba-PWV in the prediction of hypertension and the monitoring of its concomitant metabolic risk factors in a hypertensive population. The purpose of this study was to investigate whether radial pulse wave variables improve the risk prediction of incident hypertension beyond traditional cardiovascular risk factor Ba-PWV, and detect the association of metabolic risk factors with Ba-PWV and radial artery pulse wave parameters, which might provide a probability for remote wearable monitoring of radial artery pulse wave variables in the hypertension development and management.523 Chinese subjects were enrolled in the study from April 2016 to March 2018, and they were all from the First People's Hospital of Taicang affiliated to Suzhou University. Inclusion criteria were complete data on brachial-ankle pulse wave velocity (Ba-PWV), complete data on radial artery pulse wave variables, and the related metabolic blood biochemical indicator data. The recruited participants were divided into two groups: normotensive group and hypertensive group. According to the Chinese guideline for the prevention and management of hypertension (revised edition in 2018) , the incThe Medical Ethics Committee of the First People's Hospital of Taicang affiliated to Suzhou University approved the study, and written informed consent was obtained from all included subjects according to the Declaration of Helsinki.Patients' metadata were collected . Physical examinations included blood pressure, pulse pressure, brachial-ankle pulse wave velocity (Ba-PWV), and blood biochemical indicators for metabolic risk factors data. In this study, blood pressure and Ba-PWV were measured via the commercially available digital automatic BP monitor and arteriosclerosis detector .h1, h4, h5, t1, t3, t4, t5, h3/h1, h4/h1, w/t—was performed using the software included in the DDMX-100 type pulse measurement device . In the continuous data, To identify the association between radial pulse variables and blood pressure, linear and stepwise regression analysis was performed using two different models. Model 1 was adjusted for age, sex, and BMI. Model 2 included model 1 and was additionally adjusted for duration time of hypertension, history of taking antihypertensive drug, and controlling condition of blood pressure.R2 (explained variance) improves with the addition of the new risk factor [To compare the discriminative ability among models with and without radial artery pulse wave variables, the area under the receiver-operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated. The reference model included only age, sex, BMI, and Ba-PWV, whereas the new model included reference model and radial pulse wave variables. Furthermore, the potential additional value of radial pulse wave variables was assessed by the risk assessment plot. This is a popular method to assess the performance/usefulness of a new biomarker by proposing two new statistical indicators, namely, NRI and IDI, in addition to the classical AUC. And this risk model is based on Cox proportional hazards for time-to-event data and logistic regression for case-control data. As this a case-control study, the logistic regression models were employed with sex as dichotomous and age, BMI, Ba-PWV, and radial pulse wave variables (in one of the two models) as continuous predictors. The outcomes of the models are dichotomous (hypertension or not). The AUC was a summary measure for discrimination between individuals who developed hypertension and those who did not. NRI focuses on reclassification tables constructed separately for participants with and without events and quantifies the correct movement in categories—upwards for events and downwards for nonevents—when adding the new risk factor . IDI meak factor . BecauseP values were 2-tailed, and those <0.05 were considered statistically significant.All statistical analyses were performed with IBM SPSS 21.0 , and the risk assessment plot was conducted in Matlab R2016a. All reported The baseline characteristics of 523 participants are shown in P < 0.05). As for the radial artery pulse wave variables, t3 and t5 of hypertensive group were lower than those of the normotensive group, while h3/h1 and w/t of hypertensive group were higher than those of the normotensive group (P < 0.05).Higher BMI, systolic blood pressure, diastolic blood pressure, pulse pressure, FPG, TG, UA, Ba-PWV, and proportions of male but lower HDL-C values were observed in the hypertensive group than in the normotensive group , h1 value , t3 value , and t5 value . Diastolic blood pressure (DBP) was independently associated with t3 value , w/t value , t1 value , and h1 value . Pulse pressure (PP) was independently associated with h1 value , h3/h1 value , and t1 value .The association between radial artery pulse wave variables and blood pressure in the total studied population is shown in h3/h1 value , h1 value , t3 value , and t5 value , and so did pulse pressure (PP) with h1 value , h3/h1 value , and t1 value . However, diastolic blood pressure (DBP) is only independently associated with t5 value  and h3/h1 value .Besides, after additional adjustment for duration time of hypertension, history of taking antihypertensive drugs, and controlling condition of blood pressure (model 2), systolic blood pressure (SBP) was still independently associated with h3/h1 and h1 value but lower t3 and t5 value. Diastolic blood pressure (DBP) was positively associated with h3/h1 value but negatively associated with t5 value independently of the above adjusted risk factors. For pulse pressure (PP), h1 value, h3/h1 value, and t1 value were its independent factors. In one word, among all the pulse wave variables, the common influential factor for SBP, DBP, and PP was h3/h1 value, which suggested that h3/h1 value was the most related pulse wave variable to blood pressure.The above results suggested that higher systolic blood pressure (SBP) was independently correlated with higher h3/h1 value was the only related pulse wave variable to systolic blood pressure, diastolic blood pressure, and pulse