To examine published and unpublished data documenting the role of sympathetic neural factors in the pathogenesis of different hypertensive phenotypes. These phenotypes relate to attended or unattended blood pressure measurements, to nighttime blood pressure profile alterations, and to resistant, pseudoresistant, and refractory hypertension. Results of original clinical studies as well as of recent meta-analyses based on the behavior of different sympathetic biomarkers in various hypertensive forms will be also discussed.Studies performed in the past decade have shown that office blood pressure measurements, including in recent years those characterizing unattended or attended blood pressure assessment, are associated with profound changes in the behavior of different sympathetic biomarkers. This is the case for the clinical hypertensive phenotypes characterized by alterations in the nocturnal blood pressure profile and by sleep duration abnormalities. This is also the case for the clinical conditions defined as resistant, refractory, and pseudoresistant hypertension.Data reviewed in the present paper highlight the relevance of sympathetic neural factors in the development and progression of different clinical hypertensive phenotypes. This suggests that a common hallmark of the majority of the essential hypertensive states detectable in current clinical practice is represented by the alteration in the sympathetic blood pressure control. More than a decade ago, our group in Milan published in this journal a review focused on the role of the sympathetic nervous system in the pathogenesis of essential hypertension and in the development of the related metabolic disease •. DuringThe aim of the present paper is to provide an update on the new findings collected on this issue during the last decade. Following an introductory paragraph summarizing the information collected in the past on the role of the sympathetic nervous system in essential hypertension, we will address four major issues, on which a special interest has been focused due to their potential clinical implications. First, we will examine the evidence recently collected on the role of the sympathetic nervous system in determining the hemodynamic responses to office blood pressure measurements  and more specifically to the attended or unattended blood pressure assessment. This will be followed by an analysis of the data collected with the aim to better define the possible relationships between sleep quality and quantity and sympathetic activation occurring in the essential hypertensive state. Third, the main features of the sympathetic profile characterizing different hypertensive phenotypes, including resistant, pseudoresistant, and uncontrolled hypertension, will be examined. We will finally describe the behavior of various sympathetic biomarkers in uncomplicated hypertension and in pathological conditions, characterized by an elevated cardiovascular risk, frequently associated with the hypertensive state, such as obesity, obstructive sleep apnea, and metabolic syndrome.Figure As mentioned above, new information has been gained during the last decade on different pathophysiological and clinical topics, which have a common background, i.e., the involvement of the sympathetic nervous system in the blood pressure regulation and its alterations occurring in hypertension. These new data will be discussed in the following sections.As known since several years, office blood pressure measurement by a doctor via the sphygmomanometric technique triggers an alerting reaction in the patients by favoring a blood pressure and heart rate increase which may persist for several minutes after the visit and interfere with the evaluation of the “real” blood pressure values . In ordeThe information about the sympathetic responses to blood pressure measurements has been expanded in more recent years with 2 new sets of data. The first one refers to the assessment of nurse blood pressure measurements on hemodynamic as well as sympathetic variables . This waThe second set of new data very recently collected on the sympathetic responses to office blood pressure evaluation refers to the attended or unattended blood pressure measurements •. The baThe interest in hypertension research for the behavior of sympathetic cardiovascular function during sleep is multifold and founded on at least three major evidences. First, abnormalities in the quality/quantity of the nighttime blood pressure reduction, characterizing the non-dipping, extreme dipping and reverse dipping profile, represent strong predictors of an increased cardiovascular risk and may favor the development and progression of target organ damage ••, 17••.2), showed superimposable 24-h blood pressure values. Sympathetic nerve traffic in the peroneal nerve was significantly greater in patients with short sleep time duration than in those characterized by long sleep time, similar difference being detected in the remaining group of patients displaying a medium sleep time duration. This was the case also for 24-h heart rate values, significantly more elevated in the group with short sleep duration, suggesting that the adrenergic overdrive was detectable both at peripheral and cardiac level. Of particular interest was the observation that the sympathetic activation seen in the patients with short time sleep was accompanied by a reduced baroreflex control of sympathetic neural function, as assessed by a computerized system relating each spontaneous sympathetic neural burst to the diastolic blood pressure and the cardiac interval during which the burst was generated [Data collected in the past years have confirmed the occurrence in almost all the above mentioned clinical phenotypes of a marked sympathetic activation, a common hallmark which supports in many of the of the abovementioned clinical conditions the close relationships between sleep disorders, hypertension, and neuroadrenergic abnormalities , 3••. Reenerated . It thusIn the past decade, the clinical relevance of resistant, pseudoresistant, and refractory hypertension has been consistently increased, also in consideration of the new therapeutic perspectives offered by bilateral renal nerve ablation ••, 24•. Two further sets of data collected in recent years in this research area deserve to be mentioned. The first one refers to the observation that a peculiar clinical phenotype such as the one represented by uncontrolled masked hypertension (MUCH) displays a very pronounced out-of-clinic sympathetic activation, which may favor the development and progression of this clinical condition . The secAssessment of sympathetic cardiovascular influences in hypertension and in the related disease, such as obesity, metabolic syndrome, and obstructive sleep apnea, has been based on direct and indirect approaches to evaluate adrenergic function, such as microneurographic assessment of muscle sympathetic nerve traffic, assay of venous plasma norepinephrine concentration, and power spectral analysis of the heart rate signal •, 8•.Because muscle sympathetic nerve traffic recording represents the more direct and sensitive approach to assess sympathetic function in humans •, 2, manIn the last decade, the suggestion has been advanced that information on sympathetic cardiovascular function can be obtained via a simpler method, namely, via assessment of resting heart rate values . The bacThe large amount of new data collected during the past decade on the behavior of sympathetic mechanisms in the pathophysiology of different hypertensive phenotypes, including those characterizing clinical forms of resistant hypertension and those detected during the nighttime period, have permitted to gain new insights on the role of neuroadrenergic factors in the development of the hypertensive state. Both pharmacological and non-pharmacological therapeutic interventions  should thus address this neurogenic abnormality, thereby allowing not only to decrease elevated blood pressure values but also by counteracting the sympathetic overdrive to reduce an elevated cardiovascular risk.


Hypertension is a key modifiable risk factor for cardiovascular disease – the leading cause of death in the UK. Good blood pressure (BP) control reduces mortality. However, health inequities may lead to variability in hypertension monitoring and control.To investigate health inequities related to ethnicity, sex, age, and socioeconomic status in the monitoring, treatment, and control of BP in a large cohort of adult patients with hypertension.A cross-sectional cohort study of adults with hypertension registered with general practices in North East London on 1 April 2019.Multivariable logistic regression was used to estimate associations of demographics and treatment intensity for the following hypertension management indicators: a) BP recording in past 12 months; b) BP on age- adjusted target; and c) BP on age-adjusted target and BP recorded in past 12 months.In total, 156 296 adults were included. The Black ethnicity group was less likely to have controlled BP than the White ethnicity group . The Asian ethnicity group was more likely to have controlled BP . Ethnicity differences in control could not be explained by the likelihood of having a recent BP recording, nor by treatment intensity differences. Older adults (aged ≥50 years) were more likely to have controlled hypertension than younger patients.Individuals of Black ethnicity and younger people are less likely to have controlled hypertension and may warrant targeted interventions. Possible explanations for these findings are presented but further research is needed about reasons for ethnic differences. In the past decade, the reduction in CVD mortality has stalled and, for some disadvantaged groups, mortality rates have actually increased.8–10 Similar inequities have been described in Europe and the US.11,12Health inequities in the management of hypertension have been investigated in several regional and national patient cohorts in the UK and these have found the Black ethnicity group to be significantly less likely to have controlled blood pressure than the White ethnicity group and, in some studies, the Asian ethnicity group to have better controlled blood pressure.13 However, supported by local quality improvement programmes, the control of blood pressure was among the best in England in the national NHS Quality and Outcomes Framework (QOF) reward and incentive programme up until the pandemic.14The North East London locations investigated in the current study are among the most ethnically diverse and deprived in the UK.5 The current study included adults with hypertension and aimed to analyse sociodemographic inequities in recording and control of blood pressure, and inequities in treatment intensity.Regular monitoring of blood pressure and appropriate treatment initiation and escalation are fundamental in effective management of hypertension.A cross-sectional study was carried out in five contiguous North East London clinical commissioning groups (CCGs): City and Hackney; Newham; Redbridge; Tower Hamlets; and Waltham Forest. The study cohort was derived from currently registered patients in general practices that used the EMISWeb electronic health record system . Pseudonymised coded demographic and clinical data were extracted by the study’s data analyst from CCG-level GP electronic health records using the EMISWeb ‘Population Reporting’ tool.https://clinicalcodes.rss.mhs.man.ac.uk/medcodes/article/200).15 For each cohort individual, the following demographic data were extracted: age in years on index date; sex; home lower layer super output areas (LSOA); and ethnic group code (see Supplementary Box S2).The study cohort comprised adults aged ≥18 years, with diagnosed hypertension on the index date: 1 April 2019. The QOF ‘HYP_COD’ reference codeset identified hypertension, excluding individuals with a subsequent ‘hypertension resolved’ code (see Supplementary Box S1 and The most recent systolic blood pressure (SBP) and diastolic blood pressure (DBP) values (mmHg) and their entry dates were extracted. Blood pressure recordings made >12 months before the index date were omitted. Blood pressure recordings were also omitted for individuals with unreliable or unfeasible blood pressures, namely: incomplete recording ; separately recorded blood pressures elements (SBP date different from DBP date); and SBP <70 mmHg or SBP ≥270 mmHg or DBP <40 mmHg or DBP ≥150 mmHg .angiotensin-converting enzyme inhibitors/angiotensin receptor blockers;beta-blockers;potassium-sparing diuretics;calcium channel blockers;thiazide-type and thiazide-like diuretics;centrally acting antihypertensives;alpha-blockers; andloop diuretics.Medicines prescribed in the 6 months up to and including the index date were considered for eight classes of antihypertensive medication (see Supplementary Box S2):6,16,17 The number of different classes prescribed were therefore grouped into categoric treatment intensity: 0 (untreated); 1 (possibly undertreated); or ≥2 medications.Only the most recently prescribed antihypertensive in each medication class was considered. Most individuals with hypertension require ≥2 antihypertensive drugs to maintain their blood pressures within an acceptable range.18 The unknown ethnicity group comprised individuals with no ethnicity code recorded, unclassified codes, and the ‘not stated’ codes.Ethnic groups were categorised according to top-level Office for National Statistics 2001 census categories and comprised: White ; Black and Black British ; Asian and Asian British ; Mixed ethnicity ; and other ethnic groups.19An individual’s Index of Multiple Deprivation (IMD) was based on their small area indicators (LSOA) and used the 2019 national quintiles from quintile 1 (most deprived) to quintile 5 (least deprived).15Blood pressure was deemed controlled as per NHS QOF indicators HYP003 and HYP007: individuals <80 years of age: SBP ≤140 mmHg and DBP ≤90 mmHg (HYP003); individuals ≥80 years of age, SBP ≤150 mmHg and DBP ≤90 mmHg (HYP007).Blood_Pressure_Recorded was true of individuals with a valid blood pressure recorded within 12 months of the index date;Hypertension_Controlled considered the entire cohort  and was true for patients