Is short-term blood pressure variability from one physician office visit to the next (hereafter referred to as visit-to-visit blood pressure variability) associated with increased long-term mortality risk?In this cohort study, 16 688 patients with hypertension who were 50 years of age or older with coronary artery disease were followed up for a mean of 10.9 years. When comparing quintiles of systolic blood pressure variability measures, higher quintiles were associated with long-term mortality even after adjusting for baseline demographic characteristics, mean blood pressure, and comorbidities; the signal was stronger in women compared with men.These findings support efforts to identify and minimize visit-to-visit blood pressure variability to potentially reduce excess mortality later in life. Accumulating evidence indicates that higher blood pressure (BP) variability from one physician office visit to the next (hereafter referred to as visit-to-visit BP variability) is associated with poor outcomes. Short-term measurement (throughout 1 year) of visit-to-visit BP variability in high-risk older patients may help identify patients at increased risk of death.To evaluate whether short-term visit-to-visit BP variability is associated with increased long-term mortality risk.The US cohort of the International Verapamil SR-Trandolapril Study (INVEST), a randomized clinical trial of 16 688 patients aged 50 years or older with hypertension and coronary artery disease, was conducted between September 2, 1997, and December 15, 2000, with in-trial follow-up through February 14, 2003. The study evaluated a calcium antagonist (sustained-release verapamil plus trandolapril) vs β-blocker (atenolol plus hydrochlorothiazide) treatment strategy. Blood pressure measurement visits were scheduled every 6 weeks for the first 6 months and biannually thereafter. Statistical analysis was performed from September 2, 1997, to May 1, 2014.Visit-to-visit systolic BP (SBP) and diastolic BP variability during the first year of enrollment using 4 different BP variability measures: standard deviation, coefficient of variation, average real variability, and variability independent of the mean.All-cause death, assessed via the US National Death Index, beginning after the exposure assessment period through May 1, 2014.For the present post hoc analysis, long-term mortality data were available on 16 688 patients . During a mean (SD) follow-up of 10.9 (4.2) years, 5058 patients (30%) died. All 4 variability measures for SBP were significantly associated with long-term mortality after adjustment for baseline demographic characteristics and comorbidities. After comparison of lowest vs highest variability measure quintiles, the magnitude of the association with death remained statistically significant even after adjustment for baseline demographic characteristics and comorbidities . The signal was stronger in women compared with men. Associations of diastolic BP variability measures with death were weaker than for SBP and were not significant after adjustment.This study suggests that, in a large population of older patients with hypertension and coronary artery disease, short-term visit-to-visit SBP variability was associated with excess long-term mortality, especially for women. Efforts to identify and minimize visit-to-visit SBP variability may be important in reducing excess mortality later in life.NCT00133692ClinicalTrials.gov Identifier:  This cohort study evaluates whether short-term blood pressure variability from 1 physician office visit to the next is associated with increased long-term mortality risk among adults with coronary artery disease (CAD). Office BP is known to vary substantially from visit to visit (heareafter referred to as visit-to-visit BP variability), which is often attributed to random variation around the patient’s “true” BP owing to measurement errors.4 Nonetheless, accumulating evidence indicates that increased visit-to-visit BP variability is associated with worse cardiovascular disease (CVD)9 outcomes independent of mean BP and other CVD risk factors.Blood pressure (BP) measured during a physician office visit (hereafter referred to as office BP) remains the usual measurement for diagnosing and monitoring hypertension worldwide. However, it is questionable whether the usual BP measurement alone can account for all future BP-related cardiovascular events.19 In addition, findings from earlier studies have been mixed; some found that higher visit-to-visit BP variability was associated with increased mortality,21 whereas others showed no association.1 Also, most studies had few patients that focused on relatively short-term outcomes, populations without CAD, and relatively younger populations, and many were observational cohorts without a standardized BP measurement.22 Moreover, to our knowledge, there is a paucity of information regarding associations between short-term BP variability and long-term, all-cause mortality among older patients, particularly women, with CAD. Accordingly, we evaluated associations between short-term BP variability patterns and long-term, all-cause mortality among US patients enrolled in the International Verapamil SR-Trandolapril Study (INVEST).23Whether short-term, visit-to-visit BP variability  portends increased risk of long-term, all-cause mortality is less well established. Although hypertension is the most prevalent modifiable risk for coronary artery disease (CAD), previous BP variability studies have focused mostly on patients without CAD.24 In brief, INVEST was an international prospective, randomized, blinded end point evaluation design trial that enrolled patients between September 2, 1997, and December 15, 2000, with in-trial follow-up through February 14, 2003. Eligible patients aged 50 years or older with hypertension and stable CAD were randomly assigned to receive either a calcium antagonist–based (sustained-release verapamil plus trandolapril) or β-blocker–based (atenolol plus hydrochlorothiazide) strategy, with protocolized titration to achieve a target BP of less than 140/90 mm Hg (<130/85 mm Hg for those with kidney impairment or diabetes). Patients were assessed for treatment response, compliance, and adverse effects during scheduled protocol visits every 6 weeks for the first 6 months and biannually thereafter. The mean (SD) patient follow-up was 2.7 (1.1) years . The BP measurement was in accordance with prior Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommendations.25 In brief, when performing BP measurements, a quiet room was used, with the patient performing minimal extraneous activity, sitting with uncrossed legs and feet flat on the floor. Blood pressure was measured twice using a standard mercury sphygmomanometer with the appropriate BP cuff size, separated by at least 2 minutes, and investigators were instructed to measure BP in a given patient at approximately the same time of day throughout the trial. The primary outcome was the first occurrence of death, nonfatal myocardial infarction, or nonfatal stroke. The outcomes comparing strategies were equivalent, and excellent BP control (approximately 72%) was achieved in each treatment group23; thus, for this analysis, patients from both treatment groups were pooled into a single cohort. The antihypertensive drugs and doses used are detailed elsewhere.23 INVEST was conducted according to principles of the Declaration of Helsinki.26 Institutional review boards and ethics committees at the participating sites23 approved the protocol, and patients provided written informed consent.The present data were obtained from a post hoc analysis of the results from INVEST. The INVEST design and primary and secondary outcomes are published in detail.27 Possible matches were identified according to NDI guidelines.27 To be considered a confirmed death, we required 4 or more of 5 matches among Social Security number, name, date of birth, city, and state in the NDI. Follow-up for all-cause mortality began at each patient’s 1-year visit and ended on the date of death or date of the NDI search (2014). Patients who died before the 1-year visit were excluded from all analyses  reporting guideline.For this study, the outcome of interest was all-cause mortality. INVEST was planned and powered for US-only analyses, and data on long-term, all-cause death were not available for non-US participants; thus, the present study included only the US cohort. All-cause death was ascertained through the US National Death Index (NDI) search.28; and (4) variability independent of the mean (VIM). The latter was computed by dividing an individual’s SD to the meanx and multiplying it by the population’s meanx, where “x” is derived by fitting a regression curve through a plot of SD against the mean  standard deviation (SD); (2) coefficient of variation (CV), which is the SD divided by the mean; (3) average real variability (ARV) across multiple visits assessed by calculating the mean absolute differences between successive BP measurements in each clinic visit, taking into account the order of BP measurements (in contrast to CV and SD) and tending to be less affected by trends30 In addition, SD and CV are associated with visit-to-visit BP outlier values, whereas ARV accounts for between-visit time intervals and BP measurement order. VIM is constructed to have no correlation with the mean BP but is dependent on the distribution of the BP within a cohort.7 Prior evidence suggests that SD, CV, and VIM are highly correlated and may convey similar information about variability around the mean BP across visits. Conversely, because ARV captures variability from one visit to another, it may convey different information.30 To assess these correlations in our high-risk, sex-diverse, and racially/ethnically diverse older cohort, we calculated all 4 metrics, capturing variability between consecutive visits and overall variability.The SD, CV, and ARV are necessarily correlated with mean BP.Statistical analysis was performed from September 2, 1997, to May 1, 2014. Categorical variables were presented as frequencies and percentages, and continuous variables were presented as mean (SD) values. We aimed to investigate the association between each short-term, visit-to-visit BP variability measure and long-term mortality. We also estimated the association between mean BP (during the same time frame) and long-term mortality.To calculate BP variability traits for each participant, we used systolic BP (SBP) and diastolic BP (DBP) measurements from clinic visit number 1 (baseline) through visit number 6 (1 year after randomization) . We used the Cochran-Armitage test for trend to evaluate dose-response association across quintiles of BP variability measures with mortality, even if the association was not statistically significant for any particular exposure level. We also modeled the association of BP variability measures as a continuous variable, with long-term mortality evaluated using Cox proportional hazards regression models and restricted quadratic splines with knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles of each BP variability measure. All analyses were performed using SAS, version 9.4. A 2-sided P < .05 was considered statistically significant.For each variability measure, we categorized patients into quintiles to compare different degrees of BP variability in association with mortality using the lowest quintile as a reference. The Kaplan-Meier method assessed the cumulative incidence of death for each variability measure. We used Cox proportional hazards regression analysis to calculate crude and adjusted hazard ratios (aHRs) and 95% CIs, with long-term mortality as the dependent variable and each BP variability measure as the primary independent variable of