pressure; therefore, the new model additionally included radial artery pulse wave variable h3/h1. The new model had a higher area under the receiver-operating characteristic curve (0.86) than the reference model . The continuous net reclassification improvement for the new model was 50.0% (P=0.017). The integrated discrimination improvement for the new model was 3.16% (P=0.044). The risk assessment plot supported the additional value of radial artery pulse wave variable h3/h1 in the incident hypertension risk assessment , TC , and LDL-C ; next was Ba-PWV with FPG  and TG , while t4 and h5 were the only independent factors for HDL-C  and UA , respectively.All the six metabolic risk factors, after adjusting for age, sex, BMI, blood pressure, pulse pressure, duration time of hypertension, history of taking antihypertensive drugs, and controlling condition of blood pressure, are independently associated with radial artery pulse wave variables/Ba-PWV. t4), the diastolic period of the left ventricle (t5), and the height of the dicrotic wave (h5) were associated with higher FPG, TC, LDL-C, and UA and lower HDL-C.The above results indicate that arterial stiffness is more related to FPG and TG, while the pulse wave variables such as the decrease of the systole period of the left ventricle , is an independent additive predictor of incident hypertension beyond the traditional cardiovascular risk factor Ba-PWV. The radial artery pulse wave variable h3/h1, which represents the amplitude ratio of tidal wave to main wave, can reflect the intensity of reflection wave [h3/h1 was selected as one of the four important features to classify the pulse image  of TCM by application of Gradient Boosting Decision Tree (GBDT) along with the other radial artery pulse wave variables, h4/h1, w/t, and Rf [h3/h1 was significantly higher at cold than at base stage, which indicates that h3/h1 might be an important indicator of the arterial stiffness of radial artery. Unlike Ba-PWV, which is actually the direct reflection of arterial stiffness of the brachial-ankle arterial segments by calculating the pulse wave velocity, the pulse wave parameters we used in this study are actually time-domain features extracted from the pressure wave of the radial artery. As for the relationship between them, they both can reflect the arterial stiffness. However, based on our previous study [h3/h1 can improve the risk prediction of hypertension.By identifying the radial pulse wave variable ion wave . In addi, and Rf . Further, and Rf  studied us study , the mait4), the diastolic period of the left ventricle (t5), and the height of the dicrotic wave (h5) were especially associated with higher FPG, TC, LDL-C, and UA and lower HDL-C. These results also indicated that radial artery pulse wave signals might be one kind of supplementary indicators beyond Ba-PWV to manifest the above abnormal metabolic risk factors. It is reported that pathophysiological changes in the arterial vascular system occurring in the metabolic syndrome might be an important factor which increases the cardiovascular risk. And the changes of arterial vascular system involve both macrovascular adaptions  and microvascular adaptions  [In the clinical setting, high blood pressure usually coexists with other cardiovascular risk factors , for example, in the form of metabolic syndrome, which will increase the cardiovascular risk. Therefore, we further preliminarily detected the association of other metabolic risk factors  with Ba-PWV and radial artery pulse wave variables in this study. And we found that the decreased changes of systole period of the left ventricle (ilation) . These mh3/h1 is a significant predictor of hypertension. In addition, we found that both Ba-PWV and radial artery pulse wave parameters were associated with the combined metabolic risk factors independently of other confounding risk factors in a general hypertensive population. This study would provide an experimental basis for application of remote wearable monitoring of hypertension risk evaluation and management. The wearable devices based on radial artery pulse wave can be developed to provide remote dynamic monitoring, which mainly includes timely data monitoring and risk assessment. By integrating the timeliness, accessibility, and individuality of Internet technology, an accurate management system can be created for the prevention, monitoring, intervention, and protection of the hypertensive patients. In the end, it can help the primary care doctors to predict the disease change and take timely treatment measures to prevent the exacerbation of the disease, thus realizing individualized treatment for patients.To the best of our knowledge, this is the first retrospective study to show that radial artery pulse wave parameter h3/h1 might improve the incident hypertension risk prediction beyond the already-known risk factor Ba-PWV. Further longitudinal studies should be conducted to determine whether these changes of radial artery pulse waves evolve in the clinical development of hypertension. Finally, in this retrospective study, we only investigate the history of taking antihypertensive drugs rather than the concrete type of the current antihypertensive drugs. More prospective studies are needed to identify the impact of different concrete types of the current antihypertensive drugs on the radial pulse wave changes.Our study has some limitations. A major limitation of the present study is that we only measured clinical BP rather than ambulatory or home blood pressure, which is unable to identify masked hypertension at baseline and white-coat hypertension at follow-up. In addition, as this was a cross-sectional study, we only found that radial artery pulse wave variable h3/h1 is directly and independently associated with systolic blood pressure, diastolic blood pressure, and pulse pressure and might be related to the occurrence of hypertension in addition to the traditional Ba-PWV. Moreover, radial artery pulse wave variables t4, t5, h5 are independently related to its concomitant metabolic risk factors. Therefore, radial artery pulse wave signals might provide a valuable additional tool for remote wearable monitoring in hypertension risk evaluation and management.Our current findings suggest that radial artery pulse wave variable