with a blood pressure measure within the QOF age-adjusted target. Individuals without a recorded blood pressure within 12 months of the index date were considered to be above target blood pressure; andBlood_Pressure_Controlled considered only individuals with both blood pressure recorded within 12 months of the index date and with blood pressure within the QOF age-adjusted target.Three binary outcome variables of blood pressure management were considered:15 However, it is unlikely that all individuals with no blood pressure recorded in the past year actually have uncontrolled blood pressure. By considering only individuals with a blood pressure recorded in the past 12 months, as is the case with this study’s Blood_Pressure_Controlled indicator, a more reliable estimate of overall management of blood pressure can be obtained. Here, the authors used Hypertension_Controlled to simplify comparison of this study’s findings with other audits that treat ‘out of date’ blood pressure recordings as the QOF does, and Blood_Pressure_Controlled as the author’s preferred indicator of blood pressure control (see Discussion).The difference between Hypertension_ Controlled and Blood_Pressure_Controlled is worth clarifying. The former aligns with the NHS’ QOF management of hypertension indicators. QOF takes a ‘worst-case scenario’ approach: individuals on the hypertension register who do not have a blood pressure recorded in the past 12 months are deemed to have uncontrolled hypertension.Data were processed, aggregated, and validated, and descriptive statistics derived using Python (version 3.9.1). Univariate and multiple logistic regression analyses  were performed using R (version 4.0.5), with subanalyses performed by treatment intensity. Forest plots were generated using the forestplot Python package (version 0.2.0).The study cohort was derived from 190 out of 199 practices in the participating five North East London CCGs with a population of approximately 1.23 million adults, of whom 156 296 (12.7%) had hypertension. The nine excluded practices used a different electronic health record system.n = 142 126/156 296) had a valid blood pressure recorded in the 12 months before and including the index date (Blood_Pressure_Recorded).The summary characteristics of the study cohort are described in n = 114 653/156 296) had controlled blood pressure to age-adjusted targets. Of those with recorded blood pressures, 80.7% (n = 114 653/142 126) had controlled blood pressure as per age-adjusted targets (Blood_Pressure_Controlled) (data not shown).Using the entire cohort , that is Hypertension_Controlled, 73.4% (n = 149 974/156 296) of the entire cohort had an ethnicity code assignable to one of the five known ethnicity groups considered in this study, and only 2.7% (n = 4279/156 296) of cohort individuals had no ethnicity code recorded ; all other ethnicity groups (except for the unknown ethnicity group) were all within 10% of the reference White ethnic group (Blood_Pressure_Recorded and ethnicity were modelled using unadjusted and adjusted logistic regression in relation to the White ethnicity group . In the P<0.001), and for the Black ethnicity group the OR was 1.09 , as shown in In the multivariate model, the ORs for blood pressure recording were essentially unchanged. For the Asian ethnicity group the OR was 1.62  and the Black ethnicity group was 10% less likely  to have controlled hypertension than the White ethnicity group  and ethnicity were likewise modelled using univariate and multivariate models . In the P<0.001) whereas the Black ethnicity group was 8% less likely .In the multivariate model , the AsiP<0.001) whereas the Black ethnicity group was 8% less likely  as shown in The relationship between Blood_Pressure_ Controlled  and ethnicity was modelled as for the two previous indicators . In the P<0.001); the Black ethnicity group was 13% less likely to have a controlled blood pressure .These differences were accentuated in the multivariate model . The Asin = 39 854/156 296), individuals in the 30–39 years age bracket  were 39% less likely to have controlled blood pressure . Conversely, individuals in the 80–89 years bracket  were 175% more likely to have controlled blood pressure . When re-grouping the data, individuals aged <50 years were 40% less likely to have controlled blood pressure than those ≥50 years  (data not shown).Data from the multivariate analysis of the Blood_Pressure_Controlled indicator (the authors’ favoured indicator of control as explained in the Method and Discussion) were considered to understand the impact of age, deprivation, sex, and treatment intensity on effective management of hypertension . CompareP<0.001). Females were 14% more likely to have controlled blood pressure than males (P<0.001).The likelihood of blood pressure control decreased with decreasing deprivation . PatientP<0.001).Relative to untreated individuals, the likelihood of blood pressure control increased with treatment intensity by approximately 38% regardless of treatment intensity  is shown in Supplementary Figure S2.n = 908/7639) and 7.3% (n = 2627/36 169), respectively. Individuals in the Black ethnicity group were similarly or less likely to be untreated or be on a single antihypertensive medication than the White ethnicity group. In the controlled blood pressure group, 8.5% (n = 2016/23 850) of the Black ethnicity group were untreated and 32.9% (n = 7851/23 850) on a single agent (compared with 9.4% [n = 4084/43 659] and 34.4% [n = 15 033/43 659] for the White ethnicity group). In the uncontrolled blood pressure group, 13.6% (n = 918/6731) of the Black ethnicity group were untreated and 31.7% (n = 2133/6731) on a single agent compared with 13.0% (n = 1329/10 233) and 36.0% (n = 3685/10 233) for the White ethnicity group.Individuals in the Asian ethnicity group were the least likely to be untreated in both the uncontrolled and controlled blood pressure groups: 11.9%  to have controlled blood pressure .A multivariate analysis was conducted for the Blood_Pressure_Controlled indicator for: a) untreated individuals; b) individuals on one class of antihypertensive; and c) individuals on ≥2 classes of antihypertensives. The ORs by ethnicity group for this treatment intensity subanalysis are shown in This cross-sectional study of an unselected, large cohort of 156 296 adult patients with hypertension from 190 GP practices in North East London, identified inequities in the monitoring and control of hypertension by ethnicity, age, sex, and deprivation.20The Black ethnicity group was more likely to have uncontrolled hypertension than White or Asian ethnicity groups. This was not because of less frequent recording of blood pressure in the Black ethnicity group, as these individuals were in fact more likely to have a blood pressure recorded within 1 year than those in the White ethnicity group — nor was this finding owing to associations with age, sex, or deprivation. Regardless of treatment intensity, control of blood pressure in the Black ethnicity group was worse, and in the Asian ethnicity group better, than in the White ethnicity group. It is of note that despite better control of hypertension in the Asian ethnicity group, CVD mortality is higher in this group than in both the White and Black ethnicity groups.10,21–23 Issues relating to medication cost burden on working-age adults and adherence may also be contributory factors in particular in younger people (aged <50 years).10,24,25These data suggest that lower levels of blood pressure control in the Black ethnicity group cannot be directly attributed to relative underrecording of blood pressure or less intensive treatment. Other possible factors include unidentified confounding factors, differences in age at diagnosis, initial treatment choice and dosage, treatment escalation, adherence, and physiological treatment resistance.24 Similar concerns have been expressed about statin undertreatment in younger patients.26Patients with hypertension aged <50 years were 40% less likely than those older to have controlled hypertension. Given that 16.8% of the cohort was aged <50 years , this represents a notable treatment inequity.7 The QOF HYP003 and HYP007 indicators may be suitable for performance assessment in incentive programmes but do not provide reliable indicators of the management of hypertension — considering both Blood_Pressure_Recorded (an indicator of monitoring) and Blood_ Pressure_Controlled (an assumption-free indicator of control) is preferable.Lastly, this study highlights the importance of indicator choice in assessing cohort-level management of hypertension. The difference between Blood_Pressure_Controlled and the QOF derived Hypertension_Controlled indicators has been previously noted as reflecting missing recordings rather than reduction in control.27 This is relevant because subgroups of, for example, South Asian, includes Indian, Bangladeshi, and Pakistani, and it is possible that one of these groups could have higher or lower BP than another; similarly, Black ethnic group might conceal differences in a Black subgroup such as Kalahari bushmen.The study cohort was unselected, included almost all (95%) general practices in the region, and had a high level (96%) of recorded ethnicity in an ethnically diverse population with broad representation of the three principal ethnic groups discussed. However, it is important to be mindful that high-level ethnicity groupings can conceal underlying heterogeneity between constituent ethnicity groups.The study was cross-sectional and trajectories of the patient groups through time were not addressed. Treatment changes within 6 months would not be captured accurately, possibly overestimating treatment intensity in a small number of patients. In North East London, 72.6% of the population were in the two most deprived quintiles, and only 10.6% in the two most affluent. The urban density and the fact that the wealthy and deprived often live in close proximity means that area-level measures such as IMD quintile reduce gradients between extremes of deprivation. In addition, the most affluent may be away from their London residences for prolonged periods or access alternative health services that may further influence blood pressure recording and control, and contribute to apparent poor management in this group.8–12 This study found younger individuals had poorer control than older individuals, a finding not replicated in a cross-sectional population- based study of almost 100 000 individuals with hypertension enrolled in the UK Biobank database .9 In the current study, the Black ethnicity group had similar access to primary care-based blood pressure recording as other ethnicity groups, a finding similar to that in a South East London-based study.8The current study confirms previous findings of inequities in the control of blood pressure in patients with hypertension, with poorer control in the Black ethnicity group and better control in the Asian ethnicity group in comparison with the White ethnicity group, as well as better control in females compared with males.et al, comparing management of people with newly diagnosed hypertension from European, South Asian, and African/African Caribbean ethnicities, the findings of poorer control in the Black ethnicity group was similar to the current study, but the South Asian group was found to have similar levels of blood pressure monitoring and control in comparison with other ethnic groups.10 The current study found higher levels of blood pressure monitoring and of blood pressure control in the Asian ethnicity group than in the White ethnicity group. However, the UK-wide study considered only recently diagnosed patients, which may account for differences in findings in the South Asian ethnicity group.In a UK-wide study by Eastwood et al10 did not find differences between blood pressure control in the African/African Caribbean and European groups. However, cost of prescriptions are of concern as a possible contributing factor in working age adults.28The current study showed that, regardless of treatment intensity, the Black ethnicity group was less likely to have controlled hypertension. When considering only individuals who were adherent to their antihypertensive treatment, Eastwood 29 The second considered persistence with oral medication for type 2 diabetes. Relative to the White ethnicity group, non-persistence was more likely in the Black and the Asian ethnic groups .30 Such findings do not explain the higher likelihood of controlled blood pressure in the current study’s Asian ethnicity group. Furthermore, this study found no evidence that the Black ethnicity group was undertreated.Two UK-based studies investigated the impact of ethnicity on medication adherence, although neither considered antihypertensive medication. The first considered diabetes, dyslipidaemia, or hypothyroidism medication within an ethnically diverse inner-city cohort and found lower adherence in Asian or Black patients.20 Given the higher risk of cardiac death, there should be no complacency in the need to improve blood pressure control in the Asian ethnicity group and the higher levels of stroke in the Black ethnicity group raise similar concerns.The age-standardised mortality rates (ASMR) from ischaemic heart disease (IHD) for the Bangladeshi, Pakistani, and Indian ethnicity groups are significantly higher than in the White ethnicity group — who in turn have a higher ASMR than the Black ethnicity group.22,27,31Further research is needed to understand ethnic differences in IHD and stroke mortality, and the relevance of thresholds for blood pressure control or ethnicity- specific treatment pathways.In North East London and the UK more generally, a focus on the optimisation of blood pressure control in people of Black ethnicity and in younger people could be an important step in addressing the monitor and control of hypertension inequities.The impact of medication costs in younger working age groups deserves further attention and, in particular, the role of single pill combination therapies that reduce patient costs and improve adherence.4,32,33Easier access to monitoring of blood pressure is relevant to all people with hypertension particularly those of working age.