interest, in separate models. We also assessed similar prediction models with the mean BP (during 1 year) as the predictor. Covariates included in all adjusted models were age, sex, race/ethnicity, study site, treatment assignment group, body mass index, mean BP, history of diabetes, hypercholesterolemia, prior myocardial infarction, coronary artery bypass graft surgery or percutaneous coronary revascularization, heart failure, left ventricular hypertrophy, peripheral arterial disease, prior transient ischemic attack or stroke, and kidney insufficiency. These covariates were selected a priori as evidence demonstrated that they are associated with hypertension and mortality.23 17 131 resided in the US. The 16 688 patients alive at the end of the first year of follow-up contributed to this analysis. Their mean (SD) age was 66.5 (9.9) years, and 54% were women. The population was racially/ethnically diverse, with 45% White participants, 37% Hispanic participants, and 16% Black participants. The mean (SD) body mass index  was 29.5 (5.8); 29% of participants had a history of diabetes, 29% had prior myocardial infarction, and 29% had undergone revascularization  but not mean SBP (Pearson r = 0.016). Qualitatively similar findings were observed for DBP variability measures.The mean (SD) number of BP measurement visits was 4.0 (1.6), and the mean (SD) follow-up duration was 255.9 (90.2) days. The mean baseline SBP (SD) was 148.2 (19.0) mm Hg, and the mean (SD) baseline DBP was 85.0 (11.0) mm Hg . During During a mean (SD) follow-up of 10.9 (4.2) years, 5058 deaths occurred (27.9 deaths per 1000 person-years). Mean BP was weakly associated with mortality for SBP measurements  and DBP measurements . In general, the cumulative incidence of all-cause mortality was progressively higher at higher levels of SBP variability for all measures . In unadP values for interaction, we also stratified the analysis by treatment groups, which revealed a predilection for stronger association with the primary outcome in the calcium antagonist–based group vs the β-blocker group  with CAD. In this high-risk population, short-term (within the first year after randomization), visit-to-visit SBP variability, but not DBP variability, was associated with long-term mortality. Our findings remained consistent even after adjustment for a robust set of well-measured potential confounders. Compared with the lowest quintiles, the highest quintiles of SBP variability measures were associated with a 14% to 18% increased risk of long-term mortality. Across all 4 BP variability measurements, the signal was significantly stronger among women, a cohort often underenrolled in CVD trials. Our data add to and expand the growing evidence of the prognostic value of visit-to-visit BP variability and its association with poor outcomes for older patients with hypertension and CAD.INVEST was the largest randomized clinical trial of older patients with hypertension  with a similar representation of men and women. Our population was well characterized, with protocolized BP measurements. Furthermore, the mortality signal with SBP variability was consistent even after adjustment for multiple baseline covariates. This association, as in prior BP variability studies,7 was probably not associated with poor BP control because approximately 72% of INVEST patients achieved goal BP levels by the end of trial follow-up.23Prior studies document an association of higher BP variability with CVD,47 Others have suggested that β2-adrenoceptor desensitization is associated with less β2-mediated arterial relaxation.48 Moreover, greater BP variability was associated with myocardial fibrosis, hypertrophy, and dysfunction in humans and animal models.49 All of these factors may play a role in the long-term increase in mortality observed with higher BP variability.Many theories have been proposed to explain the underlying pathologic mechanisms associated with higher BP variability. Animal models suggest greater arterial remodeling, endothelial dysfunction, vascular injury, and coronary atheroma progression.50 In addition, mechanisms have been proposed to explain higher visit-to-visit BP variability, including impaired baroreceptor function,51 inflammation,54 and kidney impairment.55 Higher BP variability was also bidirectionally associated with greater arterial stiffness and remodeling in human studies and population-based cohorts.59 Evidence suggests that increased arterial stiffness is associated with higher BP variability, whereas, on the other hand, increased BP variability is associated with increased arterial wall stiffness.60 Also, for women, estrogen has an intricate role to play in vascular function.61 It is possible that the present cohort, being older and with a higher proportion of women in menopause, had higher BP variability and possibly a stronger association with mortality. Finally, low medication adherence has been proposed as a cause of BP variability.62 However, adherence rates in INVEST were estimated to be 78% to 82% at 24 months and likely even higher at 12 months (the BP measurement duration in this study).23 Thus, we believe that it is unlikely that nonadherence played a major role.Prior studies reported that female sex, older age, obesity, “white coat hypertension” , and certain antihypertensive medications are associated with higher BP variability patterns.63 although the true number remains unknown and difficult to estimate.64 In this study, the easy-to-calculate BP variability measures were associated with mortality and are highly feasible for clinical practice through automated calculations within electronic records. Future BP variability research should focus on causal pathways of worse outcomes and interventions to reduce individual BP variability between visits. In the meantime, current electronic health systems should routinely incorporate BP variability measures in the clinic to identify patients at higher risk for future CVD events and mortality who may warrant more intensive preventive measures to mitigate their residual risk and reduce their morbidity and mortality  is resistant to bias, clinically relevant, and patient centered. Besides the mean BP, we used 4 different BP variability measures and adjusted for a wide range of confounders in the final analysis. Last, our study had among the longest follow-up durations for the outcome of interest.65 Finally, the present data are a post hoc analysis of a randomized clinical trial, a limitation that requires caution when interpreting conclusions.This study also has several limitations. The generalizability of the findings to other populations (those without CAD or of younger age) or to patients in real-life settings is unclear. Also unclear is the optimal number of visits and the time interval between clinic visits for BP variability assessments. We could not account for BP variability between clinic visits, out-of-office or home BP measurement, or compare manual vs automated BP measurements or the ideal number of BP measurements at each visit. Data on compliance with antihypertensive drugs during follow-up were not available. Our outcome of interest was based on death certificates, not on primary trial follow-up data, which can predispose to misclassification. Nevertheless, the NDI has been validated as an accurate measure of death in the US, particularly for those that have not occurred recently.Visit-to-visit BP variability remains underused in clinical settings. Although antihypertensive medications reduce SBP and DBP, higher short-term BP variability is associated with residual risk for adverse long-term mortality even among patients with controlled BP. Short-term (approximately 1 year) SBP variability measures were associated with mortality more than a decade after measurements in older patients with CAD, even when using variability measures not correlated with mean BP. This association was stronger for women. Next steps should embrace incorporating variability measures in the clinic. Further research should address this excess risk measure with novel therapies or combinations of medications to reduce mortality risk.


The two most common modes of death among chronic heart failure (CHF) patients are sudden cardiac death (SCD) and pump failure death (PFD). Periodic repolarization dynamics (PRD) quantifies low-frequency oscillations in the T wave vector of the electrocardiogram (ECG) and has been postulated to reflect sympathetic modulation of ventricular repolarization. This study aims to evaluate the prognostic value of PRD to predict SCD and PFD in a population of CHF patients. 20-min high-resolution (1000 Hz) ECG recordings from 569 CHF patients were analyzed. Patients were divided into two groups,  An estimated 64 million people suffer from HF worldwide and the total associated cost in health programs is estimated to reach $400 billion by 20304. HF is a clinical syndrome accompanied by a high burden of co-morbidities5 and poor prognosis6.Approximately 1–2% of the adult population in Western societies is diagnosed with heart failure (HF)7 and accounts for more than 60% of all cardiovascular deaths out of hospital8. SCD is defined as death due to unexpected circulatory arrest that occurs within an hour of the onset of symptoms or during sleep9. Another common cause of death in CHF is pump failure death (PFD), resulting from progressive pump failure. Treatment with 10. Based on this evidence, there is an important need to successfully predict the mode of death in CHF, which could contribute to a more cost-effective use of medications or devices.In chronic HF (CHF) patients, sudden cardiac death (SCD) represents the cause of death in 30–50% of them11, QT interval variability index (QTVi)12, baroreflex sensitivity13, fragmented QRS15, T-wave alternans17 or turbulence slope18 have been investigated. Periodic repolarization dynamics (PRD) has been proposed to assess sympathetic modulation of ventricular repolarization by measuring low-frequency  oscillations in the T-wave vector19. Elevated PRD has been related to increased arrhythmic risk in a range of cardiac diseases and conditions22.A variety of non-invasive indices derived from resting electrocardiograms (ECGs) or ambulatory Holter recordings have been proposed for stratifying CHF patients according to their PFD and SCD risk. Among others, heart rate variability (HRV)23. Such an imbalance leads to worsening of prognosis in CHF patients24, with higher likelihood for PFD and SCD26. On this basis, we hypothesize that, if the PRD index is a marker of sympathetic-associated repolarization instability, it could be used for risk prediction in a CHF population. This work specifically aims to assess the capacity of the PRD index, calculated by using an update of the originally proposed algorithm27, for SCD and PFD risk stratification of CHF patients. PRD was analyzed both individually and in combination with other repolarization and autonomic-related ECG indices to predict SCD and PFD.Autonomic imbalance, with increased sympathetic activity and withdrawal of vagal activity, has been described as a hallmark of HFMUerte Subita en Insuficiencia Cardiaca) study. From the 992 included in the original MUSIC study28, 341 patients had atrial fibrillation, flutter or pacemaker and were excluded for the present analysis. Out of the remaining 651 patients, 82 patients did not have an available high-resolution ECG recording and were therefore not included. Mean left ventricular ejection fraction (LVEF) was 37.0 ± 13.8% (range 12–70%), with most patients (55%) presenting The study population consisted of 569 CHF patients (409 men and 160 women), aged 20–80 years  in in vivo studies on HF patients37. Through in silico simulations, synergistic 39. Those results have been supported