Great efforts to advance the diagnosis and treatment of hypertension for controlling hypertension have been made; however, the rates of uncontrolled blood pressure are still high. This study explored the rate of uncontrolled hypertension in patients with hypertension managed in an urban hospital of Vietnam and identified associated factors. A cross-sectional survey was performed from August to October 2019 among hypertensive patients at an urban hospital in Hanoi, Vietnam. Blood pressure was evaluated at the time of medical examination. Demographic, clinical, and behavioral characteristics were also collected. Multivariate logistic regression was used to identify the factors related to uncontrolled hypertension. Among 220 patients, the rate of uncontrolled hypertension was 40.5%. Females had a lower likelihood of having uncontrolled hypertension compared to males . Higher duration of diseases  and higher body mass index  were positively associated with uncontrolled hypertension. Patients who carried supplies needed for self-care, cut down on stress, exercised regularly, and stopped/cut down on smoking were also less likely to develop uncontrolled hypertension. This study reveals that uncontrolled hypertension was common among hypertensive patients in Vietnam. Improving self-care capacity and encouraging healthy behaviors are critically important to control blood pressure, particularly among patients who were males and had high disease duration and body mass index. High blood pressure, or hypertension, has been well recorded as a leading cause of morbidity and mortality in both developed and developing nations. People with hypertension are particularly vulnerable to cardiovascular diseases (CVDs), stroke, or renal failures . It is eVietnam has been witnessed a rapid epidemiological transition in the last decade, resulting in a significant increase in noncommunicable diseases, including hypertension . A recenA cross-sectional survey was performed from August to October 2019 among hypertensive patients at an urban hospital in Hanoi, Vietnam. This hospital currently managed approximately two thousand hypertensive patients living and working in Hanoi, Vietnam. Participants were eligible for the study if they had been confirmedly diagnosed to suffer from hypertension according to the guideline of Vietnam Ministry of Health (persistently systolic blood pressure level of ≥140 mmHg and/or persistently diastolic blood pressure level of ≥ 90 mmHg). Moreover, participants had to be at least 18 years old, registered to manage and treat hypertension in the hospital. We excluded patients who (1) had impaired cognitive conditions and (2) were inpatients or hypertensive patients without registration of chronic disease management at the hospital. Among 250 patients who were invited to participate in the study, a total of 220 patients (response rate 88%) agreed to be enrolled in the survey.Data collection was carried out by undergraduate medical students from Hanoi Medical University. They were trained carefully in communication skills with patients as well as manners to collect data consistently. Patients were invited when they finished all procedures  and waited for medication dispense. If they were willing to participate, they were invited to a private counseling room for an interview and to protect their privacy. Patients have informed briefly the purpose of the study as well as their benefits. After completing the survey, their weight and height were measured.Office blood pressure was evaluated by using the Japanese Alpk2 sphygmomanometer at the time of medical examination. Blood pressure was measured twice; the second measure was done 10 minutes after the first measure. The mean of the two measures was used for analysis. Uncontrolled hypertensive patients were defined as those having a systolic blood pressure level of ≥140 mmHg and/or diastolic blood pressure level of ≥90 mmHg according to the guideline of Vietnam Ministry of Health; otherwise, they were classified as controlled hypertensive patients.During the interview, patients were asked to report their sociodemographic and behavioral characteristics . Weight, height, and body mass index were measured after completing the survey. Other demographic and clinical covariates such as age, gender, comorbidities, number of antihypertensives used, last low-density lipoprotein (LDL), last high-density lipoprotein (HDL), and last triglyceride measures were extracted from the electronic medical record system of the hospital. We also employed eight items from the Condition-specific Recommendations and Adherence scale to evaluate the frequency of different recommended health behaviors for hypertensive patients . These bp value of less than 0.2 to select the variables. Adjusted odds ratios (OR), p value, and 95% confidence interval (CI) were revealed. The level of statistical significance was set at the 5% level.Descriptive statistics and multivariable regression models were applied in this study. Since continuous variables in this study, namely, age, duration of disease, number of comorbidities, body mass index, last low-density lipoprotein, last high-density lipoprotein, last triglyceride, and adherence score had nonnormal distribution, median and interquartile range were presented. Chi-squared and Mann–Whitney tests were used to examine the difference of demographic, clinical, and behavioral characteristics between controlled and uncontrolled hypertensive patients. Multivariate logistic regression, along with a stepwise forward selection strategy, was employed to identify associated factors with hypertensive conditions. The log-likelihood test was performed with a threshold of a p < 0.05). Meanwhile, there was no difference in the rate of uncontrolled hypertension among age, education, occupation, living location, smoking, and alcohol groups (p > 0.05)  than in female one (33.0%) ( > 0.05) .p < 0.05).p < 0.05)  was remarkably higher than their counterparts (31.7%) ( < 0.05) .The results of multivariate logistic regression are presented in The present study revealed the substantially high rate of uncontrolled hypertension (40.5%) among patients receiving antihypertensive treatment in a Vietnamese hospital. Moreover, risk factors for uncontrolled hypertensive conditions were found comprising being male, increasing body mass index, following unhealthy or sedentary lifestyles, and not preparing essential medications for self-care. This study indicated critical results that can suggest important implications for controlling hypertension in hospital settings of Vietnam.The rate of uncontrolled hypertension among hypertensive patients in our study 40.5%) could be comparable to the previous study performed in ten provinces of Vietnam (37.7%) . This fi% could bMale patients tended to be at higher risk of uncontrolled hypertension, which was supported by several studies in both developed and developing countries –23. LiteOur study was in line with prior research that increasing body mass index was a major risk factor for uncontrolled hypertension , 27–29. Several major limitations should be acknowledged. First, data from this study were obtained via a cross-sectional design, which did not allow us to measure the causal relationship between uncontrolled hypertension among hypertensive patients and its related factors. Second, our sample was recruited by using a convenient sampling method in one hospital; therefore, the result of this study should be cautious about being applied in other settings. Third, several variables such as home blood pressure monitoring, class of drugs, or clinical inertia therapeutic were not included in this study. Further research should be warranted to investigate associations between these factors and uncontrolled blood pressure.This study reveals that uncontrolled hypertension was common among hypertensive patients in Vietnam. Improving self-care capacity and encouraging healthy behaviors are critically important to control blood pressure, particularly among patients who were males and had high disease duration and body mass index.


Among all subjects, 23% were found to have decreased estimated glomerular filtration rate (eGFR). A strong correlation between KIM-1/cr. and a cumulative dose of ifosfamide was observed . In addition, a moderate correlation between NGAL/cr. and a cumulative dose of cisplatin was identified . The AUC for KIM-1/cr. was 0.52, whereas NGAL/cr. showed a diagnostic profile describing the AUC of 0.67. Univariable regression showed significant associations between NGAL/cr. ratio and subjects after unilateral nephrectomy , cumulative dose of cisplatin , and age at diagnosis . The multivariable model demonstrated only cumulative dose of cisplatin as an independent factor influence on NGAL/cr. ratio. The results of our study showed increased levels of urine KIM-1 and NGAL many years after completion of the childhood solid tumors treatment, which correlated positively with a cumulative dose of ifosfamide and cisplatin. This study also suggests that unilateral nephrectomy could affect the concentration of the studied biomarkers. The deterioration of renal function after childhood solid tumors treatment is the result of using the intensive multimodal therapy. In recent years, urinary kidney injury molecule-1 (KIM-1) and urinary neutrophil gelatinase-associated lipocalin (NGAL) have been introduced as potential promising biomarkers of early kidney damage. The aim of the present study was to determine whether anticancer treatment has any effect on the concentration of KIM-1 and NGAL and its association with renal impairment in survivors of childhood solid tumors. Sixty patients previously treated for solid tumors were involved in this study. The median time after end of treatment was 8.35 years. Urine KIM-1 and NGAL levels were measured using immunoenzymatic ELISA commercial kits. Higher levels of urine NGAL, KIM-1/cr. (creatinine), and NGAL/cr. ratios were found in comparison with healthy controls ( In recent decades, the number of childhood cancer survivors (CCS) has increased significantly with the improvement of diagnostic and treatment methods with the cure rate of over 80% for all types of cancers. However, these patients experience many health problems after the end of the treatment. Any organ or system may be affected due to anticancer treatment and cancer itself ,2,3. RenNephrotoxicity is the result of using the multimodal therapy, including cytostatics , abdominal radiotherapy, immunotherapy, surgery (nephrectomy) and supportive treatment, which may adversely affect the kidneys . The vast majority of these drugs are administered during childhood solid tumors (CST) treatment. Thus, survivors of CSTs are particularly vulnerable to the development of impaired renal function later in life. Kidney injury may have many distinct clinical pictures, including reduced estimated glomerular filtration rate (eGFR), loss of tubular function, and hypertension ,6,7. In KIM-1 is a type of I cell transmembrane glycoprotein, which is produced in the kidneys and is not detectable in healthy subjects. It was observed that renal ischemic or toxic injury increased the level of KIM-1 by the up-regulation of mRNA in proximal tubule cells. Most studies investigated the role of KIM-1 as a biomarker for various etiologies of acute kidney injury (AKI), including cisplatin-induced injury, showed KIM-1 to be a promising predictor .NGAL is a member of the lipocalin family that is secreted by a different type of human tissue, including kidneys, gastrointestinal tract, respiratory system, and neutrophils. In kidneys, NGAL is excreted from the loop of Henle epithelial cells and, in healthy people, it is detectable in urine at a very low level. Similar to KIM-1, the increase in the excretion of urine NGAL occurs in response to the renal tubular damage (ischemic or toxic) and depends on its degree. Various studies have