The use of creatinine-based glomerular filtration rate (GFR)-estimating equations to evaluate kidney function in elderly individuals does not appear to offer any performance advantages. We therefore aimed to develop an accurate GFR-estimating tool for this age group.99mTc-DTPA) renal dynamic imaging were included. Data were randomly split into a training set containing 80% of the participants and a test set containing the remaining 20% of the subjects. The Back propagation neural network (BPNN) approach was used to derive a novel GFR estimation tool; then we compared the performance of the BPNN tool with six creatinine-based equations  in the test cohort. Three equation performance criteria were considered: bias (difference between measured GFR and estimated GFR), precision (interquartile range [IQR] of the median difference), and accuracy P30 (percentage of GFR estimates that are within 30% of measured GFR).Adults aged ≥ 65 years who underwent GFR measurement by technetium-99 m-diethylene triamine pentaacetic acid , and higher than that of the Asian modified CKD-EPI . The median bias between BPNN and each of CKD-EPI , EKFC , BIS1 , and MDRD  was not significant. However, the BPNN had the highest precision IQR (14.31 ml/min/1.73 m2) and the greatest accuracy P30 among all equations (78.28%). At measured GFR < 45 ml/min/1.73 m2, the BPNN has highest accuracy P30 (70.69%), and highest precision IQR (12.46 ml/min/1.73 m2). The biases of BPNN and BIS1 equations were similar , smaller than any other equation.The study included 1,222 older adults. The mean age of both the training cohort (n = 978) and the test cohort (n = 244) was 72 ± 6 years, with 544 (55.6%) and 129 (52.9%) males, respectively. The median bias of BPNN was 2.06 ml/min/1.73 mThe novel BPNN tool is more accurate than the currently available creatinine-based GFR estimation equations in an older population and could be recommended for routine clinical use.The online version contains supplementary material available at 10.1186/s12877-023-04027-5. Accurate estimation of kidney function in older adults is an important step to management of chronic kidney disease.BPNN tool highly improved precision and accuracy, although bias remains suboptimal.2.BPNN tool can be recommended for clinical use routinely, especially for patients with GFR < 45 ml/min/1.73 mThe online version contains supplementary material available at 10.1186/s12877-023-04027-5. Glomerular filtration rate (GFR) is regarded as the best overall index of kidney function in health and disease. Accurately estimating the GFR is an important step in the diagnosis, classification and management of chronic kidney disease (CKD) , especia2 6], new AContinuous variables were expressed as the mean and standard deviation (SD) or median . Categorical variables were presented as count (n) and percent frequency (%). Three criteria were considered when evaluating and comparing the performance of the BPNN model and four other equations in the test cohort: bias, precision, and accuracy. Bias was expressed as the median difference between the measured GFR and estimated GFR. Precision was expressed as the IQR of the difference between measured GFR and estimated GFR. Accuracy was defined as the percentage of estimates within 30% of the measured GFR (P30). According to the K/DOQI guidelines, a P30 value ≥ 75% is sufficient for making good clinical decisions . The 95%http://www.R-project.org) software. All tests were 2-sided, with p < 0.05 indicating statistical significance.Mood’s median test was used to compare the median biases . If Mood2, and 43 (19.12%) of measurements had GFR values less than 30 ml/min/1.73 m2.Of the initial 1,768 participants, 1,222 met the study criteria  of these participants had a GFR below 30 ml/min/1.73 m2.In the test cohort, the mean (SD) age was also 72 (6) years, and 129 (52.87%) were male. Of these participants, 121 (49.59%) had diabetes and 187 (76.64%) had CKD. The median (IQR) measured GFR was 46.81 (32.28–65.6) ml/min/1.73 mWe proposed a BPNN model with four independent variables for GFR estimation, including age, sex , serum creatinine, and diabetes (present or absent). As the BPNN model was complicated, we therefore provided an excel file Table  to imple2 and 0.75, respectively, in the test set from the study cohort.To provide a good performance of the estimation model, our study cohort was randomly divided into two subsets: training and test sets. The training set included 978 individuals (80% of the study cohort) and the test set included 244 individuals (20% of the study cohort). The four variables of specific interest were used in both sets Table . The MAE2, which was significantly smaller than that of LMR ; the median bias between BPNN and each of CKD-EPI , EKFC , BIS1 , and MDRD  was not significant  ml/min/1.73 m2, 15.18 (12.78–17.16) ml/min/1.73 m2, and 14.74 (12.36–17.27) ml/min/1.73 m2, respectively. The precision IQRs of the new Asian modified CKD-EPI and MDRD were 20.42 (18.30−22.76) and 19.29 (16.79−21.85), respectively. Regarding accuracy, the P30 of BPNN was highest: 78.28% (73.07–83.49%). The P30 between BPNN and each of CKD-EPI, EKFC, and LMR was significant (more accurate in the former) . The P30 between BPNN and each of the new Asian modified CKD-EPI and MDRD was also significant . The P30 of BPNN vs. BIS1 was not significant   ml/min/1.73 m.07–15.86The quantile regression graphs demonstrate good correlation between the measured GFR and the BPNN, CKD-EPI, EKFC, BIS1, LMR, Asian modified CKD-EPI, and MDRD equations Fig. . In the Statistically, the strength of agreement between two methods can be assessed by the Lin’s CCC Figure . In the 2. At measured GFR < 45 ml/min/1.73 m2, the BPNN has the lowest MSE (106.48), highest accuracy P30 (70.69%), and highest precision IQR (12.46). The biases of BPNN and BIS1 equations were similar , which were smaller than any other equation.We then did subgroup analysis between patients with less than 45 and those with greater than 45 ml/min/1.73 mWe developed a new equation, the BPNN model that combines the four variables of age, sex, serum creatinine, and diabetes, to estimate GFR in persons aged 65 years and older. Using data from an independent test cohort of 244 individuals, we validated the BPNN model and showed that it was more accurate than the widely-used CKD-EPI equation as well as the EKFC, BIS1, LMR, and MDRD equations. The BPNN model has highest precision and greatest accuracy among aforementioned equations, although the bias is not optimal. This has important implications for public health and clinical practice.Machine learning is an emerging field of medicine where vast resources are applied to integrate computer science and statistics into medical problems ; it can As with the previously established GFR-estimating equations, we also included age and sex –9. This 2 Previous studies have found that the CKD-EPI equation had adequate performance in older populations with different levels of GFR [2 [The MDRD equation, which was developed in whites and African Americans with CKD, tends to have differences in performance among subgroups . For this of GFR . The Kids of GFR . Howeverf GFR [2 , 30.In addition, although the original CKD-EPI equation takes four-level race  into account, it requires more research to validate the performance of this equation in Chinese patients. Therefore, a new Asian modified CKD-EPI equation was developed aiming to improve the performance of the original one in determining GFR in Chinese adults with CKD . HoweverThe EKFC equation is a modified FAS creatinine-based equation that combines the properties of the FAS and CKD-EPI equations and can be applied to the full spectrum of age and kidney function . It was There are few studies specifically to develop GFR-estimating equations in older adults. The LMR equation was developed in a cohort of 850 Swedish Caucasians referred for GFR measurement . In this2; precision IQR, 11.1 ml/min/1.73 m2; P30, 95%). Other studies, however, had some inconsistent results [The BIS1 equation was developed in a population-based cohort of 570 patients aged 70 years and older who underwent iohexol clearance measurement [ results , 33–36. 99mTc-DTPA renal dynamic imaging as a reference method for GFR measurement. To date, measurements of GFR have generally relied on renal clearance of exogenous filter markers  [99mTc-DTPA renal dynamic imaging for measuring GFR, which is recommended by the Nephrology Committee of the Society of Nuclear Medicine [All the performance above revealed the BPNN model was more accurate than other equations in this age group. These results are consistent with previous results from the validation dataset . SpecifiTc-DTPA)  or endogTc-DTPA) . 99mTc-DMedicine , is wideMedicine , 41.99mTc-DTPA and a single shot plasma disappearance. Nevertheless, its renal clearance has been found to be close to inulin, with a consistency of 0.99 over a wide range of GFR, suggesting that the renal system treats these similarly [The study had several limitations, such as a lack of cystatin C, which is less affected by muscle mass. More accurate GFR measurements, such as inulin clearance, were not applied, as inulin is typically used in research work and is too inconvenient for use in everyday practice. Additionally, the sample size of the test dataset is relatively small. Further studies with a larger older population are required to externally validate the performance of our novel model. Third, as this was a retrospective study, we could not calculate the bias when mixing a steady state infusion method with a true clearance calculation such as imilarly . Finally2. Based on deep machine learning, future research should be directed towards the evaluation of cystatin C for GFR estimation, either alone or in combination with serum creatinine.In summary, the machine learning method  improved the precision and accuracy of methodologies for estimating GFR, although bias remains suboptimal. The 4-variable novel BPNN tool was more accurate than the currently available creatinine-based GFR estimation equations in elderly individuals, especially in older adults with GFR below 45 ml/min/1.73 mBelow is the link to the electronic supplementary material.Additional file 1: Table S1.Additional file 1: Table S2.Additional file 3: Figure