by subsequent experimental studies showing that increased sympathetic activity potentiates such oscillations and 40. In the presence of calcium overload and/or reduced repolarization reserve, both being commonly associated with HF, the amplitude of LF oscillations of APD have been theoretically shown to be magnified, facilitating the occurrence of arrhythmogenic events41. A recent in vivo study in a canine model of ventricular remodeling caused by chronic atrioventricular block has provided evidence that dogs inducible for ventricular arrhythmias present higher LF oscillations of repolarization than non-inducible dogs42. Based on all these observations, the results of our study possibly suggest that CHF patients with high PRD present augmented repolarization variability that can lead to destabilization of repolarization and promote arrhythmogenesis.PRD measures the magnitude of LF oscillations in the T wave vector of the ECG and has been postulated to reflect sympathetic modulation of ventricular repolarization47. The use of markers providing information about different pathophysiological processes associated with CHF has been shown to be very useful49. Here, a combination of PRD and other ECG-based indices are tested for SCD and PFD risk prediction. For PFD prediction, the combination of PRD with TS, measuring heart rate turbulence, stratifies the study population into two groups according to the risk of PFD. The risk of dying from PFD is two and a half times higher in patients with high PRD  and Holter recordings . In terms of SCD prediction, the stratifying ability of PRD is enhanced when combined with the marker IAA evaluating T-wave alternans amplitude over 24 h. While T-wave alternans, measured by IAA in this work, is related to abnormal cardiac function17, PRD measures changes in sympathetic modulation of ventricular repolarization19. The synergistic information provided by the two variables serves to improve SCD prediction. In all the above described findings, the risk stratification capacity of PRD is maintained when accounting for competing risk events in survival analyses.Since CHF is a complex clinical syndrome, some studies have reported the benefit of using combined ECG risk markers and/or a risk score integrating information from various clinical and ECG variables to improve clinical decision making28, was not a significant predictor of SCD in multivariable regression models comprising PRD or combined ECG markers. When the endpoint was CD, 52, and found the dichotomized variable to be a predictor of both SCD and PFD. However, as our CHF population includes only patients in NYHA classes II and III, only 7% of the patients had NT-proBNP values above 5180 pg/mL.NT-proBNP concentration, dichotomized using the threshold (1000 pg/mL) proposed in the original MUSIC study19, we hypothesized that PRD and HRV markers could add complementary information. However, our results show that HRV markers do not have a relationship either with SCD or PFD and, thus, we have not combined them with PRD for risk stratification purposes. On the other hand, of the clinical variables assessed in our study, NYHA class and LVEF 53. Regarding NYHA class, as it reflects a subjective assessment and can change frequently over short periods of time28, its interpretation is more critical than other variables. The analysis conducted in this work suggests that the adjunct use of clinical variables and ECG-based markers can improve the prognostic value of all of them and render a risk score with remarkably superior performance to predict the two most common modes of death in CHF patients.On the basis of previous studies showing that PRD is unrelated to HRV and respiratory activity35 and subsequently updated by Palacios et al.27 Here, we use 20-min ECGs, from which the 5-min segment associated with minimum PRD is selected. This is an advantage as compared to a number of previously analyzed markers, such as IAA17, QTVi12, TS54, 55, 56 or TMR57, which require longer ECG recordings or specific protocols, like stress tests or steady heart rate, for their evaluation. While the combination of PRD with other Holter-based markers improves risk stratification, it requires long-duration recordings. On this basis, we propose that PRD could be used in an initial step to select patients with high CD risk. Over those selected patients, the use of longer duration signals and associated variables could be useful to specifically predict each of the death modes. Several works have proposed other markers related to repolarization variability measured from short-term ECG recordings, such as the variance normalized by the mean of QT end, QT peak or T-peak-to-T-end (Te) intervals, and have evaluated them in CHF populations. In recent studies, the mean and/or standard deviation of Te have been shown to predict 30-day mortality59 and mortality in hospital60 among decompensated CHF patients.An important aspect regarding the use of PRD is the fact that it can be measured from 5-min ECGs by using the phase-rectified signal averaging (PRSA)-based method employed in this study, first described by Rizas et al.To sum up, our study documents the prognostic value of PRD in combination with other Holter-derived markers to predict PFD and SCD in a large cohort of CHF patients. Future studies on CHF cohorts including a larger number of SCD and PFD victims would allow conducting more robust statistical analysis to confirm the findings here reported. Also, studies on larger populations would facilitate assessing the capacity of PRD for risk stratification in specific CHF patient subpopulations, such as those with reduced or preserved LVEF or at different NYHA classes, among others.28. All methods were performed in accordance with the relevant guidelines and regulations.The MUSIC study is a prospective, multicenter, longitudinal study designed to assess risk predictors of cardiac mortality and SCD in ambulatory patients with CHF. Patients were consecutively enrolled from the specialized CHF clinics of eight University Hospitals between April 2003 and December 2004. All had symptomatic CHF (NYHA class II–III) and were treated according to institutional guidelines. The study included patients with either depressed or preserved LVEF. Patients with preserved LVEF were included if they had CHF symptoms and a prior hospitalization for HF or some objective signs of HF confirmed by chest X-ray (findings of pulmonary congestion) and/or echocardiography . Patients were excluded if they had recent acute coronary syndrome or severe valvular disease amenable for surgical repair. Patients with other concomitant diseases expected to reduce life-expectancy were also excluded. All patients gave written informed consent and the study protocol was approved by all the institutional investigation and ethics committees from the following participant hospitals: Valme Hospital, Santiago de Compostela Hospital, Son Dureta Hospital, Arrixaca Hospital, Gregorio Marañon Hospital, Joan XXIII Hospital, Insular Las Palmas Hospital, Sant Pau Hospital28.For each patient, two ECG recordings were available: a 24-h ambulatory ECG sampled at 200 Hz in 3 orthogonal X, Y and Z leads using SpiderView recorders  and a prior 20-min ECG sampled at 1000 Hz while patients were resting in supine position. In this study, PRD was measured from the 20-min ECG recording. Patients were followed every 6 months on an outpatient basis for an average of 48 months. Death was defined as SCD if it was: (1) a witnessed death occurring within 60 min from the onset of new symptoms, unless a cause other than cardiac was obvious; (2) an unwitnessed death  in a window around the T-wave, similarly to previous works27, a modified version of the original method described in Rizas et al.19. This method included the following steps: T waves were selected using the T wave windows defined in section ECG pre-processing.A constant value was subtracted from each T wave in each of the analyzed leads so that the amplitude at The average electrical vector was calculated for each T-wave window. The angle A 10th-order median filter was used to attenuate outliers and artifacts in the Steps (i) to (iii) are illustrated in Fig. PRD was measured in the preprocessed signal by using the method described in Palacios et al.63 was applied to evaluate the oscillations measured by the PRD index35: 5.M = 9 was established because it allows detecting frequencies in the range of interest (from 0.025 to 0.1 Hz), as fully described in Bauer et al.63.Anchor points were defined by comparing averages of 6.L values were defined around each anchor point. Anchor points in the last L samples of the L could not be defined around them. In this study, L = 20 was chosen, as it allowed detection of frequencies in the range of interest.Windows of 27.The PRSA series was obtained by averaging the For each 5-min segment, a PRD value was defined as the difference between the maximum and minimum values of the PRSA series. For the 20-min recording of each subject, a unique PRD value was calculated as the minimum PRD over the analyzed 5-min segments with 4-min overlap.Over the obtained Illustrative examples of By setting a cutoff point of 1.3364. Power spectral density (PSD) was estimated based on the periodogram. LF and high-frequency (HF) powers were calculated as the areas under the PSD within the 0.04–0.15 Hz and 0.15–0.5 Hz frequency bands, respectively. Normalized powers, denoted by LFn and HFn, were obtained by dividing LF and HF powers by the sum of the two. The ratio between LF and HF powers, denoted by LF/HF, was additionally computed65.For the 5-min segment with minimum PRD, HRV indices were computed as in Bailón et al.28, were included in our analysis.Clinical variables such as LVEF 17. IAA was shown to risk stratify for SCD in the study population here analyzed when dichotomized at 17. On the other hand, turbulence slope, TS, describing the initial phase of sinus rhythm deceleration after a VPB, was determined as the maximum positive slope of a regression line assessed over any of 5 consecutive RR intervals within the first 20 sinus RR intervals after a VPB during the 24-h ECG recording51. TS was shown to stratify risk for both SCD and PFD when dichotomized at 2.5 ms/RR, with 51.Additionally, other Holter-based indices calculated in previous studies of our group were considered based on their risk prediction power. On the one hand, the index of average alternans, IAA, quantifying the average amplitude of T-wave alternans over a 24-h period, was computed by automatic ECG analysis66 proportional hazards regression models and Fine and Gray analysis for competing risk29 were used for prediction of endpoints. Hazard ratios (HR) and 95% confident intervals (CI), expressed as HR [95% CI] were quantified. P values Continuous variables are presented as median [interquartile range (IQR)]. The Mann–Whitney U test (or Wilcoxon rank-sum test) was used for univariate comparisons of continuous variables between patient groups. Survival probability was estimated by Kaplan–Meier analysis, with the log-rank test used to assess group differences. Univariate and multivariate CoxThis study tests PRD, a non-invasive marker of repolarization instability associated with low-frequency oscillations in sympathetic activity, as a predictor of SCD and PFD risk in CHF patients. The combination of PRD with an index of T wave alternans further enhances the capacity of PRD for SCD risk stratification. Additionally, the combination of PRD with heart rate turbulence slope allows predicting PFD risk. Altogether, the value of ECG markers, either derived from short-term ECGs or ambulatory Holter recordings, is highlighted as a means to improve prognosis in CHF patients beyond commonly used clinical variables.