highlighted that urinary NGAL is a sensitive biomarker of renal damage in AKI patients as well as other kidney diseases such as tubulointerstitial nephritis, diabetic nephropathy, or nephrotic syndrome .There is a limited number of published studies assessing the applicability of KIM-1 and NGAL as early biomarkers of kidney injury in long-term childhood solid tumor survivors with a subtle deterioration of renal function undetectable by standard methods. From an individual and social point of view, rapid diagnosis and prompt implementation of the treatment are vital to preserve normal kidney function and to maintain the quality of life and lifespan of CST survivors. The aim of the present study was to determine whether anticancer treatment used in childhood has any effect on the concentration of urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in survivors of childhood solid tumors many years after treatment.Sixty subjects  visiting the follow-up outpatients’ clinic for childhood cancer survivors at the Department of Pediatric Oncology and Hematology, Medical University of Bialystok (Poland), from 2018 to 2019, were involved in this study. They were treated between 1995 and 2016 in childhood for various types of solid tumors . Inclusi2 (m2). Blood pressure (systolic (SBP) and diastolic (DBP)) were measured three times using a standardized sphygmomanometer with 2 min intervals. Hypertension was defined as a mean SBP and/or DBP level equal or above 95th percentile adjusted for age, sex, and height. The control group consisted of 53 age-matched healthy peers  who were offspring of the department’s employees and healthy school pupils recruited form the OLAF study [For all participants, careful clinical history, including demographic information, comorbidities, data associated with treatment, such as used nephrotoxic cytostatics , and abdominal radiotherapy, was derived from the CCS database. All patients underwent a full physical examination and had a normal ultrasound of the kidney and urinary tract performed by an experienced radiologist. Anthropometric traits were collected using standard procedures. Body mass index (BMI) was calculated using the following formula: weight (kg) / heightAF study . This grAF study .2) was calculated using the updated Schwartz formula: eGFR = 0.413 x (height in cm / serum cr. in mg/dL). Urine KIM-1 and NGAL levels were measured using commercial immunoassays  according to the instructions for the ELISA kit. The tested urine biomarkers were calculated per milligram urine creatinine (cr.) in order to avoid the effect of urine dilution . Urine albumin concentration was determined by Lowry’s method. Subjects with a urinary albumin/creatinine ratio between 30 and 300 μg/mg were considered to have albuminuria. The stages of chronic kidney disease (CKD) were classified according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, and it is defined by structural or functional abnormalities of the kidney for ≥3 months, with or without decreased eGFR or eGFR <60 mL/min/1.73m2 for ≥3 months, with or without kidney damage [After a 12 h night, fasting peripheral blood was collected from each participant for routine laboratory testing. Clean catch urine samples were stored at −80 °C for further analysis. The serum creatinine level was measured by enzymatic method, and the estimated glomerular filtration rate  and independent variables postulated as having a potentially negative impact on kidney function. The correlations between KIM-1/cr. and NGAL/cr. and a cumulative dose of cytostatics were calculated by Spearman correlation coefficients. The receiver operating characteristic (ROC) curve was used to establish the diagnostic value of the urine biomarkers and the optimum cut-off values. Statistical analysis was performed using STATA 12.1 version , and statistical significance was determined at 0.05. All continuous variables were tested for normal distribution using Shapiro–Wilk tests. Data were expressed as mean and standard deviation (SD) or median (Me) and interquartile range (IQR) when appropriate. In the analysis of the categorical variables, chi-square test or Fisher exact test was used. Continuous variables were compared with the Student The demographic characteristics of the study group are presented in p < 0.001). The age at diagnosis and time elapsed since the end of the treatment were not correlated with the level of KIM-1 and NGAL. Among all subjects, 14 (23%) were found to have decreased eGFR: 13 below 90 mL/min/1.73m2 and 1 between 30 and 59 mL/min/1.73m2. Additionally, we retrospectively analyzed data about eGFR measurement at least 3 months before the study time. All subjects with eGFR <90 mL/min/1.73m2 at the time of the study also had decreased eGFR at least three months earlier. One of all participants with eGFR <60 mL/min/1.73m2 met the criteria of CKD according to KDIGO guidelines.In the group of solid tumors, significantly higher levels of urine NGAL, KIM-1/cr., and NGAL/cr. ratios were found in comparison with healthy peers , Table 22) and those who had normal eGFR (> 90 mL/min/1.73m2) were observed , cumulative dose of cisplatin , and age at study . Other independent variables such as age at diagnosis , follow-up time , cumulative dose of cytostatic agents—cyclophosphamide , ifosfamide , methotrexate , and abdominal radiotherapy  did not affect the NGAL/cr. ratio. Confounding factors in the univariable analyses at p ≤ 0.05 were included in multivariable model , age at study , age at diagnosis , time after end of treatment , cumulative dose of cyclophosphamide , ifosfamide , cisplatin , methotrexate , and abdominal radiotherapy . Due to the fact that in univariable analysis, potential confounding factors did not affect significantly the KIM-1/cr. ratio, the multivariable model was not built.Taking into account the fact that the results may differ in patients after kidney removal, we conducted a separate analysis in CCS with solitary functioning kidney. In this subgroup, we did not show any significant changes in the level of urine biomarkers or fasting