Renal sympathetic denervation (RDN) has been shown to lower arterial blood pressure both in the presence and in the absence of antihypertensive medication in an observation period of up to 3 years. However, long-term results beyond 3 years are scarcely reported.We performed a long-term follow-up on patients who were previously enrolled in a local renal denervation registry and who underwent radiofrequency RDN with the Symplicity Flex® renal denervation system between 2011 and 2014. The patients were assessed to evaluate their renal function by performing 24-hour ambulatory blood pressure measurement (ABPM), recording their medical history, and conducting laboratory tests.P < 0.001 for both systolic and diastolic ABP). The number of antihypertensive medications used by the patients significantly decreased from 5.4 ± 1.5 at baseline to 4.8 ± 1.6 at long-term FU (P < 0.01). Renal function showed a significant but expected age-associated decrease in the eGFR from 87.8 (IQR: 81.0–100.0) to 72.5 (IQR: 55.8–86.8) ml/min/1.73 m2 (P < 0.01) in patients with an initial eGFR > 60 ml/min/1.73 m2, while a non-significant decrease was observed in patients with an initial eGFR < 60 ml/min/1.73 m2 at long-term FU [56.0 (IQR: 40.9–58.4) vs. 39.0 (IQR: 13.5–56.3) ml/min/1.73 m2].Ambulatory blood pressure readings for 24 h were available for 72 patients at long-term follow-up (FU) [9.3 years (IQR: 8.5–10.1)]. We found a significant reduction of ABP from 150.1/86.1 ± 16.9/12.0 mmHg at baseline to 138.3/77.1 ± 16.5/11.1 mmHg at long-term FU (RDN was accompanied by a long-lasting reduction in blood pressure with a concomitant reduction in antihypertensive medication. No negative effects could be detected, especially with regard to renal function. High blood pressure remains one of the leading cardiovascular risk factors and the leading cause of premature death, affecting more than 30% of the adult population worldwide . VariousIn patients in whom secondary causes for hypertension, which need specific treatments, can be excluded, the guidelines recommend lifestyle changes and, depending on additional risk factors and hypertension severity, antihypertensive medication –4. NeverIn recent randomized sham-controlled trials, renal denervation (RDN) has been shown to effectively reduce blood pressure in the absence or presence of antihypertensive medication over a period of up to 6 months –12. MoreThe aim of this analysis is to evaluate the long-term efficacy and safety of radiofrequency RDN in a cohort of patients with treatment-resistant hypertension, with a particular focus on the course of blood pressure in patients who initially did not respond to RDN treatment.www.drks.de; identifier: DRKS00004173). All patients underwent baseline evaluation through 24 h ambulatory blood pressure (ABP) measurement and laboratory tests prior to renal denervation. A total of 108 patients were available for long-term follow-up (FU). For 72 of these patients, complete 24 h ABP measurements were available. Patients who declined an on-site visit and ABP measurement (ABPM) were asked to take a telephonic interview and undergo ABPM and laboratory tests through their primary care physician. This study was approved by the local ethics committee.After obtaining approval from the local ethics committee, we identified and contacted 245 patients who were previously enrolled in a local renal denervation (RDN) registry and who underwent radiofrequency RDN with the Symplicity Flex® renal denervation system at the University Hospital Halle , Germany, between 2011 and 2014  according to guideline recommendations , 16. TheBlood samples were drawn to determine the electrolyte, creatinine, urea, and HbA1c levels.Spot urine tests for determining the albumin and creatinine levels were completed during FU of the original registry up to 12 months of FU.Patients who were not willing or able to complete an on-site visit at long-term FU were asked to have the relevant laboratory tests, electrocardiogram, and ABPMs performed by their primary care physician. Antihypertensive medication was recorded and divided into nine classes .The primary efficacy endpoint was the change in mean systolic ABP at long-term FU. The safety endpoints were the change in renal function [the estimated glomerular filtration rate (eGFR) was calculated by using the CKD-EPI equation] and new-onset renal artery stenosis.Early response to RDN treatment was defined as a reduction in mean systolic ABP ≥ 5 mmHg at a 3-month FU.t-test. The median and the 25% and 75% quartiles were calculated to describe skewed variables. The between-group differences of these variables were compared using the Mann–Whitney test. Normal distribution was tested using the Kolmogorov‒Smirnov test. Between-group differences in categorical variables were compared using the χ2 test. Categorical variables between baseline and long-term FU were compared by using McNemar's test. Urine albumin levels between baseline and FU were compared by using the signed-rank test.Continuous symmetrically distributed variables are presented as means ± standard deviation and confidence intervals. Between-group differences were compared using the To evaluate the changes in systolic and diastolic ABP, the glomerular filtration rate during FU and linear mixed-effects models were used to account for repeated observations in the same patients over time.To identify independent correlates of the early response to RDN treatment (as defined above), the following baseline characteristics were assessed in a one-step multivariate binary logistic regression analysis: age, male gender, BMI, number of ablations, systolic ABP, diastolic ABP, mean heart rate, coronary artery disease, atrial fibrillation, current smoking, diabetes mellitus, number of prescribed antihypertensive medications, eGFR, BNP > ULN, and HbA1c.In case of missing observations in any of the recorded variables, all other available follow-up observations were included in the calculations. No imputation of missing data was done. All endpoints were analyzed exploratively.P ≤ 0.05 was considered statistically significant. Statistical analyses were performed by using SPSS Version 28 , and GraphPad Prism version 9 .A score of From a total of 245 potential participants, data for 108 patients were available for this analysis. A total of 85 patients were lost to FU, 15 declined participation, and 37 were deceased . Of the At the time when the procedure was carried out, the patients were 63.2 ± 8.8 years old, and 60 of them (55.6%) were male.2, which increased slightly but significantly to 31.6 ± 5.4 during long-term FU. Atrial fibrillation  was noticed in 11.1% of patients at baseline and 35.2% at long-term FU (P < 0.01). The proportion of patients with chronic kidney disease  increased from 10.2% to 33.3% (P < 0.01).The patients were mildly obese with a BMI of 30.9 ± 5.1 kg/mOf the patients, 13.9% had known coronary artery disease. Diabetes mellitus was present in 43.5% of patients. The patients were treated with 12.4 ± 3.1 ablations. The baseline characteristics are given in The median time to FU was 9.3 (IQR: 8.5–10.1) years.P < 0.01, and diastolic ABP from 86.1 ± 12.0 to 77.1 ± 11.1, P < 0.01).Both mean systolic and mean diastolic blood pressure of the overall cohort significantly decreased from baseline to long-term FU . Reduced blood pressure was also evident at all subsequent FU time points .Changes in systolic and diastolic blood pressure over time of patients whose ABPMs were complete at baseline and FU are shown in n = 35, 47.9%), with respect to baseline characteristics, no significant differences were found except for baseline systolic ABP, which was significantly higher in the early responder group .A total of 38 of 73 patients (52.1%), whose blood pressure readings were available at baseline and at 3-month FU, responded early to RDN treatment (as defined by a reduction in mean systolic blood pressure ≥5 mmHg). When early responders at the 3-month FU were compared with non-responders (P = 0.03), systolic ABP (Exp(B) 1.09, 95% CI: 1.02–1.17, P = 0.01), mean heart rate (Exp(B) 0.92, 95% CI: 0.85–1.00, P = 0.04), and dipping (Exp(B) 0.22, 95% CI: 0.05–0.96, P = 0.04; In the multivariate logistic regression analysis to identify independent correlates of early treatment response (as defined above), it was found that age (Exp(B) 0.85, 95% CI: 0.73–0.99, P = 0.02; When applying the model to determine whether there was a clinically meaningful reduction in systolic ABP of 10 mmHg during the long-term FU, it was found that only systolic ABP was an independent predictor of the long-term treatment response (Exp(B) 1.11, 95% CI: 1.02–1.21, In the comparison of early responders and non-responders, a significantly pronounced reduction in blood pressure was already observed at the 3-month FU in the early responder group, whereas in the non-responder group, a gradual reduction over the follow-up period was observed after an initial increase in mean systolic and diastolic blood pressure. While systolic ABP was significantly higher in the early responder group at baseline, there was no significant difference between the two groups at long-term FU .P < 0.01). When comparing patients classified as early responders at 3 months with non-responders, it was found that a slightly but not a significantly higher number of antihypertensive agents was being consumed by non-responders during FU. Between baseline and long-term FU, a non-significant decrease in the number of antihypertensive agents being consumed could be observed in both groups  and other antihypertensive medication  decreased significantly. In contrast, the low proportion of MRA at baseline increased significantly at long-term FU . Patients treated with MRA tended to have lower blood pressure than patients without