Total arch replacement (TAR) with Frozen elephant trunk (FET) treatment of acute DeBakey type I aortic dissection (ADIAD) is complicated, carries a high complication/mortality risk and remains controversial on the optimal hypothermic level, cerebral perfusion and visceral organ protection strategy. We developed a new strategy named “Brain-Heart-first” in which the surgical procedures and the management of cardiac perfusion/cerebral protection during Cardiopulmonary bypass (CPB) were redesigned, and TAR with FET technique can be performed under mild hypothermia with satisfactory outcomes.Our aims were to describe a new surgical strategy under mild hypothermia (≥30°C) for the treatment of ADIAD and to report the operative outcomes of 215 patients.We conducted a retrospective analysis of 215 consecutive cases of ADIAD treated with our new strategy.The durations of CPB, aortic cross-clamping, antegrade cerebral perfusion, operation, mechanical ventilation support, and Intensive Care Unit stay were 139.7 ± 52.3 min, 55.6 ± 27.4 min, 14.1 ± 3.1 min, 6.0 ± 1.7 h, 40.0 h and 4.0 d, respectively. The 30-day mortality was 9.8%, with cerebral stroke occurring in nine patients (4.2%), paraplegia in one patient (0.5%) and postoperative renal injury requiring dialysis in 21 patients (9.8%). The blood transfusion of red blood cells and fresh frozen plasma during surgery and the first 24 h after surgery was 4.0 u and 200.0 ml, respectively.The Brain-Heart-first strategy can be widely used with low technical and resource requirements and provides a safe alternative for conventional TAR with FET technique in ADIAD patients with satisfactory operative results. Although the application of total arch replacement (TAR) combined with frozen elephant trunk (FET) technique in acute DeBakey type I aortic dissection (ADIAD) still remains controversial, it has evolved as an accepted choice for patients with aortic disease involving the aortic arch and supra-arch branches (including ADIAD) –5. HowevA total of 215 consecutive patients with ADIAD who underwent treatment using our new Brain-Heart-first strategy under mild hypothermia (≥30°C) by a single surgical team were enrolled between May 1, 2017 and December 31, 2020. The preoperative characteristics of patients are listed in 2/min, and systemic cooling was commenced to induce mild hypothermia. During the cooling phase, the ascending aorta was replaced using a 4-branched graft, and the aorta root/valve/coronary was reconstructed or replaced if necessary. Approximately 4-5cm length was reserved at the proximal end of the 4-branched graft to cross-clamping during the potential reoperation  and a transesophageal echocardiographic monitoring probe were placed routinely. Bilateral regional cerebral oxygen saturation was monitored using near-infrared spectroscopy (NIRS) . Cardiopulmonary bypass (CPB) was instituted through the right atria to the right axillary artery by cannulation . Femoral artery cannulation was performed if necessary, e.g., when the pumping pressure was >250 mmHg. CPB was initiated with a flow rate of 2.0-2.4 L/mperation .2/min and the IA was cross-clamped, ligatured, and cut off. Meanwhile, the perfusion flow rate was regulated based on pump pressure and NIRS monitoring to ensure the fluctuation of rSO2 and the blood pressure in the LCCA of <10% above or below the baseline. Then, the circulatory arrest of the lower body was instituted. The aorta arch was transected at the end part of zone-0 or the initial part of zone-1  reached >70%. After the LSA was anastomosed, the blood pressure of the left radial artery was recovered, and then the arterial pressure catheter in the second branch could be removed. The perfusion tube was transferred from the first branch to the fourth branch of the 4-branched graft (reducing the perfusion flow rate to 8 ml/kg.min within 10 s), and the IA was anastomosed with the first branch finally  was anastomosed with the second branch of the 4-branched graft, and the innominate artery (IA) and the left subclavian artery (LSA) supplied the cerebral circulation system temporarily . Then, tf zone-1  . The informed consent was signed by all patients to allow the use of their data for research, and this study was approved by the Ethics Committee of the Second Xiangya Hospital .25, Q75). Categorical variables are presented as absolute numbers and percentages.Data were statistically analyzed using SPSS 22.0 software . Continuous, normally distributed variables are presented as mean ± standard deviation. Continuous, non-normally distributed variables were shown as the median , Intensive Care Unit (ICU) stay, and hospitalization were 40.0 h, 4.0 days, and 16.0 days, respectively. The median amounts of red blood cells (RBC) and fresh frozen plasma (FFP) transfusion during surgery and the first 24 h after surgery were 4.0 u and 200.0 ml, respectively. The drainage within the first 24 h after surgery was 640.0 ml. Of the 215 patients, 88 (40.9%) had postoperative acute kidney injury : 41 (19.1%) in stage 1, 15 (7.0%) in stage 2, and 32 (14.9%) in stage 3. Renal injury requiring dialysis occurred in 21 patients (9.8%). For the 39 patients with preoperative renal injury (creatinine clearance rate < 50 ml/min), 20 (51.3%) had their renal function recovered to normal, 3 (7.7%), 3 (7.7%), and 13 (33.3%) had stage 1, 2, 3 postoperative AKI, respectively. Postoperative cerebral stroke occurred in nine patients (4.2%), and paraplegia in one patient (0.5%). The 30-day mortality was 9.8% (21/215 patients) , 4.Of the 215 patients, 21 were died in 30 days after surgery. For the other 194 patients, 2 were lost to follow-up; 192 (99.0%) completing an average follow-up of 19.9 ± 13.2 months, 16 of which died during follow-up (2 unidentified sudden deaths and 14 non- ADIAD-associated deaths), resulting in a survival rate of 91.7% (176/192 patients). There was 1 (0.5%) requirement for reoperation . No other patients need reintervention for the progressive descending aorta enlargement or anastomotic leak. The patients with postoperative paraplegia who survived had their physical strength recovered to normal gradually after cerebrospinal fluid drainage.The conventional TAR with FET procedure for patients with ADIAD requires deep or moderate hypothermic circulatory arrest (HCA) in the absence of hybrid procedures or new devices, which means longer cooling and rewarming phase and brings specific challenges in cardiac, neurologic, and distal organ protection –6. Our nAs we known, type I aortic dissection extends from the aortic root  through the ascending aorta and aortic arch to the descending aorta. Conventionally, it was considered that the heart was far easier to be protected than the brain. Therefore, during the past decades, most surgeons give priority attention to the reconstruction of the arch and distal aorta. The reconstruction of the proximal aorta is started after the completion of the arch and distal aorta repair , 4, whicvia the right axillary artery. Therefore, sufficient cerebral perfusion through bilateral carotid arteries was achieved during the process of the arch and descending aorta repair. The only potential cerebral ischemic injury was existed in the anastomotic phase of LCCA. However, the right common carotid artery and LSA had continuous perfusion in this phase. Meanwhile, the temperature was decreased around to 30.0°C and the time for LCCA anastomosis was 10.3 ± 2.9 min, which would be safe for the cerebral perfusion. Furthermore, the blood pressure of the LCCA was monitored and was adjusted to balance the cerebral perfusion flow and avoid hypo/hyper-perfusion in bilateral common carotid arteries. As we known, a high perfusion pressure allows collateral flow from the brain to the spinal cord, with similar outcomes to those observed under a low perfusion pressure (−1·min−1) (2/min) was produced naturally by the blood pressure, conforming with the physiological characteristics of cerebral perfusion. The perfusion flow rate during ACP/LBA was significantly increased, and effective cerebral protection was achieved as demonstrated with NIRS monitoring, without increasing the rate of stroke.In addition to deep or moderate HCA which is essential for conventional TAR, antegrade and retrograde as well as unilateral and bilateral cerebral perfusion have been adopted with satisfactory results –20. Howepressure . In our 1·min−1) –20, 22, The lower body arrest time depends on the duration of anastomosis of the 4-branched graft with the FET graft. The most sensitive distal organ to ischemia is the spinal cord. Evidence showed that warmer cerebral perfusion might help to improve the collateral flow from the brain to the spinal cord, and this blood backflow may contribute to the protection of the spinal cord, which could tolerate ischemia under hypothermia at 30-32°C for 30 min . In our With these modifications, deep or moderate HCA is no longer needed, and the CPB time would be shortened naturally . It is kIn our opinion, the application of the Brain-Heart-first strategy in TAR with FET technique for patients with ADIAD may be able to end the dispute related to cerebral perfusion strategy  to some extent, and the arch replacement and cerebral protection are no longer the bottleneck. The surgical difficulties are transferred from the “arch” to the “root,” and a surgeon with skills to perform the Bentall procedure may be easily trained to perform this extensive repair. After the reconstruction/repair of the proximal aorta/aortic root, what remains to be done is the four routine graft-arterial anastomoses to reconstruct the arch and descending aorta, including the 2nd branch of the 4-branched graft with LCCA, the trunk of 4-branched graft with the stented graft, the 1st and 3rd branches of the 4-branched graft with LSA and IA, respectively. What's more, the procedure can be performed in a routine operation room with no need of expensive devices or complex operations involving interventional cardiologists and radiologists. For some complex cases or under particular circumstances, or for some surgeons who are not experienced enough, we suggest the Brain-Heart-first strategy be performed under moderate or even deep hypothermia to ensure patient safety. Therefore, we think it may be possible to transfer the results 1:1 to other centers, especially for high-volume centers.In conclusion, the Brain-Heart-first strategy can be widely used with low technical and resource requirements and can provide a safe alternative for conventional TAR with FET technique in ADIAD patients with satisfactory operative results.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Xiangya Hospital. The patients/participants provided their written informed consent to participate in this study.KS, LT, and HT: conception, study design, protocol, and writing. KS, LT, JX, DX, JL, SW, and YC: data collection and assessment. HT and XZ: project oversight and supervision. KS, LT, HT, and XZ: critical revisions for important intellectual content. All authors read and approved the final manuscript.This study was funded by the Key Research and Development Program of Hunan Province (No. 2019SK2022).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