serum creatinine, as shown in le model . Similar2. The AUC for the KIM-1/cr. ratio was 0.52 (95% CI: 0.33–0.69) with the best cutoff value of 1.74 ng/mL , while NGAL/cr. showed a diagnostic profile describing the AUC of 0.67 (95% CI: 0.51–0.83) with the best cutoff value of 5.17 ng/mL .ROC analyses were performed to determine the diagnostic profile of both ratios, KIM-1/cr. and NGAL/cr., in identifying CCS with reduced renal function —eGFR < 90 mL/min/1.73m2). Nevertheless, we did not show any significant differences.Due to the fact that some cytostatic agents such as cyclophosphamide, ifosfamide, cisplatin, or methotrexate may induce deterioration of kidney function, we performed the analysis investigating the association between the type of used cytostatics and the number of patients with decreased eGFR (< 90 mL/min/1.73mp < 0.05). In addition, a moderate correlation between NGAL/cr. ratio and a cumulative dose of cisplatin was observed . The mean level of urine biomarkers  and its ratios  did not differ among the study participants exposed to abdominal radiotherapy during childhood from those who were treated with chemotherapy only. We did not carry out the analysis between the types of cancers, as these groups were underrepresented for meaningful evaluations. Moreover, due to the fact that children in the first years of life may be more exposed to drug-induced nephrotoxicity, the study group was divided according to the time of diagnosis (0–3 years vs. 3 years and more); however, no differences in the concentration of the KIM-1 and NGAL were found. The independent factors that were found to have a significant correlation with urine NGAL/cr. and KIM-1/cr. in univariable regression were used as explanatory variables to create a multiple regression model. It resulted in the creation of the model presented in Further analysis checked the correlations of urine biomarkers ratios (KIM-1/cr. and NGAL/cr.), and a cumulative dose of cytostatics used during chemotherapy in CCS was performed . A stronIn the last two decades, many markers have been tested to find the most sensitive and specific indicators of drug-induced nephrotoxicity ,6,16. ThThe role of the urinary biomarkers in identifying early stages of kidney injury is still unclear ,22,23,242) were found many years after the end of the treatment. Our results are consistent with some, but not all, previous reports, and they provide further evidence that treatment-related factors impair renal function in CST survivors [In this prospective cohort study carried out on childhood solid tumor survivors, 23% of subjects with decreased eGFR  in survivors of childhood solid tumors many years after the end of the treatment. In this study, a significantly increased urinary excretion of NGAL as well as higher NGAL/cr. and KIM-1/cr. ratio in CST survivors were found, as compared to the reference group. This finding may indicate renal tubular damage many years after anticancer treatment. We also noticed that females have a significantly higher level of NGAL and NGAL/cr. ratio than males, which is in accordance with some previous studies. Contrary to expectations, no association between urine biomarkers and eGFR was observed. In the study conducted in adults (mean age 57 ± 16), Bolignano et al. demonstrated that NGAL closely reflects the entity of renal impairment in patients with CKD and represents a strong risk marker for progression of CKD . It is nIn addition, we performed a separate analysis for those survivors who underwent a unilateral nephrectomy. Univariable regression analysis showed significant correlation between NGAL/cr. and individuals after simple nephrectomy, but the size of the subset of subjects was relatively small. Due to lack of data, further research is needed in this area. Likewise, older age at study correlated positively with a higher level of NGAL/cr.; however, the time elapsed since the cessation of treatment seems to be too short to draw a conclusion. Moreover, we also performed single regression and correlation analyses of KIM-1/cr. and NGAL/cr. with a cumulative dose of cytostatics used during the therapy. In CST survivors, we found a positive correlation between KIM-1/cr. ratio and a cumulative dose of ifosfamide as well as NGAL/cr. ratio and a cumulative dose of cisplatin used during childhood. These results suggest that the two most commonly used chemotherapeutics in the treatment of solid tumors  may affect the deterioration of kidney function. Data from the literature confirm tubular damage immediately or a few days after the infusion of cisplatin or ifosfamide; however, there are no data on long-term survivors of childhood solid tumors ,17,18. RThere are several limitations in this study. The single-center research should be interpreted in a context of possible bias that may occur. Secondly, due to the fact that the study group consisted of survivors of heterogenous solid tumors that were treated using distinct treatment modalities, it was difficult to determine the impact of each treatment protocol. Therefore, the authors focused mainly on the analysis of the effect of particular cytostatic agents rather than the specific types of tumors. Thirdly, in the current study the same reference group was used as in our previous study for acute leukemia survivors . FinallyIn summary, the results of our pilot cross-sectional study carried out in survivors of solid tumors showed increased levels of urine KIM-1 and NGAL many years after completion of the treatment, which correlated positively with a cumulative dose of ifosfamide and cisplatin. This study also suggests that unilateral nephrectomy could affect the concentration of the biomarkers studied. However, conclusions from this study should be drawn with caution, as nephrotoxicity remains under several multifactorial environmental effects. Moreover, the utility of KIM-1 and NGAL as early markers of tubular damage many years after childhood solid tumors treatment and influence of cytostatic agents on the kidneys needs to be confirmed in longitudinal large prospective cohort studies.