this therapy; however, this difference was not statistically significant .The medication prescribed at baseline and long-term FU is shown in 2) as calculated through the CKD-EPI formula using plasma creatinine with a median eGFR of 87.8 (IQR: 81.0–100.0) ml/min/1.73 m2, which remained stable over the FU period up to 12 months. Similarly, the estimated GFR in patients with a baseline eGFR < 60 ml/min/1.73 m2 and a median eGFR of 56.0 (IQR: 40.9–58.4) ml/min/1.73 m2 was stable up to 12 months after RDN. A decrease in the eGFR was observed at the long-term FU in both groups  compared with that at baseline in patients with normal renal function during RDN. There was a non-significant reduction in the eGFR to 39.0 (IQR: 13.5–56.3) ml/min/1.73 m2 in the group of patients with impaired renal function during RDN; The renal function of the patients was determined by measuring their plasma creatinine levels. In addition, urine albumin values were available for the first 12 months of FU. At baseline, most patients (89.8%) had a normal renal function  mg/L at baseline to 4.8 (IQR: 3.0–13.7) mg/L at 12 months (P < 0.01 for comparison with baseline). Urinary albumin levels of patients with an eGFR < 60 ml/min/1.73 m2 at the time of ablation increased during the FU [baseline 5.7 (IQR: 4.4–87.7) mg/L and 12 months 13.5 (IQR: 2.9–26.2) mg/L]. However, the changes observed in patients with impaired renal function were not significant  response to RDN and the role that reinnervation and remodeling of sympathetic and parasympathetic nerve fibers play in this context are complex, and therefore, have not yet been fully understood , 24. FroAs in many other reports , 25, 26,However, it must be noted that, to date, there has been no uniform definition of (early) treatment response to RDN. Therefore, we decided to use a dichotomous definition of early treatment response for a clinically relevant reduction in systolic ABP by ≥5 mmHg at 3-month FU from baseline systolic ABP as in previous studies .P < 0.01). In recent years, MRAs have become increasingly important in the drug therapy of resistant hypertension and have received higher grades of recommendation in the corresponding guidelines . This finding is consistent with that of other reports demonstrating this over a FU period of 12 2). This od of 12  months. patients , 33. AltAs is common in registry studies, especially over a long period of time, FU results are available only for a limited proportion of the patients originally included (the number of patients for whom information on the variables given in Compared with the registry of randomized controlled trials, this registry includes a more heterogeneous population. However, it represents a real-world collective. The lack of a control group is also a limitation of this study. Adherence to antihypertensive drug therapy was not assessed. However, recent data from controlled trials indicate that the effect of RDN is independent of the medication taken or of adherence , 12, 34.In this analysis, a long-lasting and profound ABP reduction was seen with a concomitant reduction in antihypertensive medications. Moreover, the results provide an additional indication that RDN can sustainably and progressively lower blood pressure over a period of more than 3 years, even in patients who do not initially respond to the therapy, underscoring its importance as a complementary treatment for arterial hypertension. Also in the long term, no negative effects of RDN can be detected, especially with regard to renal function. Therefore, RDN can be considered an effective, long-lasting, and safe treatment method for arterial hypertension combined with lifestyle modification and drug therapy.


Perihematomal edema (PHE) after spontaneous intracerebral hemorrhage (sICH) is associated with clinical deterioration, but the etiology of PHE development is only partly understood.We aimed to investigate the association between systemic blood pressure (BP) variability (BPV) and formation of PHE.From a multicenter prospective observational study, we selected patients with sICH who underwent 3T brain MRI within 21 days after sICH, and had at least 5 BP measurements available in the first week after sICH. Primary outcome was the association between coefficient of variation (CV) of systolic BP (SBP) and edema extension distance (EED) using multivariable linear regression, adjusting for age, sex, ICH volume and timing of the MRI. In addition, we investigated the associations of mean SBP, mean arterial pressure (MAP), their CVs with EED and absolute and relative PHE volume.p = 0.673). Furthermore, we found no association between mean SBP, mean and CV of MAP and EED, nor between mean SBP, mean MAP or their CVs and absolute or relative PHE.We included 92 patients , median PHE volume 22.5 mL (IQR 10.2–41.4). Median time between symptom onset and MRI was 6 days (IQR 4–11), median number of BP measurements was 25 (IQR 18–30). Log-transformed CV of SBP was not associated with EED (B = 0.050, 95%-CI −0.186 to 0.286, Our results do not support a contributing role for BPV on PHE, suggesting mechanisms other than hydrostatic pressure such as inflammatory processes, may play a more important role. Spontaneous intracerebral hemorrhage (sICH) is a devastating disease with a poor outcome , 2. BesiFormation of PHE is driven by osmotic and hydrostatic pressure gradients [difference between intracranial pressure and systemic blood pressure (BP)], reflecting the blood brain barrier (BBB) permeability . Not onlVarious measures of PHE are available, including absolute and relative PHE volume (aPHE and rPHE), and the edema extension distance  . It is sWe aimed to investigate the association of BPV, measured by coefficient of variation (CV) of systolic BP (SBP) within the first week after sICH, with the formation of PHE measured by EED up to 21 days after sICH. Second we assessed the associations of mean SBP, CV of mean arterial pressure (MAP) and mean MAP within the first week after sICH with EED. Third we investigated the associations of these BP measurements with aPHE and rPHE volume.This study was part of the Finding ETiology of spontaneous Cerebral Hemorrhage (FETCH) study, a prospective multicenter study in adults with CT-confirmed sICH that aimed to characterize underlying pathophysiological mechanisms. Patients were recruited between October 2013 and December 2018 in three Dutch hospitals . The FETCH study was approved by the Medical Ethics Review Committee of the UMCU . We obtained written informed consent from all patients. We conformed to ICMJE Recommendations.For the current study, we included patients who underwent 3 tesla (T) brain magnetic resonance imaging (MRI) within 21 days after symptom onset and had at least five measurements of BP registered within the first week after symptom onset. We collected baseline characteristics including date and time of symptom onset, Glasgow Coma Scale (GCS) score and National Institute of Health Stroke Scale (NIHSS) score on admission, systolic and diastolic BP measurements (SBP and DBP) during admission , past medical history , vascular risk factors  and previous medication . BP measurements were collected as part of routine care and were performed by inflatable cuff measurements at the brachial artery. Definitions can be found in the * in Radboudumc and UMCU; susceptibility-weighted imaging (SWI) in LUMC) ; Philips Healthcare, Best, The Netherlands ] was performed using a standard protocol, amongst which Fluid Attenuated Inversion Recovery (FLAIR), and blood sensitive sequences (T2in LUMC) .http://www.itksnap.org/) (One trained reader (AW) manually segmented ICH and PHE volumes on axial FLAIR sequences using ITK-SNAP 3.8 (ap.org/) , blindedThe primary outcome parameter was EED, calculated as lume43π) . SecondaWe calculated means, standard deviations (SD) and CV of SBP, and MAP  who had at least five BP measurements available within the first week. Baseline characteristics of included and excluded patients were similar . Baselinp = 0.677; We found no association between log-transformed CV of SBP in the first week with EED in univariable regression analysis  in the first week after symptom onset and EED on 3 T MRI within 21 days after symptom onset. Neither was there an association between mean SBP, mean MAP or CV of MAP and EED. Furthermore, we found no association between CV of SBP, mean SBP, mean MAP or CV of MAP and aPHE or rPHE.post-hoc analysis of the ATACH-2 trial  found a consistent association between different measures of BPV  with clinical outcome in 913 participants, but not with absolute PHE growth on CT at 24 h as compared to baseline CT (BPV is associated with a higher risk of cardiovascular events and death due to cardiovascular diseases . Althougeline CT . A seconeline CT . The abseline CT . Additioeline CT , 9, 10. eline CT . Anothereline CT . The ATAeline CT . Howevereline CT .Our study has several strengths. First, we selected patients from a prospective multicenter cohort study in which 3 T MRI was performed in all patients, irrespective of clinical deterioration. Second, we studied PHE on 3 T MRI up to 21 days, which is closer to represent peak PHE than studies that investigated PHE at 24 or 72 h. Third, we analyzed PHE on MRI scans, which is superior to CT for the investigation of PHE, which is illustrated by our excellent inter-observer reproducibility . Our stuThe 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 Medical Ethics Review Committee of the University Medical Centre Utrecht, the Netherlands. The patients/participants provided their written informed consent to participate in this study.LS, FS, and CK contributed to the conception and design of the current study. CK, FS, MWa, MWe, and WJ contributed to the conception, design, and execution of the FETCH study. CK, FS, LS, MWa, MWe, SV, and WJ contributed to patient inclusions and data collection. LS and AW performed statistical analyses and wrote the draft of the article. All authors contributed to manuscript revision, read, and approved the submitted version.