IntroductionAsthma is a clinical syndrome characterized by reversible and recurrent airway obstruction leading to the symptoms of wheezing, cough, shortness of breath, fatigue, and respiratory distress. It is one of the most common lung pathologies worldwide. Its incidence is on the rise in Pakistan, which may be due to overt environmental pollution or improving screening protocols. Irrespective more and more patients are now being diagnosed as cases of asthma and this has led to renewed interest in research for the subject locally.Vitamin D plays a key component of the immune system and its deficiency has been associated with diseases, such as inflammatory bowel disease, celiac disease, rheumatoid arthritis, depression, sepsis, and coronavirus disease 2019 (COVID-19) pneumonia. The role of vitamin D in exacerbation, prevention, causation, and treatment of asthma is still up for debate. However, as more data emerges, it is becoming evident that vitamin D in one way or another is linked to outcomes in asthma. Especially the deficiency of vitamin D in asthma and its supplementation has garnered great attention in scientific trials. Our research is just one small step in this direction. This study aims to evaluate the frequency of vitamin D deficiency in patients with asthma.MethodsThis was a retrospective cross-sectional cohort conducted at the Department of Medicine of Abbasi Shaheed Hospital Karachi (ASHK) during March 2019 to August 2019. Patients of either gender aged ≥18 years that were diagnosed with cases of asthma were eligible to be included in the study. Asthma was defined in accordance with the latest guidelines issued by the Pakistan Chest Society. A vitamin D level of <20 ng/dl was considered deficient. Patient confidentiality was made certain. ResultsA total of 97 (62.98%) of the 154 patients included in the study had <20 ng/ml of vitamin D level. The mean vitamin D level recorded in this study was 15.34±4.21 ng/dl. The male-to-female ratio was 1:5. The mean age of our cohort was 42.78±4.56 years. The mean duration of disease, i.e., asthma was 6.7±3.68 years. Both the age of the patients and duration of the disease were found to be statistically significant with respect to vitamin D levels in asthmatics.ConclusionsThe frequency of vitamin D deficiency is very high in patients with asthma. These suboptimal levels are significantly influenced by the age of the patient and the duration of the disease. Asthma is one of the most prevalent pulmonary pathologies around the world . Its incVitamin D is a key component of the immune system and its deficiency has been reported in inflammatory bowel disease, rheumatoid arthritis, celiac disease, clinical depression, encephalomyelitis, sepsis, and most recently in patients with COVID-19 pneumonia -10. The Pfeffer and Hawrylowicz previously described the benefits of optimization of vitamin D levels in the asthma patient leading to improved outcomes . Other rAs mentioned before, the prevalence of vitamin D deficiency is very high in Pakistan . At thesThis was a retrospective cross-sectional cohort conducted during March 2019 to August 2019. It was held at the Department of Medicine of Abbasi Shaheed Hospital Karachi (ASHK). All data were collected from the records section of the Department of Medicine. Patient confidentiality was made certain at all times. Patients aged ≥18 years of either gender that were diagnosed with cases of asthma were eligible to be included in the study. Asthma was defined according to the latest guidelines issued by the Pakistan Chest Society (PCS) at the time this research was being carried out; these guidelines have since been updated [Asthma was defined by the history of typical symptoms such as wheezing, shortness of breath, cough, or chest tightness with variation to time and place for a minimum of two months along with the demonstration of airflow limitation on pulmonary function tests, i.e., forced expiratory volume (FEV1) of less than 80% of that predicted, and a forced expiratory volume/forced vital capacity (FEV1/FVC) ratio of <0.7. Additional investigations such as radiological imaging, allergy testing, nitric oxide test, sputum eosinophils, methacholine challenge, and provocative testing for exercise were also accepted as additional proof of asthma. Neither the severity levels of asthma nor the types of asthma i.e. allergic versus nonallergic were evaluated for this study. Vitamin D levels were analyzed using the COBAS  machine. A level of <20 ng/dl was taken as deficient. BMI was calculated by dividing the weight of the patient in kilogram(s) by height in meter(s) squared.Patients with chronic decompensated liver disease, renal impairment (creatinine >1.5 mg/dl), those taking vitamin D or calcium supplements, taking medications for tuberculosis, patients on chemotherapy, immunocompromised patients, patients who had undergone parathyroidectomy, and patients with underlying parathyroid and/or thyroid disorders were excluded from the study.2). A chi-square test was used. A p-value of ≤0.05 was considered significant.Data was entered on Statistical Package for the Social Sciences (SPSS) for Windows, Version 21.0. Chicago, SPSS Inc. The consecutive and nonprobability sampling technique was used for this study. Mean and standard deviation were calculated for quantitative variables of age, vitamin D levels, duration of asthma, and BMI. Frequency and percentages were computed for qualitative variables of gender, age groups (<40 or ≥40 years), duration of asthma (<5 or ≥5 years), and BMI  patients had a vitamin D level of <20 ng/ml. The majority of the patients had a BMI of ≥25 kg/mEight-seven (56.49%) females, more than half of the cohort had vitamin D deficiency, by contrast only 10 (6.49%) male patients had vitamin D deficiency. However, post-stratification gender was not found to be a statistically significant factor with respect to vitamin D deficiency in patients with asthma; similar trends were seen with BMI. On the other hand, older patients and those with a longer duration of disease had statistically significant vitamin D deficiency. Subgroup analysis is shown in Table The incidence of allergic asthma is highest during childhood and adolescence while the incidence of nonallergic asthma increases with age and has predominance for the female gender; most cases of nonallergic asthma are diagnosed between the ages of 38-53 years with a peak incidence in the fourth decade of life . The preSince nonallergic asthma is mostly diagnosed in the fourth decade of life, the duration of disease/illness corresponded accordingly to the age of our patients. The median age and duration of illness in our study were 45 years and five years, respectively. Nearly 70% of the patients had asthma for a time period of more than five years and with a few exceptions just about all patients had asthma for a minimum of three years. However, It is critical to remember that the duration of disease was recorded since asthma was diagnosed on pulmonary function tests and/or on imaging; there is a disconnect between the onset of the symptoms of asthma and its diagnosis in Pakistan due to several reasons, and it would not be surprising if the real-life duration of the disease in most patients were much longer.2 to 25 kg/m2, however, patients with a BMI of >25 kg/m2 have consistently been observed to have a high risk of adverse events irrespective of geographical location (within the Asian continent) [2 for all ethnicities and it was concerning to record such a high frequency of obesity in our study. The mean BMI of 25.76±3.61 kg/m2 recorded in our cohort is congruous with antecedent data [2) than ours. Perhaps this was the one reason that in our study BMI did not reach statistical significance for either the incidence of asthma or reduced vitamin D levels in asthmatics.Asians are at a greater risk of adverse cardiovascular events and type 2 diabetes compared to their European counterparts for the same levels of BMI, but no clear cut-off BMI has been decided upon by the WHO with respect to this matter . The risntinent) . As of nent data ,24. LampInternational and local authors have described exceedingly high rates of vitamin D deficiency among adult asthmatic patients ,27. KamrThe overall rate of vitamin D deficiency for females in our study was 56.49%, this is lower than what was reported by both Kamran et al. and Mehboobali et al., but the relative rate of vitamin D deficiency for females was approximately 70% in our study, which is higher than reported in either study ,28. WhilBoth the age of the patients and duration of the disease were found to be extremely important with respect to vitamin D levels in asthmatics. The age and duration of the disease represent a single continuum of the disease. Both are correlated and proportional. The longer the duration of the disease the more aged the patient will be. This is especially true for nonallergic asthma, as most cases are diagnosed during the third, fourth, or fifth decades of life . FactorsData from recent trials and reviews suggest that vitamin D supplementation is safe and beneficial in patients with asthma ,15. EvidLimitations of the studyComplete nutritional assessment was not performed in any of the patients. The impact of medications being used by the patients such as steroids, inhalers, histamine receptor blockers, proton pump inhibitors, etc. was not analyzed at all. Smoking history was not assessed in the study. Comorbid were not recorded.The frequency of vitamin D deficiency is very high in patients with asthma. The reduced vitamin D levels are significantly affected by the duration of the disease and the age of the patient. Further research is required to ascertain if these greatly reduced levels are specific to asthma and its disease process or point to a greater underlying medical problem in the Pakistani population.