Adults born prematurely have an increased risk of early heart failure. The impact of prematurity on left and right ventricular function has been well documented, but little is known about the impact on the systemic vasculature. The goals of this study were to measure aortic stiffness and the blood pressure response to physiological stressors; in particular, normoxic and hypoxic exercise.n = 10) were recruited from the Newborn Lung Project Cohort and matched with term‐born, age‐matched subjects (n = 12). Aortic pulse wave velocity was derived from the brachial arterial waveform and the heart rate and blood pressure responses to incremental exercise in normoxia (21% O2) or hypoxia (12% O2) were evaluated.Preterm participants (Aortic pulse wave velocity was higher in the preterm groups. Additionally, heart rate, systolic blood pressure, and pulse pressure were higher throughout the normoxic exercise bout, consistent with higher conduit artery stiffness. Hypoxic exercise caused a decline in diastolic pressure in this group, but not in term‐born controls.In this first report of the blood pressure response to exercise in adults born prematurely, we found exercise‐induced hypertension relative to a term‐born control group that is associated with increased large artery stiffness. These experiments performed in hypoxia reveal abnormalities in vascular function in adult survivors of prematurity that may further deteriorate as this population ages. The long-term consequences of prematurity are not well understood. We found that adult survivors of prematurity have increased blood pressure during exercise and evidence of arterial stiffening. This population has been described extensively  was recruited from the general public of Madison, WI.All participants gave informed consent prior to participation. This protocol was approved by the Institutional Review Board at the University of Wisconsin and conducted in accordance with the Declaration of Helsinki2max was determined as the highest 20s value of oxygen consumption achieved  with measures of cardiac anatomy, pulmonary function tests . Participants were blinded as to the gas condition. Upon reporting to the laboratory, a 3F catheter was placed in the brachial arterial under local anesthesia and an intravenous catheter was placed in an antecubital vein. The arterial catheter was attached to a clinical grade pressure transducer (Edwards Lifesciences). A temperature sensing pill was swallowed for the measurement of core temperature .Each participant completed two research visits. On one occasion, participants breathed 21% OParticipants then sat on the same magnetically braked ergometer used for maximal exercise testing and donned nose clips and a mouthpiece for breath‐by‐breath measures of ventilation and metabolism. They remained seated quietly for at least 5 min until blood pressure and heart rate stabilized. Participants then began cycling at 50 W and the workload was increased 10 W every 2 min. Unlike the traditional exercise test used for screening, this prolonged graded exercise test was chosen in order to allow us to resolve subtle differences between the groups. The exercise protocol was terminated when participants could not maintain a cadence ≥55 RPM, despite strong verbal encouragement. Arterial blood gases were measured at rest and every other workload. The experiments described here were part of a larger project and the blood gas results have been previously reported  that was verified monthly against a water manometer. The calibration of the transducer was performed at the end of the experiment in order to maintain the sterility of the arterial line.Heart rate, derived from the arterial pressure waveform, and blood pressure recordings were collected for 5 min at rest and continuously throughout exercise (LabChart8 (AD Instruments). The final 45s of each stage was used for the analysis of blood pressure and heart rate. Aortic pulse wave velocity was derived from the intrabrachial artery pressure waveforms obtained during the resting phase as previously described  and significance was set a priori at p < .05. Anthropometric, pulmonary function, and exercise capacity comparisons were made using a two‐sample t test. The impact of exercise and hypoxia on heart rate and blood pressure was evaluated using a repeated measure, nested multivariate linear model where the percent of maximal workload was the covariate, and the individual subject, group (preterm vs. term), baseline value of the parameter during nomoxic rest, and the gas (normoxia vs. hypoxia) were included as factors. An interaction term (group × gas) was also included in the analysis. Results of the multivariate linear model analysis are given in Table Data are reported as mean ± 33.1The preterm and term‐born groups were well matched with no difference between gender, age, height, weight, body mass index (BMI), and body surface area (BSA) Table . Mild pr1, FVC, FEV1/FVC, and DLCO  (Table p = .059). Systolic and diastolic blood pressures were not different between groups in the period immediately before the onset of before exercise (Table p = .001).Aortic pulse wave velocity measured at rest was higher in the preterm group (6) Table  and was se Table . Normoxip < .001). Heart