Electronic nose (e-nose) is a new technology applied for the identification of volatile organic compounds (VOC) in breath air. Measuring VOC in exhaled breath can adequately identify airway inflammation, especially in asthma. Its noninvasive character makes e-nose an attractive technology applicable in pediatrics. We hypothesized that an electronic nose could discriminate the breath prints of patients with asthma from controls. A cross-sectional study was conducted and included 35 pediatric patients. Eleven cases and seven controls formed the two training models (models A and B). Another nine cases and eight controls formed the external validation group. Exhaled breath samples were analyzed using Cyranose 320, Smith Detections, Pasadena, CA, USA. The discriminative ability of breath prints was investigated by principal component analysis (PCA) and canonical discriminative analysis (CDA). Cross-validation accuracy (CVA) was calculated. For the external validation step, accuracy, sensitivity and specificity were calculated. Duplicate sampling of exhaled breath was obtained for ten patients. E-nose was able to discriminate between the controls and asthmatic patient group with a CVA of 63.63% and an M-distance of 3.13 for model A and a CVA of 90% and an M-distance of 5.55 for model B in the internal validation step. In the second step of external validation, accuracy, sensitivity and specificity were 64%, 77% and 50%, respectively, for model A, and 58%, 66% and 50%, respectively, for model B. Between paired breath sample fingerprints, there were no significant differences. An electronic nose can discriminate pediatric patients with asthma from controls, but the accuracy obtained in the external validation was lower than the CVA obtained in the internal validation step. Asthma continues to be one of the main concerns of pediatricians. It is one of the most frequent chronic diseases in childhood with an increasing prevalence in developed countries, and its management incurs a high cost. According to the GINA consensus, the clinical aspects, pulmonary function test and response to bronchodilator treatment can indicate a diagnosis of asthma. Symptoms are variable and pulmonary function tests may be difficult to perform in small children ,2,3,4. TExhaled breath contains volatile organic compounds as a result of metabolism; the composition of VOC is modified by respiratory and non-respiratory diseases. The analysis of VOC’s composition can identify specific profiles for each disease, making the diagnosis more accurate. The gold standard for detecting VOC’s composition is mass spectrometry or chromatography, but these methods are expensive and are not readily accessible ,8. The use of an e-nose for analyzing the exhaled breath composition is an innovative technique in the field of medicine. It can be the key to a quick diagnostic method for many acute or chronic diseases. Studies in this field have shown promising results regarding the ability of e-nose to recognize diseases; however, it is necessary to perform more clinical trials so that the technique can be validated and used in clinical practice ,14,15,16In medicine, e-nose has been studied so far, especially in adults, for diseases, such as asthma ,17, lungmax − R0)/R0, where R0 is the resistance during a baseline gas flow and Rmax is the maximum resistance during exposure to the sample. The raw sensor response, converted into a value, is then introduced into the data analysis system, creating a characteristic fingerprint, which can be analyzed by the recognition system , to test the external validation of these models and to evaluate the reproducibility of the measurements.Subjects. We included 35 patients, aged 5 to 18 years, who were evaluated in the Third Pediatric Clinic of the Clinical Hospital for Pediatric Emergencies from Cluj-Napoca, Romania, between 1 February and 30 June 2020. The study design had two steps. First, there was the training stage and then the validation stage of the obtained models on a new set of patients. The study group included children diagnosed with asthma and the control group included children assessed in the hospital for non-respiratory chronic diseases. The training set included 18 patients, 11 cases and 7 controls, which formed the two training models A and B. The validation set included 9 cases and 8 controls.Inclusion criteria. Asthma patients: aged between 5 to 18 years, diagnosis of asthma at least 6 months before and no past medical history of chronic disease or acute respiratory tract infection in the last 4 weeks. Controls: aged between 5 to 18 years, no respiratory disease, no past medical history or family history of atopy, recurrent wheezing or asthma and no acute respiratory tract infection in the last 4 weeks. We used the same inclusion criteria for patients and controls in the training models and in the validation set.For the diagnosis of asthma, we considered GINA consensus criteria—a history of variable respiratory symptoms: recurrent episodes of wheezing, breathlessness, chest tightness and cough, especially at night or during the early morning; the presence of symptoms induced by physical activity, allergen exposure, cold air, laughing, or during viral infections; and also lung function test criteria . RegardiPatients and caregivers signed the informed consent, and the study was approved by the Ethics Committee of the “Iuliu Hațieganu” University of Medicine and Pharmacy from Cluj-Napoca, Romania, no. 359 of 28 September 2017.Breath sample. In the absence of a standard protocol for the collection of exhaled breath samples, we used the protocol proposed by Dragonieri et al. ; the meaThe test was performed for each patient; they were not allowed to eat and drink two hours before the test and it was contraindicated to take inhaled medication or oral antihistaminic drugs 12 h before the test. The patients were asked to breathe 5 times into a device with a VOC filter from ambient air. After a forced inspiration through this device, the patient exhaled a volume of air, equal to their vital capacity, into a 5 L Tedlar sampling bag. The sample from the Tedlar bag was then connected to the e-nose device (Cyranose 320). The changes in the resistance of the nanosensors were stored as primary data, which were then analyzed by the recognition system .Data analysis. The study had a cross-sectional case-control design. The exhaled air was first analyzed online by the onboard learning software of the Cyranose 320 (PCNose). The raw sensor response was converted into a value, as described above, and then introduced into the data analysis system. Secondly, the results were confirmed offline by the CDAnalysis program, version 11.2, through the double cross-validation implementation of canonical discriminant analysis on the principal component reduction using Matlab software. The data were processed through Savitzky–Golay filtering and baseline correction, based on the recommendations of the manufacturer. Using PCA, the data from the 32 sensors were reduced to a set of principal components. PCA generated two- and three-dimensional graphs, visualizing the differences between groups. For the construction of the recognition algorithm, canonical discriminative analysis (CDA) was performed to maximize the distance between groups. The online software calculated a cross-validation value (CVV) while the offline software calculated cross-validation accuracy (CVA). M-distance quantifies the discrimination between groups. An M-distance of more than 3 was indicative of a high probability of discrimination. To compare the clinical characteristics, Fisher, chi-square, ANOVA and t-test were used. For the diagnostic performance of the training models in the external validation phase, we used the uncorrected chi-square Pearson test, Yates test, Mantel Haenszel test and Fisher test. Pearson’s correlation coefficient was calculated to evaluate the breath prints’ reproducibility.There were 18 patients in the training models divided into two smaller sets: model A with 11 subjects (6 with asthma and 5 controls); and model B with 12 patients (5 with asthma and 7 controls). Five of the seven controls in model B were the same as those in model A. For the external validation set, we had 17 subjects: 9 patients with asthma and 8 controls. The first step in our study was the internal validation step of the two training models. In the two models, asthmatic patients had distinct breath prints from controls. After applying the training models, A and B, the subjects from the external validation set were classified. We evaluated training models based on their accuracy, sensitivity, specificity, positive predictive value and negative predictive value. The results are shown in p-value was 0.01. The results are presented in Five asthma patients and five controls were used to evaluate the breath prints’ reproducibility. Each subject gave a second breath print at a distance of five minutes from the first breath print. Pearson’s correlation coefficient was calculated for every pair of breath prints. In 8 of the 10 subjects, the coefficient was greater than or equal to 0.8, and the The diagnostic performance of the e-nose in pediatric asthma was evaluated. There was no difference between asthmatic and control groups when assessing for variations due to sex and living environment. It is important to note that patients with asthma were younger than the control patients in model A. Matched groups by age is not recommended by Dragonieri et al., taking into consideration that breath prints are not influenced by age , but theRegarding the statistical analysis, we applied the frequently used method of double validation (PCA and CDA).In the first step of the study, the internal validation of both models A and B could adequately discriminate patients with asthma from the controls. We obtained a high cross-validation accuracy value of 90% for model B and 63.63% for model A for the offline program. The M-distance was equal to or more than 3 for both models.Our results are comparable with the results found in the literature. Dragonieri et al. obtained a model to discriminate mild asthmatic patients from healthy young subjects with a CVA of 100% and an M-distance of 5.32. Severe asthmatics were distinguished from healthy controls with a CVA of 90% and an M-distance of 2.7 . The samIn the field of pediatric asthma, studies regarding breath print analysis by e-nose are limited. The first one reported a sensitivity of 74% and a specificity of 91% for distinguishing between asthma patients and controls, with better results when discriminating between asthma and cystic fibrosis . The secThe second objective of the study was an external validation of the two models. The diagnostic accuracy of the models in the external validation phase was modest and smaller than the accuracy obtained in the first phase. These differences were also highlighted by Leopold et al. . As showLast but not least, we achieved the third objective of the study. Between paired fingerprints of the same subject, there were no significant differences. We obtained very good associations for 8 of the 10 pairs of breath prints. E-nose presents good reproducibility for a short period of time. Reproducibility was evaluated previously within-day and between-day ,34.As shown by studies using gas chromatography time of flight mass spectrometry, VOC analysis can differentiate preschool asthmatic children from transient wheezing children . Future One limitation of our study was the small sample size, which can explain the limited discriminative power of the e-nose in this study. Our results require confirmation with a larger sample size. In our study, we included children older than five years for a better accuracy of asthma diagnosis based on GINA consensus; for children under five years old, breath air collection is possible , but to In conclusion, we would like to emphasize the need for a standard protocol for collecting breath samples in pediatric patients. In the absence of such a protocol, the results of different studies are difficult to analyze. Even though our study was performed on a small group of patients, the discriminative power of the models was satisfying. This could be improved by models based on more breath prints and better-defined groups. Additionally, it is important to keep in mind the need for external validation of the models. External validation provides valuable information on the discriminative power of the e-nose breath analysis, which could become a routine investigation in every day clinical practice, making the diagnostic process easier, reducing costs and helping the therapeutic decision.