Background: Serum magnesium levels are associated with cardiovascular disease and all-cause mortality in the general population and chronic kidney disease patients, but the association between serum magnesium levels and cardiovascular risk after kidney transplantation is not established. We sought to evaluate whether exposure to low serum magnesium levels after renal transplantation is related to cardiovascular morbidity and mortality.Methods: We conducted a single center retrospective study that included all transplanted patients who had a functioning graft for at least 6 months after transplantation between January 2001 and December 2013. We calculated exposure to magnesium using time weighted average for serum magnesium levels, using all values available during the follow-up. Several statistical methods were used, including liner regression analysis, χ2 test, and multivariate Cox proportional hazard model.Results: Four hundred ninety-eight patients were included. Median follow-up was 5.26 years. High time weighted average of serum magnesium was associated with a hazard ratio of 1.94 for all-cause mortality and major cardiovascular outcome compared to low levels . The high quartile of time weighted average of serum magnesium was associated with death censored major cardiovascular outcome  in multivariate analysis.Conclusions: Exposure to low serum magnesium levels in renal transplant recipients was associated with a lower risk for all-cause mortality and major cardiovascular outcome. These findings contrast the higher risk found in the general population. Magnesium (Mg) is the second most prevalent intracellular cation  and has Data from epidemiological studies suggests that low sMg levels are associated with increased cardiovascular disease (CVD) and all-cause mortality in the general population , 4.In chronic kidney disease (CKD) patients, there is an increasing body of evidence for an inverse association between sMg and insulin resistance, new onset diabetes , hyperteMagnesium deficiency is common after kidney transplantation mainly due to the effect of calcineurin inhibitors (CNI) on tubular magnesium handling. CNI induce hypomagnesemia through downregulation of the renal expression of epidermal growth factor (EGF) and transient receptor potential channel melastatin 6 (TRMP6) in the distal collecting tubule, leading to Mg wasting . HypomagThe aim of this study was to evaluate whether there is association between exposure to low magnesium blood levels after renal transplantation and cardiovascular morbidity and mortality.This is a single-center retrospective cohort study. The study protocol was approved by the Rabin Medical Center (RMC) institutional review board (IRB).We searched the RMC kidney transplant registry between January 2001 and December 2013 and selected all transplanted patients who had a functioning graft for at least 6 months after transplantation. We collected sMg values and calculated time weighted average (TWA) for sMg levels using all values available since the renal transplantation and during the follow-up period. TWA was calculated by multiplying each sMg value by the time of exposure, summing all the values, and dividing them by the time interval between the first and last values. We evaluated cumulative TWA of sMg from time of transplantation for each time point, by calculating TWA between the time of transplantation to the end of each 6-month interval. As a result, the exposure variable for this study was the mean sMg (weighted for time of exposure) during all the follow-up time until the time of the event. Schematic description of TWA for sMg at each time point is depicted in We excluded patients with less than six magnesium blood level values available, patients who were lost to follow-up, multiple organ transplant patients, and patients who experienced cardiovascular events during the first 6 months after the transplantation.The primary endpoint was the composite outcome of all-cause mortality and major cardiovascular outcome (MACE) defined as non-fatal myocardial infarction (MI), non-fatal cerebrovascular accident (CVA), coronary revascularization, peripheral revascularization, and hospitalization due to acute coronary syndrome, congestive heart failure (CHF) exacerbation, or peripheral vascular disease (PVD).Secondary endpoints included the separate components of the primary outcome, graft survival, and overall survival. The outcome of MACE was determined by two physicians (I.V. and M.M.). The physicians opened every medical file and did not rely on the written diagnosis. Whenever there was a doubt about the diagnosis, the physicians consult with a senior nephrologist (R.R. or B.R.Z.) in order to ascertain the MACE event. In any disagreement, another senior nephrologist (R.R. or B.R.Z.) was consulted.The time period from transplantation was divided into 6-month intervals. The primary exposure was TWA of sMg from the transplantation to the end of each interval. Each patient was assigned into a group according to the TWA of sMg at the beginning of each interval. As the TWA of sMg changed over time, each patient could be assigned to a different group at each time interval. Each outcome episode was attributed to the TWA of SMg calculated from the transplantation to the end of the previous time interval, and analysis was done by time-varying manner. A schematic description of the study design is depicted in Baseline patient characteristics are presented as means and standard deviations or median and interquartile range, as appropriate.Data was collected from the patients' electronic health records. Recipient data included age, gender, baseline kidney disease, body mass index (BMI), history of hypertension, diabetes mellitus, ischemic heart disease, MI, coronary revascularization, CHF, valvular disease, PVD, CVA, past renal replacement therapy, and transplantations. Transplantation data included donor type (living or deceased), age and gender, panel reactive antibodies (PRA) status, human leukocyte antigen (HLA) mismatch, induction therapy, maintenance immunosuppression therapy, delayed graft function, hospitalization length, and episodes of acute rejections.Laboratory data was collected at 6 months post-transplantation and included creatinine, urea, low-density lipoprotein (LDL) cholesterol, glucose, cholesterol, albumin, hemoglobin, white blood cells (WBC), platelets, and hemoglobin A1C (HBA1C). At 6 months, we also evaluated for development of hypertension and diabetes and recorded medications prescribed including immunosuppression medication , magnesium supplements, blood pressure medications , anti-aggregates, statins, and proton pump inhibitors. The protocol for magnesium supplementation at our clinic was magnesium citrate 100 mg thrice daily, and it was given at the discretion of the treating physician.2 test for discreet variables.We used multiple imputations using liner regression analysis, with five repeats for missing data analysis. Mean and standard deviation described normally distributed variables, whereas median and range described non-normally distributed variables. For differences between groups, we used analysis of variance (ANOVA) for continuous variables and χp-value of 0.05. We also forced into the model variables that were significantly associated with TWA of magnesium at 6 months post-transplantation. The variables in the multivariate analysis included recipient age and gender, BMI, history of heart disease, diabetes mellitus, smoking status, donor age, Mg supplementation, maintenance immunosuppression therapy, duration of dialysis, serum albumin, and eGFR. The full models of the multivariate analysis are presented in For modeling time to first event, we used time varying univariate and multivariate Cox proportional hazard model, with quartiles of TWA sMg as time dependent variable. We compared quartiles of sMg according to the TWA of sMg from the time of transplantation to each time point. The proportionality assumption was validated by evaluating each variable for interaction with time and assessing for the null hypothesis. For multivariate analysis, we used forward stepwise analysis with possible confounders using inclusion In order to further evaluate the risk of our primary and secondary outcomes, we used repeated measures generalized estimating equations (GEE). We used the cumulative TWA of magnesium level at the beginning of each time interval as repeated measures variable and the odds for an event during each interval as response variable using binary logistic model. The multivariable adjusted model included the same variables used for the time varying Cox analysis.In order to increase the internal validity of our results, we performed several sensitivity analyses. We analyzed the association between sMg level and the primary outcome in all the patients in the cohort including patients with <6 sMg values and patients that had CV event during the first 6 months post-transplantation. We also analyzed the association between the highest sMg value and the primary outcome. Lastly, we evaluated the association between TWA of sMg at 1 year and the secondary outcome of death censored CV events using competing risk analysis with non-CV death as the competing risk.Between January 1, 2003 and December 31, 2013, 649 patients were transplanted; 498 were included in the final cohort. Reasons for exclusion were as follows: MACE within 180 days of transplant (The patients' characteristics according to TWA of magnesium concentration during the first 6 months post-transplantation are presented in During a median follow-up time of 5.26 years [interquartile range (IQR) 4.21–7.37], 145 outcome events occurred including 98 events of MACE and 47 events of death.We divided the patients into quartiles according to TWA of sMg at each time point. p = 0.009]. The results were not significantly changed by multivariate adjustment . We also analyzed the data by repeated measures GEE with comparable results  and  for univariate and adjusted analysis, respectively (see p = 0.003) and  for the highest quartile vs. the lowest quartile by univariate and multivariate analysis, respectively  1.94, 95% Confidence Interval (CI) 1.18–3.19, vely see . Sensitively see .p = 0.05). The results were not significantly changed by multivariate adjustment  and patients that had CV events during the first 6 months post-transplantation. This analysis showed comparable results though, with numerically smaller effect size, when compared to the lowest quartile; the highest quartile was associated with increased risk of the primary outcome  and  for univariate and multivariate analysis, respectively. The results of association between sMg quartiles and death censored MACE and the full multivariate model are presented in Comparable results were obtained when the secondary outcome of death censored MACE  was evaluated. The high quartile of TWA of magnesium was associated with this outcome . However, by multivariate analysis, the association was significant  , the highest quartile of TWA of Mg at 1 year was non-significantly associated with CVD by univariate analysis  see .p = 0.062) and  for univariate and adjusted analysis, respectively. As can be seen, the trend for increased odds for CV events was non-significant by univariate analysis but became significant after multivariate adjustment  and , respectively. By multivariate analysis, only the third quartile was significantly associated with mortality, while there was only a non-significant trend for the fourth quartile  due to CVD, 30 (39%) due to infections, 7 (9.1%) due to malignancy, and 18 (23.4%) due to other or unknown cause. quartile . The fulp = 0.029 and OR 1.9, 95% CI 0.93–3.89, p = 0.081, respectively). By multivariate analysis, the association was no longer significant for both quartiles compared to the lowest quartile   see .Of the 498 patients included in the study, 495 (99.4%) had information available regarding prescribed medications 6 months post-transplantation. Sixty-six of the 495 patients (13.3%) were treated with magnesium supplementation. p = 0.103). However, by the multivariate model including TWA for sMg at 6 months, age, gender, BMI, ischemic heart disease (IHD) before transplantation, serum calcium, albumin and LDL, treatment with PPI, beta blockers, and inhibitors of the renin angiotensin, the association became significant .By univariate Cox analysis, magnesium supplementation was not significantly associated with the primary outcome   .A recent prospective multicenter study (CRIC study) that was conducted by Lavinia Negrea et al. included 3,867 patients with CKD. The study evaluated the association between sMg level and cardiovascular events and all-cause mortality. This was the largest