rate was consistently higher for the preterm group (group effect p < .001), even after considering significant differences in resting, normoxic heart rate (Table p < .001). Hypoxia caused an increase in resting heart rate in both groups (Table p < .001). We also observed a significant group × gas interaction effect (p = .01) that is likely the result of changes in resting and max heart rate. Hypoxia resulted in a 9 bpm reduction in maximum heart rate for the term‐born group, compared to a 6 bpm reduction in the preterm individuals. The term‐born group had a lower resting heart rate in hypoxia. Therefore, the overall increase in heart rate was 74 bpm compared to 68 bpm in the preterm group.In both groups, heart rate increased as a function of increasing workload  and was impacted by the addition of hypoxia (p = .013). Systolic blood pressure increased linearly in term‐born subjects performing normoxic exercise up until 90% of their maximal workload, while it plateaued at 60% of the maximal workload in preterm subjects. Both groups demonstrated a linear increase in systolic pressure with hypoxic exercise and, as in normoxia, systolic blood pressure was higher in the preterm group throughout the exercise protocol. Differences between preterm and term‐born individuals can be accounted for by pre‐exercise, systolic blood pressure (p < .001), suggesting that small differences in pre‐exercise blood pressure predict the higher systolic pressure during exercise.Systolic blood pressure increased as a function of increasing workload in both groups , even after considering effect of the normoxic, pre‐exercise diastolic pressure (p < .001). Diastolic pressure was increased by the addition of hypoxia in the term born. In contrast, exercise caused a reduction in diastolic pressure in the preterm population, and diastolic pressure was lower in the preterm group compared to controls throughout exercise (groups × gas effect p = .046). The differences in diastolic pressure largely contribute to the differences in mean arterial pressure . However, in hypoxia, the difference in mean arterial blood pressure between groups was reduced, driven by the reduction in diastolic pressure in the preterm group .Consistent with classic studies of the effect of exercise on diastolic blood pressure  and pulse pressure was higher in the preterm group compared to term‐born controls (p < .001). Hypoxia resulted in a higher pulse pressure in both groups (p < .001).The pulse pressure is the difference between the systolic and diastolic blood pressure, depends on stroke volume and arterial stiffness . We also used the brachial pressure tracings to derive the aortic pulse wave velocity based on a previously published algorithm (Pierce et al., We did not directly measure cardiac output at rest or during exercise in this study. As we note, others have observed a diminished stroke volume and cardiac output reserve during exercise in a similar preterm population (Huckstep et al., Consistent with the populations of Wisconsin and Iowa, the participants in this study were white and nonhispanic. The results may not be broadly applicable. The study was derived from NICUs in Iowa and Wisconsin, which could elicit a geographical bias. Our study excluded any participants that were diagnosed with asthma, cardiovascular defects, and cognitive or motor defects, and all participants appeared clinically normal. We suspect that the invasiveness of the protocol and intensity of the exercise selected for high‐performing individuals and our data may not be applicable to patients with long‐term clinical sequelae. However, we observed altered cardiovascular responsiveness to exercise even in individuals who appear clinically normal. There may be individuals with a more severe phenotype that we did not characterize here.4.5This is the first study to evaluate the dynamic blood pressure response to physiologically relevant stressors in adult survivors of prematurity. We found that preterm adults experience higher systolic blood pressures during exercise compared to a term‐born control group, and that this is possibly the result of increased large artery stiffness. The experiments performed in hypoxia revealed abnormalities in vascular function that may further deteriorate as this population ages. Preterm adults also require a higher heart rate during exercise, suggestive of alterations in stroke volume or oxygen extraction. Given the association between arterial stiffness and vascular dysfunction with cardiovascular diseases, our results suggest that the preterm population is vulnerable to cardiovascular diseases even in young adulthood. We propose that the addition of a cardiovascular stressor is critical to determine the full range of dysfunction in this population.The authors have no conflicts of interest to disclose.CRB, MP, ALS, ETF, KRB, MP, HMS, JMD, JS, GLP, MWE, and MLB designed the study; CRB, MP, ETF, KRB, MP, MWE, and MLB collected data; CRB, MP, ALS, HMS, JMD, JS, and MLB analyzed the data; CRB, MP, ALS, ETF, KRB, MP, HMS, JMD, JS, GLP, MWE, and MLB interpreted the results; CRB, MP, and MLB drafted the manuscript; and CRB, MP, ALS, ETF, KRB, MP, HMS, JMD, JS, GLP, MWE, and MLB edited and approved of the final manuscript.