Moreover, plasma FGF-2 showed a significant correlation with the SINBAD score , platelet count , white cell count , and age . We did not observe any significant linear relationship between the studied biomarkers and microcirculatory parameters, nor for glycemic control. In a univariate analysis using logistic regression, an increase in plasma FGF-2 was tied to greater odds of high-grade ulcers . This suggests that circulating FGF-2 may serve as a potential biomarker for predicting DFU advancement and progression. It is necessary to conduct further studies with follow-up observations to confirm this hypothesis.Despite clear evidence of inadequate angiogenesis in ischemic diabetic foot syndrome (DFS) pathogenesis, angiogenic factor level changes in patients with ischemic DFS remain inconsistent. This study aimed to assess circulating angiogenic factors concerning ischemic DFS advancement and describe their relationships with patients’ clinical characteristics, microvascular parameters, and diabetic control. The study included 41 patients with ischemic DFS (67.3 (8.84) years; 82.9% males). Angiogenic processes were assessed by identifying circulating concentrations of five pro- and two anti-angiogenic factors. We found that penetrating ulcers were related to a significantly higher FGF-2 level (8.86 (5.29) vs. 5.23 (4.17) pg/mL,  Diabetic foot syndrome (DFS) is one of the most common, chronic, and complex complications of diabetes mellitus (DM). It is estimated that the pooled worldwide prevalence of diabetic foot ulcerations (DFUs) is 6%  and the DFS with concomitant PAD is classified as ischemic diabetic foot syndrome. It is especially connected to an unpredictable and often poor prognosis . In diabIn tissue healing, a substantial balance between cell migration, proliferation, and remodeling and precise responses to inflammatory mediators and angiogenic and growth factors is necessary . One of Other integral components of pathologic processes in DFUs are structural and functional changes in the microvasculature . The mosDespite compelling evidence suggesting inadequate angiogenesis and microvascular dysfunction in the pathogenesis of diabetic foot syndrome, the alterations in angiogenic factor levels in the bloodstream or wound materials among individuals with DFUs remain inconsistent . BecauseThis study aimed to assess circulating pro- and anti-angiogenic factors concerning DFS advancement and describe potential relationships between clinical characteristics, microcirculatory parameters, and diabetic control among patients with ischemic DFS.2, or neoplasm diagnosed within 5 years were excluded from the study. The study did not include subjects with chronic infectious diseases  or autoimmune comorbidities .A single-centered, cross-sectional study involving patients recruited from the Clinical Department of Angiology between February 2021 and May 2022 was conducted. The inclusion criteria were as follows: (1) subjects aged 40–80 years old with DM type 2, (2) ischemic DFS with active lower limb ulcerations, and (3) concomitant critical limb ischemia due to PAD (category 5 or 6 in the Rutherford classification). Patients with myocardial infarction or stroke within the last 6 months, diagnosed Charcot’s foot, acute lower limb ischemia within the previous 3 months, chronic kidney disease with eGFR < 45 mL/min/1.73 mInformation on chronic disorders, smoking status, and medications was obtained during medical history collection. All data and results were stored using a certificated tool for data collection (Medrio EDC). Hypertension was defined as an SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg, or receiving antihypertensive treatment. Body mass index (BMI) was calculated by dividing weight in kilograms and height in meters squared. Hemoglobin level, platelet count (PLT), white blood cell count (WBC), creatinine, C-reactive protein (CRP), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) concentrations were measured on the day of admission to the hospital and were extracted from the hospital laboratory system. The extra blood samples were collected from all patients and tested for the biomarker levels listed below. All samples were collected after a 12 h fasting period.Angiogenic processes were assessed by identifying concentrations of 7 physiologically produced circulating biomarkers with well-documented pro- or anti-angiogenic characteristics. The five pro-angiogenic biomarkers were vascular endothelial growth factor A (VEGF-A), soluble form of vascular endothelial growth factor receptor 2 , fibroblast growth factor 2 (FGF-2) ), placental growth factor (PlGF), and platelet-derived growth factor-BB (PDGF-BB). The two assessed anti-angiogenic factors comprised pigment epithelium-derived factor (PEDF) and angiopoietin-1 (Ang-1). The main material for angiogenic factor assessment was plasma separated from ethylenediaminetetraacetic (EDTA) whole-fasting blood samples after centrifugation at 3000 rpm for 15 min. All samples were stored at −80 °C until analysis. Human VEGF-A and VEGF-R2 concentrations (pg/mL) were determined using an enzyme-linked immunosorbent assay with commercially available ELISA kits . Human PDGF-BB, ANG-1, FGF, and PIGF levels (pg/mL) were measured via the quantitative sandwich enzyme immunoassay technique . Human PEDF concentration  was determined via an immunoenzymatic method using a commercially available ELISA kit . 2 vs. ≥ 1 cm2), and depth . The components of the SINBAD classification can be summed to produce a score between 0 and 6. It divides ulcers into 3 groups: low grade (0–2), moderate grade (3–4), and high grade (5–6) [The category of chronic limb ischemia was evaluated using the symptomatic Rutherford classification, which defines category 5 as minor tissue loss and category 6 as major tissue loss extending above the transmetatarsal level . The SINde (5–6) .The status of lower limb ischemia was assessed using an estimated ankle–brachial index (ABI) and toe–brachial index (TBI). Both examinations included systolic blood pressure measurements of the brachial arteries, ankle arteries, and toe capillaries. These were performed using a sphygmomanometer, an 8 MHz blind Doppler flow detector, and digital plethysmography. ABI was determined by dividing the higher systolic blood pressure measured at the dorsalis pedis or posterior tibial artery and the higher systolic blood pressure measured at the right or left brachial artery. In addition to ABI, systolic blood pressure on the toe was measured with a plethysmographic sensor and TBI was estimated. TBI was assessed by dividing the systolic blood pressure measured at the toe capillaries and the higher systolic blood pressure at the right or left brachial artery. All examinations were performed in a controlled environment with a room temperature between 21 and 23 degrees Celsius. The measurements were taken after a 15 min rest in a supine position with the limbs parallel to the body.Microcirculation was evaluated using laser Doppler flowmetry (LDF) and the transcutaneous oximetry test (tcpO2). Both measurements were made with the Periflux 6000 , equipped with thermostatic laser Doppler probes to precisely heat the tissue at the measurement site and a modified Clark’s polarographic oxygen sensor. The probes were stabilized on the dorsal aspect of the distal part of the foot, excluding skin with necrosis or inflammation, bone prominence, or a superficial tendon. Baseline microvascular blood flow was measured for 5 min and expressed in arbitrary perfusion units (PU). The tcpO2 examination was conducted for 20 min or until the curve on the graph flattened and was presented in mmHg. The results reflect microvascular flow, including capillaries, arterioles, venules, and shunts, as well as microcirculation blood perfusion, metabolic activity, oxyhemoglobin dissociation, and tissue oxygen partial pressure. Both tests were conducted in a room at a temperature of 21–23 degrees Celsius. Testing was preceded by a 15 min resting period, during which the patient lay in a comfortable position. t-test and Fisher’s test, respectively. Pearson’s correlation coefficient was used to assess linear relationships. Tests were two-tailed and a p-value < 0.05 was treated as significant.Statistical analysis was performed in R 4.2.2  using publicly available packages . Continuous variables were summarized as mean and standard deviation, with categorical variables as counts and proportions. Right-skewed variables were log-transformed before analyses. Distribution was assessed using qqplots. Continuous and nominal variables were compared using a We assumed a moderate (r = 0.2 to r = 0.4) association between circulating angiogenesis regulating factors and clinical characteristics. Given a significance level of 0.05 and a power set at 0.80, the required sample size for a one-sided hypothesis is at least 37 patients.This research is not in conflict with any ethical norms and regulations in research studies on humans. All patients signed informed consent forms to participate in the study. The regulations of the Declaration of Helsinki were used to prepare the protocol for this study, and the proper consent for this study was obtained from the constituted committee for human subjects or animal research at Jagiellonian University Medical College (decision number 1072.6120.129.2020).In this sample (n = 41), the mean (SD) age of the patients was 67.3 (8.84) years, with an average BMI of 27.55 (3.47) and substantial male sex predominance . The cardiovascular disease risk of the population was very high: 29 were smokers (70.7%), 37 had hypertension (90.2%), 15 had coronary artery disease (36.6%), 10 had congestive heart failure (24.4%), eight had atrial fibrillation (19.5%), five had a prior history of stroke (12.2%), and four had chronic kidney disease (9.8%). All patients presented with Rutherford categories 5  or 6 . Almost half of the patients  had a prior leg amputation, distal  or proximal  to the ankle. According to the SINBAD classification, wound infection was recorded for 23 patients (56.1%), 21 had a penetrating ulcer (51.2%), and 15 patients had a forefoot wound location (36.6%). The mean SINBAD score was 4.29 (1.21). Regarding the WIfI classification system, 30 patients (93.8%) were in the highest ischemic category (tcpO2 < 30 mm Hg). Most patients were in the high-risk amputation group , while 11 patients (26.8%) were categorized as moderate risk.p = 0.01).The comprehensive clinical characteristics of subjects divided into two groups based on ulceration depth (limited vs. penetrating) are presented in p = 0.02), PLT (5.81 (0.28) vs. 5.50 (0.28), p < 0.01), and CRP levels (2.73 (1.46) vs. 1.35 (1.08), p < 0.01)  vs. 5.23 (4.17) pg/mL, .01) see .p = 0.04)  vs. 11.57 (3.56) PU, .04) see .p = 0.02). In terms of glycemic control, HbA1c levels were significantly higher in the younger group compared with patients over 68 years old (8.47 (1.72) vs. 7.30 (1.27), p = 0.02).Generally, age did not significantly impact most of the clinical features . HoweverWe did not observe any significant linear relationship between the studied angiogenic biomarkers and microcirculatory parameters  . There wp = 0.02) and smoker status (mean (SD); 8.04 (5.27) vs. 4.80 (3.77), p = 0.04) but not sex (p = 0.54), hypertension (p = 0.55), coronary artery disease (p = 0.93), prior MI (p = 0.87), or CKD (p = 0.81). Plasma FGF-2 showed a significant correlation with platelet count , white cell count , age , and the SINBAD score . No significant linear association was observed for BMI (p = 0.85), hemoglobin (p = 0.18), eGFR (p = 0.94), HbA1c (p = 0.48), TC (p = 0.52), LDL (p = 0.29), HDL (p = 0.80), TG (p = 0.53), CRP (p = 0.24), tcpO2 (p = 0.26), LDF (p = 0.76), ABI (p = 0.06), or the WIFI score (p = 0.13). Using different antidiabetic drugs was not associated with circulating FGF-2 concentrations.We found a significant correlation between circulating FGF-2 and several clinical characteristics . It was p = 0.043). Using a multivariable model with log-transformed CRP and FGF-2 concentrations, we observed an improvement in model fit. However, only the relationship with CRP remained significant . We further assessed the predictive performance of this simple model using three thresholds , which yielded a corresponding sensitivity and specificity of 94.74%/27.78%, 68.42%/72.22%, and 42.11%/88.89%, respectively.In the univariate analysis using logistic regression, an increase in plasma FGF-2 was tied to greater odds of high-grade ulcers according to the SINBAD classification . These results are consistent with observations obtained from bovine models. In aortic endothelial and smooth muscle cells, bFGF release after nicotine stimulation was greater than in controls ,32. SimiAdditionally, we presented a reverse relationship between FGF-2 and age. This phenomenon remains a subject of discussion according to Harely M. et al., who found a progressive decrease in FGF-2 with age in human mesenchyme-derived progenitor cell cultures . HoweverAlthough there is convincing evidence indicating insufficient angiogenesis in the development of DFS, the changes in circulating angiogenic factor levels in the blood or wound materials among patients with DFUs are inconclusive. Several studies have emphasized the significance of reduced levels of pro-angiogenic factors such as VEGF-A and FGF-2 in wound material, as well as the decreased expression of PlGF in the development of DFUs ,41. AddiAccording to ulceration features, our study found that ulceration depth had significant relationships with certain clinical characteristics. Penetrating ulcers were tied to lower hemoglobin levels, higher platelet counts, and CRP concentrations, which are reflective of an inflammatory state with chronic iron restriction. Our observation is consistent with conclusions obtained from the other studies. A recent systematic review showed that lower hemoglobin levels are associated with DFU advancement, non-healing ulcers, amputation, and mortality . FurtherOnly a few studies have described the effect of HbA1c levels on ulcer healing ,46. ChenThe main strength of this study is a relatively large number of assessed circulating angiogenic factors, which were evaluated in a homogeneous group of patients with ischemic DFS. Despite concerns regarding study power, we observed that FGF-2 might be tied to specific clinical characteristics reflecting DFS advancement. Nevertheless, our study does have several limitations. The main one includes the small sample size, the monocentric character of the study, and the lack of a healthy control group. This cross-sectional study examined forty-one ischemic DFS patients who represent a homogenous sample because of highly restrictive recruitment criteria . NevThis study indicated a significant correlation between elevated plasma FGF-2 levels and ulceration depth, as well as with the SINBAD score, in ischemic DFS patients. Penetrating ulcers were related to significantly higher plasma FGF-2 concentrations, and an increase in FGF-2 was tied to greater odds of high-grade ulcerations. This suggests that FGF-2 may serve as a potential biomarker for predicting DFU advancement and progression. Future research with follow-up observations should investigate changes in circulating FGF-2 over time and their relationships with DFU healing and lower limb amputation rates to verify its predictive value.