study made in CKD patients with a long follow-up of 14.6 years. The authors conclude that sMg level <1.9 and >2.1 mg/dl was associated with increased risk for all-cause mortality. Low sMg level was associated with incident atrial fibrillation but not with composite CVD events. This study is added to the growing body of evidence that propose an association between high sMg level and cardiovascular outcomes .Sakaguchi et al. in a study that included 142,555 HD patients showed a J-shaped association between serum magnesium and all-cause and cardiovascular mortality from the lowest to highest sextile, with significantly higher mortality in sextiles 1–3 and 6 . In contCheungpasitporn et al.  evaluatep = 0.01)  . Osorio  = 0.01) , perform = 0.01)  publisheOur study showed that hypomagnesemia post-transplantation was associated with a lower risk for all-cause mortality and MACE. Cheddani et al.  comparedThe difference between our results and other reports in different populations might be that after kidney transplantation sMg is mainly affected by immunosuppressive medications and kidney function , while iIn addition, our results strongly suggest that Mg supplementation was associated with higher all-cause mortality and MACE. As patients with low sMg, the main indication for Mg supplementation had a lower rate of adverse outcomes; these results do not support the routine use of Mg supplementation after kidney transplantation. It should be noted that very limited prospective interventional trials with patient-centered outcomes evaluating Mg supplementation are available. Such trials are urgently needed in order to make evidence-based decisions regarding the need for Mg supplementation.This study has several important strengths. The use of all available sMg levels and time varying exposure produces a very precise evaluation of the exposure. In addition, the outcome analysis was based on detailed reports, each read by the researchers. Furthermore, the median follow-up time of more than 5 years enables adequate evaluation. In addition, we used several statistical methods to evaluate the risk of our primary and secondary outcomes and to increase the internal validity of our results.Our study also has several limitations. Being a single center treating mostly a Caucasian population, the generalizability is limited. Also, despite extensive multivariate analysis, the possibility of residual confounding is still significant. Possible confounders might include kidney function and medications given over time as our analysis included creatinine and medications only at a fixed time point at 6 months post-transplant. Furthermore, eGFR is only rough estimation of true kidney function, and therefore, adjustment for kidney function might not be complete. Another possible confounder is nutrition status that might influence both sMg and CVD. In addition, the sample size, which is adequate for evaluation of the composite primary outcome, did not enable good evaluation of subgroups and the separate components of MACE. Also, the number of cardiovascular events in the study was small. In addition, evaluation of Mg supplementation was done only for one time point and dosing was not available. Detection bias is another possible limitation as high sMg was associated with reduced kidney function, which makes coronary angiography and the detection of CAD less likely.This study found an association between low exposure to sMg and better outcomes, which might reflect the confounding effect of better kidney function and adequate immunosuppression. Mg supplementation at 6 months post-transplantation was associated with an increased risk of all-cause mortality and MACE. This is the first study investigating the association between Mg levels and outcomes such as all-cause mortality and MACE in renal recipients. More studies, especially randomized controlled trials, are needed to further evaluate this important issue.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.IL: participated in research design, performance of the research, data analysis and in the writing of the paper. TS: participated in performance of the research, interpretation of data for the work and in the writing of the paper. BR-Z: participated in research design, in the performance of the research, in data analysis and in in the revising of the paper. RR: participated in research design, in interpretation of data for the work and in the revising of the paper. MM: participated in research design, in the performance of the research and in the revising of the paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


ANGPTL8, an important regulator of lipid metabolism, was recently proven to have additional intracellular and receptor-mediated functions. This study aimed to investigate circulating levels of ANGPTL8 and its potential association with the risk of kidney function decline in a cohort study.2 of body surface area, a decrease in eGFR of ≥ 30% from baseline, chronic kidney disease (CKD)-related hospitalization or death, or end-stage renal disease. The association between baseline ANGPTL8 levels and kidney function decline was assessed using multivariable-adjusted Cox proportional hazards models, and inverse possibility of treatment weight (IPTW) was utilized to prevent overfitting.We analysed 2,311 participants aged 40 years old and older from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Kidney function decline was defined as an estimated glomerular filtration rate (eGFR) less than 60 mL per minute per 1.73 mThere were 136 (5.9%) cases of kidney function decline over a median of 3.8 years of follow-up. We found that serum ANGPTL8 levels at baseline were elevated in individuals with kidney function decline compared to those without kidney function decline during follow-up . Compared with the first quartile, multivariable-adjusted hazard ratio  for kidney function decline was 2.59  for the fourth ANGPTL8 quartile. Furthermore, compared with patients in the first ANGPTL8 quartile, those in the fourth ANGPTL8 quartile were more likely to report a higher stage of CKD . The conclusions of the regression analyses were not altered in the IPTW models. Multivariable-adjusted restricted cubic spline analyses suggested a linear relationship of ANGPTL8 with kidney function decline .Participants with higher circulating ANGPTL8 levels were at increased risk for kidney function decline, highlighting the importance of future studies addressing the pathophysiological role of ANGPTL8 in CKD.The online version contains supplementary material available at 10.1186/s12933-021-01317-3. ElevateChronic kidney disease (CKD) is a devastating condition that is reaching epidemic levels owing to the increasing prevalence of diabetes mellitus, hypertension and obesity, as well as the ageing of the population . CKD mayPrevious cross-sectional studies revealed that ANGPTL8 levels were increased in T2DM patients with albuminuria , 17. OurParticipants in the present study were recruited from Hubei Province, China, from 2011 to 2012 as part of the Risk Evaluation of Cancer in Chinese Diabetic Individuals: A Longitudinal (REACTION) Study, which was renamed the China Cardiometabolic Disease and Cancer Cohort (4C) Study –22. The 2 or CKD-related hospitalization) (N = 245) or missing serum creatinine values at baseline (N = 979), were not fasting at baseline  or visits (N = 508), were missing body mass index (BMI) values, glucose measurements, glycaemic measures, lipid profiles or information on a history of CVD, diabetes or hypertension , or had missing outcome data (N = 935). Additionally, the highest and lowest 0.5% of ANGPTL8 values were trimmed (N = 23) , leThe Committee on Human Research at Ruijin Hospital, Shanghai Jiaotong University School of Medicine, approved the study protocol , and all of the participants provided written informed consent. All of the methods were performed in accordance with the relevant guidelines and regulations.Blood samples were collected after overnight fasting. Serum was separated by centrifugation, aliquoted and then stored at  − 80 °C. Fasting serum ANGPTL8 levels were assessed using ELISA kits  with an intra-assay coefficient of variation (CV) of ≤ 6.5% and an interassay CV of ≤ 9.2% (provided by the manufacturer). The procedures were performed in accordance with the manufacturer’s instructions. All of the samples were analysed in duplicate.2 according to the CKD-Epidemiology Collaboration (CKD-EPI) formula [2; (2) G2, 60 ≤ eGFR < 90 mL/min/1.73 m2; (3) G3, 30 ≤ eGFR < 60 mL/min/1.73 m2; (4) G4, 15 ≤ eGFR < 30 mL/min/1.73 m2; and (5) G5, eGFR < 15 mL/min/1.73 m2 [Kidney function decline was defined as meeting at least 1 of the following criteria: (1) eGFR < 60 mL/min/1.73 m formula , 25, (2) formula , (3) hos/1.73 m2 . All of 2 test for categorical variables. We used Cox proportional hazards models to investigate the association between ANGPTL8 levels at baseline and the risk of kidney function decline. The relationship between ANGPTL8 and CKD stage was tested using ordinal logistic regression. We adjusted multivariable models for baseline age, sex, BMI, high-density lipoprotein (HDL), low-density lipoprotein (LDL), TC , TGs, aspartate aminotransferase (AST), alanine transaminase (ALT), and history of diabetes, hypertension and CVD. The inverse possibility of treatment weight (IPTW) was utilized to prevent overfitting [Continuous variables are expressed as the means ± standard deviations (SDs)  or medians  . Normal distribution of the data was tested using the Kolmogorov–Smirnov test. We obtained p values using the Kruskal–Wallis test for continuous variables and the χrfitting . Stratifrfitting . A knot Of the 2,311 participants, 136 (5.9%) patients developed kidney function decline during a median follow-up of 3.8 years , FPG (r = 0.07), TGs (r = 0.04), AST (r = 0.08) and creatinine r = 0.13) and inversely correlated with HDL (r =  − 0.05), eGFR at baseline (r =  − 0.13), eGFR at the final visit (r =  − 0.11) and eGFR change , hypertension and no CVD . However, the association was diminished in individuals without hypertension or with CVD .We performed stratified analyses according to age, sex, BMI, diabetes, hypertension, CVD or hyperlipidaemia at baseline. As shown in Fig. This retrospective cohort study found that serum baseline ANGPTL8 levels were elevated and independently associated with kidney function decline. Furthermore, multivariable-adjusted restricted cubic spline suggested a dose–response relationship of ANGPTL8 with the risk for kidney function decline. However, estimates for this association in individuals with CVD or without hypertension were not statistically significant.ANGPTL8, an important regulator of TG metabolism, has recently been proven to have additional intracellular and receptor-mediated functions , 30–32. . Stratified analyses also showed that the association between ANGPTL8 levels and kidney function decline was more significant in older individuals (age ≥ 60 years). Age is related to mitochondrial dysfunction, increased oxidative stress, inflammation, and hormonal changes [The underlying mechanisms for these pathophysiological associations await exposure. Our study found that ANGPTL8 was positively correlated with age, FPG, AST, and TG but inversely correlated with HDL. Previous studies found that ANGPTL8 levels were positively related to age , 18, 35. changes , which p changes . Second, changes . Thus, d changes , 38. ANG changes  and posi changes . However changes –6, ather changes , and NAS changes . Thus, A changes , which m changes , 39, 40. changes  and hype changes . TherefoOn the other hand, ANGPTL8 shares considerable structural similarity with ANGPTL3 and ANGPTL4 . As the There are some limitations of this study. First, all of the participants in our study were Chinese adults aged ≥ 40 years, limiting the generalizability of the findings. Interestingly, the previous 4 cross-sectional studies enrolled populations with a mean age > 50 years and concluded that elevated ANGPTL8 levels were associated with kidney function decline , 33, 34,In conclusion, participants with higher circulating ANPTL8 levels had an increased risk for kidney function decline, highlighting the importance of future studies addressing the pathophysiological role of ANGPTL8 in CKD.Additional file 1: Table S1. Medication for patients with chronic diseases, according to quartile of ANGPTL8 levels. Table S2. Ordinal logistic regression analysis of the association between ANGPTL8 and renal stage. Table S3. Correlations between ANGPTL8 levels and clinical variables. Figure S1. Flow diagram for the study population selection. Figure S2. ROC curves for the performance of ANGPTL8 concentration in detecting kidney function decline.


High blood pressure is a crucial risk factor for many cardiovascular diseases, and a diet rich in whole-grain foods may modulate blood pressure. This study investigated the effects of dehulled adlay consumption on blood pressure in vivo. We initially fed spontaneous hypertensive rats diets without (SHR group) or with 12 or 24% dehulled adlay (SHR + LA and SHR + HA groups), and discovered that it could limit blood pressure increases over a 12-week experimental period. Although we found no significant changes in plasma, heart, and kidney angiotensin-converting enzyme activities, both adlay-consuming groups had lower endothelin-1 and creatinine concentrations than the SHR group; the SHR + HA group also had lower aspartate aminotransferase and uric acid levels than the SHR group did. We later recruited 23 participants with overweight and obesity, and they consumed 60 g of dehulled adlay daily for a six-week experimental period. At the end of the study, we observed a significant decrease in the group’s systolic blood pressure (SBP), and the change in SBP was even more evident in participants with high baseline SBP. In conclusion, our results suggested that daily intake of dehulled adlay had beneficial effects in blood-pressure management. Future studies may further clarify the possible underlying mechanisms for the consuming of dehulled adlay as a beneficial dietary approach for people at risk of hypertension. Hypertension is associated with mortality and morbidity related to various cardiovascular diseases . Long-teCoix lachryma-jobi L. var. ma-yuen Stapf) is a popular grain in Asian cuisine, and has been used as a traditional Chinese medicine for its antioxidative and anti-inflammatory potential [According to a 2019 meta-analysis survey, dietary consumption of whole grains rather than refined grains may aid in the prevention of non-communicable diseases . The prootential . Recent otential ,12. Dailotential . Howeverotential . Therefon = 10), an SHR + LA group fed AIN-93M with a low dose of 12% adlay powder (w/w), and an SHR + HA group fed AIN-93M with a high dose of 24% adlay powder (w/w), WKY rats were used as the normotensive control and also received a standard AIN-93M rodent diet (n = 10). We used adlay powder substituted for part of the components from the standard AIN-93M diet to ensure equal nutrient composition among the diets, as shown in We purchased dehulled adlay powder (Taichung No. 3) from the Nantou County Tsao-Tun Production Association . Eight-week-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were purchased from the National Laboratory Animal Breeding and Research Center. Rats were housed in the Experimental Animal Center as per guidelines reviewed by the Institutional Animal Care and Use Committee of I-Shou University . Rats were maintained in an environment with a constant temperature (23 ± 2 °C) and humidity (55 ± 10%) and were exposed to a 12 h light–dark cycle in accordance with the Animal Protection Act and the regulations of the Animal Care and Use Committee of the Council of Agriculture, Executive Yuan. Rats were fed a standard rat chow diet for 1 week for acclimatization. Then, SHRs were randomly assigned to three groups: an SHR group fed a standard AIN-93M rodent diet  every 4 weeks. Rats were placed in restrainers, and we recorded at least five readings to calculate the mean of blood pressure over the course of the measurement.g and 4 °C for 15 min for plasma separation. Plasma samples were collected to analyze the aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (Cr), uric acid, and phosphorus concentrations by using a Roche Modular P800 Autoanalyzer . ACE activity was analyzed according to the method previously described by Vermeirssen et al. [Blood samples were collected and centrifuged at 1500× The 24 h of urine samples were collected using metabolic cages. Urinary protein excretion, urine urea nitrogen (UUN), and Cr levels were analyzed using a Roche Modular P800 Autoanalyzer . All urine values were corrected in accordance with the Cr level.g at 4 °C for 10 min. ACE activity levels of the hearts and kidneys were determined using the method described by Yang et al. [Heart and kidney samples were homogenized in a buffer solution , and suspensions were centrifuged at 1000× g et al. .2) within the range of 25 to 35 (inclusive) or waist circumference within an indicated sex-specific range (>90 cm for men and >80 cm for women) were included in the experiment as shown in Participants were recruited through announcement posters at the I-Shou University . People with diagnoses of diabetes, cardiovascular diseases, eating disorders, or liver, kidney, or other digestive diseases; medications and supplement users; pregnant or lactating individuals; and people with an adlay allergy were excluded. We recruited 25 volunteers, and among them, 23 participants with a body mass index  of E-Da Hospital according to the guidelines in the Declaration of Helsinki (IRB No.: EMRP41104N). During the 6-week experimental period, 23 participants were asked to consume two packages (30 g/package) of dehulled adlay powder per day to replace three corresponding portions of cereal, according to the Food Exchange List of Taiwan and the dosage consumed daily in a previous study . Those pParticipants visited our research center at 07:30 a.m. at the baseline and the end of the study after a fasting period of at least 8 h. Blood pressure was measured using an automatic blood-pressure monitor on their right arm  after participants sat in a chair for at least 10 min. SBP and DBP were calculated as the average of three separate measurements.At the baseline and end of the study, we collected plasma samples after blood-pressure measurement to measure ET-1 concentrations as described before.t-test. A p-value of <0.05 indicated a statistically significant difference.All data are presented as mean ± standard deviation (SD). Data from the animal study, and on changes in blood pressure among the three subgroups according to the guideline  , we found no significant difference in plasma, heart, and kidney ACE activity among the SHR, SHR + LA, and SHR + HA groups  and ALT  activities than the WKY group did, and that both the SHR + LA and SHR + HA groups had lower AST activities than the SHR group did (p = 0.0289) and the total protein-to-Cr ratios in the rat urine were significantly higher in the SHR groups than in WKY . Both dehulled adlay groups had lower plasma Cr concentrations than the SHR group did , but no significant differences were observed in total protein/Cr, UUN/Cr, and plasma phosphorus concentrations in urine among the three SHR groups. Additionally, plasma uric acid levels were significantly higher in the SHR group and lower in the HA group   b,c. The p = 0.0164; SHR + HA vs. SHE, p = 0.0345), and no significant difference in ET-1 level was observed compared with the WKY group  , and discovered that the effects of dehulled adlay consumption on blood-pressure change were more obvious in the participants with higher baseline SBP  (p = 0.07)  a. Additi 0.0243) b. We als = 0.07) c. These In this study, we found that dehulled adlay consumption retarded the elevation of blood pressure in SHRs, and may be beneficial in blood pressure modulation in overweight and obese adults. Dietary intake of whole-grain foods may lower cardiovascular risks. A randomized controlled trial concluded that daily consumption of whole grains  resulted in greater improvements in blood pressure than a refined grain diet did in adults with overweight and obesity . ResultsIncreased daily whole-grain consumption has positive effects on blood-pressure control. The 2020 International Society of Hypertension’s Global Hypertension Practice Guidelines also include a suggestion to eat a healthy diet rich in whole grains to treat hypertension . DehulleBlood pressure is regulated by numerous mechanisms in vivo, and the renin-angiotensin system is one of such major regulatory mechanism. Increased ACE activity reveals the formation of angiotensin II, which leads to vessel constriction and elevated blood pressure. In 2017, Li et al.  observedRecent studies have found that uric acid is strongly linked to high blood pressure. A cross-sectional study reported that each 1 mg/dL increase in plasma uric acid increases the risk of hypertension by 20% . Uric acThis is the first study to apply dehulled adlay intake in the daily diet of participants with a high risk of hypertension, and we observed that replacing 60 g of staple food in daily diet with dehulled adlay helped moderate high blood pressure. In the animal study, we also discovered that dehulled adlay intake curbed blood-pressure elevation and lessened uric acid and ET-1 levels. However, some limitations were present in our study and may be rectified by further studies. First, we used a non-invasive tail-cuff method with a four-week interval to investigate the change of blood pressure in this study. A telemetry system may be more ideal, and could be used to record more hemodynamic information in future long-lasting experiments. Second, the number of human participants in this study was limited and lacked a control group. The single-arm study design followed by a pre-post evaluation can only offer preliminary information, and may not completely exclude the placebo effects of the intervention . AlthougIn conclusion, our results suggested that daily intake of 60 g dehulled adlay had beneficial effects on blood-pressure management. Future studies could further clarify the possible underlying mechanisms for the consuming of dehulled adlay as a beneficial dietary approach for people at risk of hypertension.