CH was defined as clinic blood pressure (BP) < 140/90 mmHg and 24-h BP < 130/80 mmHg; WUCH was defined as clinic BP ≥ 140/90 mmHg and 24-h BP < 130/80 mmHg; ANRH was defined as 24-h BP ≥ 130/80 mmHg in patients receiving ≤2 antihypertensive drugs; ARH was defined as 24-h BP ≥ 130/80 mmHg in patients receiving ≥3 antihypertensive drugs. (3) Results: 153 patients had CH, 153 had WUCH, 307 had ANRH and 132 (18%) had ARH. During the follow-up (8.4 ± 4.8 years), 82 HF events occurred. After adjustment for various covariates, when compared to CH, the hazard ratio  for HF was 1.30 (0.51–3.32), 2.14 (1.03–4.43) and 3.52 (1.56–7.96) in WUCH, ANRH and ARH, respectively. (4) Conclusions: among elderly treated hypertensive patients, those with ARH are at a considerably higher risk of developing HF when compared to CH. A large body of evidence indicates that out-of-office blood pressure (BP), detected by ambulatory BP monitoring or home BP recording, is superior to clinic BP in predicting cardiovascular outcomes in both untreated and treated hypertensive patients ,2,3,4,5.Resistant hypertension occurs when treatment with ≥3 drugs fails to lower BP below upper normal limits and the unsatisfactory control of BP is confirmed by ambulatory BP monitoring or home BP recording ,2,20,21.Heart failure (HF) is an important public health problem characterized by high morbidity, mortality, hospitalization rates, and cost . HyperteThe aim of this study was to assess the risk of HF in elderly treated hypertensive patients with CH, WUCH, ANRH, and ARH.This study is a retrospective investigation of our prospectively collected data. We included 745 treated hypertensive patients older than 65 years, the most frequent age presently used to define the progression to the elderly status in Western nations, from a cohort of 2264 sequential treated individuals with complete follow-up . The gloClinic BP was detected by a physician using a mercury sphygmomanometer and appropriate-sized cuffs. Measurements were performed three times in a quiet room, 2 min apart, after at least 5 min of rest, and the mean value was used as the BP for the visit. Clinic systolic/diastolic BP < 140/90 mmHg was defined as controlled hypertension, and clinic systolic BP ≥ 140 mmHg and/or clinic diastolic BP ≥ 90 mmHg was defined as uncontrolled hypertension.Ambulatory BP monitoring was executed with a noninvasive recorder  on a typical day, within 1 week from clinic evaluation. Technical aspects have been previously reported . We eval2) and LA enlargement was defined as LA diameter/body surface area ≥2.4 cm/m2 [2.7 and LV hypertrophy was defined as LV mass/height2.7 > 50 g/m2.7 in men and >47 g/m2.7 in women [A complete echocardiographic investigation, including two-dimensional, M-mode, doppler and color Doppler assessment was performed at baseline. Measurements of left atrial (LA) and left ventricular (LV) dimensions and calculation of LV mass were made according to standardized methods . LA diam.4 cm/m2 . LV massin women . LV ejecin women . AsymptoPatients were followed-up in our outpatient clinic or by their general practitioner. The occurrence of events was recorded at hospitalization or during follow-up visits or by telephone interview of the general practitioner or the patient or a family member, followed by a visit if the patient was alive. Medical records were obtained to confirm the events. In the present study, we focused on HF requiring hospitalization. Diagnosis of HF was based on symptoms and signs of HF, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide levels when available, chest X-ray and echocardiographic examination. HF subtypes were reclassified according to recent European Society of Cardiology guidelines for HF , that isp < 0.05. Analyses were made with the SPSS 21 software package . Graphs were made with Microsoft Excel 10  and GraphPad Prism 7 .The data are described as means ± standard deviation, median (interquartile range), or numbers and percentages. Groups were compared by using a one-way analysis of variance followed by a post hoc test (Scheffé), Kruskall–Wallis test followed by Mann–Whitney U test with Bonferroni’s correction and chi-square or Fisher’s exact test with Bonferroni’s correction, where appropriate. Event rate is expressed as the number of events per 100 patient-years based on the ratio of the observed number of events to the total number of patient-years of exposure up to the terminating event or censor. Survival curves were estimated using the Kaplan–Meier product-limit method and compared by the Mantel (log–rank) test. Univariate Cox regression analysis was used to evaluate the association of various factors, including ambulatory BP phenotypes, with outcome, calculating unadjusted hazard ratio (HR) and 95% confidence interval (CI). Then, multivariate Cox regression analysis was performed to evaluate the independent association with the outcome of WUCH, ANRH, and ARH when compared with CH, calculating adjusted HR and 95% CI. The forced entry model was used in multivariate analysis. Statistical significance was defined as Characteristics of the studied population are reported in Clinic and ambulatory BP data are reported in The treatment of study groups is reported in During the course of the follow-up , 82 HF events requiring hospitalization occurred, including 34 HF with reduced EF, 2 with mild reduced EF, and 46 with preserved EF . None of the HF events were preceded by coronary events in this population. Specifically, there were 10, 9, 39, and 24 events in patients with CH, WUCH, ANRH, and ARH, respectively. The event rate  was morep = 0.002) and ANRH (p = 0.026).Event-free survival curves are shown in Univariate Cox regression analysis showed that age , diabetes mellitus , LV hypertrophy  and asymptomatic LV systolic dysfunction  were significantly associated with outcome. As regards ambulatory BP phenotypes, compared to patients with CH, the risk of HF hospitalization was not significantly higher in those with WUCH , but it was significantly higher in those with ANRH  and even higher in those with ARH . The other variables reported in The results of multivariate Cox regression analysis are reported in This study shows that, in the specific setting of elderly treated hypertensive patients, the risk of HF hospitalization was 2-fold and 3.5-fold higher in ANRH and ARH, respectively, when compared to CH.Few studies have reported that ambulatory BP parameters are superior to clinic BP in predicting HF ,26. A siDespite some differences between the study by Kario et al.  and oursIn our study, patients with ANRH also had a higher risk of HF than patients with CH. However, in this group of patients, there is a margin for increasing antihypertensive therapy and reducing the risk of HF.From a therapeutic point of view, the most difficult challenge is present in patients with ARH who are already taking three or more drugs. These patients require additional therapies to reduce BP values and the risk of HF and other cardiovascular outcomes. It has recently been reported that a reduction of 5 mmHg of systolic BP is associated with a 13% reduction in HF risk . There iAnother pharmacological class with high potential in the treatment of resistant hypertension to reduce BP values and outcomes, particularly HF, is represented by glyphozines (or Sodium-Glucose Cotransporter 2 Inhibitors). In randomized trials, empaglifozin, canaglifozin, dapaglifozin, and ertuglifozin have reduced HF hospitalization by about 30% in diabetic subjects, the vast majority (>90%) of whom had also hypertension and were treated with antihypertensive drugs ,45,46,47An additional drug class that could be helpful in the treatment of ARH is the angiotensin receptor neprilysin inhibitor. Indeed, it has been reported in some studies that angiotensin receptor neprilysin inhibitor significantly reduces both clinical and ambulatory BP when compared to placebo or active treatment ,52,53,54This study has some limitations. First, we evaluated only Italian patients and our results may not be applied to other ethnic groups. Second, we assessed only treated hypertensive patients older than 65 years and our data cannot be extrapolated to other types of hypertensive populations. Third, some of these patients were followed up in our outpatient clinic and part by their family doctors. Thus, BP control was not known in all the patients. Fourth, ambulatory BP data were obtained at baseline in all the patients, but only part of them underwent repeated ambulatory BP monitoring during time; thus, potential temporal changes and their relevance could not be evaluated. Fifth, in order to maintain adequate statistical power, we did not analyze HF subtypes separately. Sixth, we did not specifically design a study to estimate the risk associated with ARH, but this study is part of a prospective evaluation of the prognostic relevance of ambulatory BP parameters and other risk markers in our initially treated hypertensive patients.Our study also has some strengths including (1) the use of ambulatory BP monitoring to define true resistant hypertension, (2) a fairly large sample size, (3) a large number of HF events, (4) adjustment of risk by means of a substantial number of covariates.Our data show that, among elderly treated hypertensive patients, those with ARH are at a considerable higher risk of developing HF when compared to CH. New therapeutic strategies including drugs that have been shown to be effective in the primary prevention of HF and in reducing BP could lighten the burden of this outcome in arterial hypertension, and particularly in resistant hypertension, in the future.