A good agreement between methods was shown with few values out of the range of ± 1.96 standard deviation. Our findings added mathematical consistency for the NIRS methodology validation in the venular P–V assessment with no flow interruption. Further research will be required to confirm the relevance of the methodology in the clinical setting.We developed a method for measuring in vivo venular volumes and the mean systemic filling pressure in the limbs using near-infrared spectroscopy (NIRS). We aimed to validate the NIRS methodology by comparing two independent methods of calculation based on different physiological approaches. Pressure–volumes (P–V) curves were recorded following graded venous occlusion on the forearm. Values from a P–V curves analysis model (method 1) were compared with data derived from a resistor-capacitance calculation model (method 2) based on arterial pressure and venous compliance. We tested these methods on 10 healthy participants at rest and during exercise and on 6 severely ill patients. Results from method 1 were comparable with those calculated by method 2. Venular volumes calculated using method 1 correlated linearly with those calculated using method 2 both in participants (R Pressure in this vascular compartment acts both as an upstream force moving blood back to the heart and as a force shifting fluids outside the microvascular bed. Consequently, post-capillary monitoring and management could be a useful tool to guarantee venous return and limit extravascular fluid leakage, particularly during diffuse inflammation.Blood volume and pressure in the postcapillary compartment  are factors that determine venous return and systemic perfusion3.Since the late 80 s, some authors have made efforts to obtain in vivo measurements of the mean circulatory filling pressure (mcfp), for use as indicator of the average integrated pressure throughout the circulatory system. These methods require an absence of blood flow for calculating the vascular pressure variables and this was obtained by hindering venous return to the heart and extrapolating to zero the resulting blood flow reduction, or by creating a stop-flow in the upper armP–V) relationship that underestimates the intravascular pressure4.Unfortunately, these methods have several relevant limitations. First, inducing mechanical changes in the cardiac output (CO) is cumbersome and requires patients who are mechanically ventilated. Second, the extrapolation of CO to zero flow assumes a forced linearity in the pressure–volume , thus omitting a crucial determinant of the cardiovascular system function.5. This pressure, called mean systemic filling pressure (MSFP) according to a definition by Magder1, is often erroneously considered as a synonym of the mcfp, but, although quite similar, it differs from the mcfp because it is only related to the volume in the systemic vein.Previously, we had developed a method for measuring in vivo pressures and volumes in venules and small veins in the limbs based on the variation in light absorption using near-infrared spectroscopy (NIRS) after downstream venous occlusion, thus obtaining a measurement of the upstream pressure for venous return, without interrupting the arterial blood flowVs, Vu). Given that a direct measurement of post-capillary pressures and volumes cannot be obtained in clinical conditions, we derived these measurements using a model based on the analysis of the P–V curves5. We applied it in two clinical conditions by obtaining data that conform to pathophysiology7. Unfortunately, this method has not yet been fully validated because no gold standard exists and limitations of previous methods do not allow us to consider them as a reference.The method we developed complies with the principles of strain gauge plethysmography and NIRS, and it has the advantage of measuring microvascular bed volume and its subdivisions: stressed and unstressed volumes , and on 6 critically ill patients consecutively admitted to the Intensive Care Unit in 2018. The patients’ average age was 58.7 ± 19.0 years and the body mass index was 26.4 ± 2.4 kg/m2 (range: 22.86–29.39). For this study, we considered 24 measurements from healthy participants and 18 measurements from patients as representing the healthy adult population and patients with an impaired microvascular function. The investigative procedures have been performed in accordance with the Declaration of Helsinki of 1975, as revised in 1983, and the research has been approved by the ethics committee of the Sapienza University of Rome at the Sant’Andrea University Hospital the hospital . All participants or their next of kin provided written informed consent before the start of the study.The study was conducted at Sant’Andrea University Hospital, Rome, Italy. We performed multiple measurements on 10 healthy volunteers within the hospital personal (3 men and 7 women), with an average age of 26.5 ± 2.2 years and a body mass index of 21 ± 2.2 kg/m8. Then, we calculated the blood volume per 100 mL of tissue after accounting for the mean corpuscular hemoglobin concentration, mean corpuscular volume, and hematocrit levels in each participant. Since the Hb in arterioles accounts for only 3% of the NIRS signal, and because these vessels as well as capillaries are poorly distensible9, the changes in [Hb]tot during venous compression represented almost exclusively the changes that occurred in the venules and small veins. Data were acquired at a sampling time of 0.1 s, thus facilitating analysis of rapid changes in the [Hb] levels with a dedicated NIMO software program.We derived the forearm microvascular bed volumes from the sum of oxygenated hemoglobin/myoglobin (oxyHb/Mb) and deoxygenated Hb/Mb (deoxy Hb/Mb) μM concentrations ([Hb]tot/[Mb]tot) measured using a NIMO-4 continuous-wave photometer 10. In addition, arterial pressure does not interfere with blood volume changes due to venous occlusions11.The red blood cell count, cell volumes and the mean corpuscular hemoglobin content were obtained for each participant. To avoid unnecessary insertion of arterial catheters, in healthy participants the arterial blood pressures was recorded non-invasively by a pneumatic cuff, whereas in patients we used data from the invasive devices they had for cardiovascular monitoring. The choice of allowing two different technologies for measuring the arterial pressure was made as, in the range of pressure we studied, the mean arterial pressure was shown to differ little between the invasive and non-invasive approach12. The study took place in temperature-controlled rooms, and participants were made to lie down in a comfortable position. To extend the range of values, we experimentally increased the extravascular pressure by graded muscle isometric contractions in healthy participants.We performed measurements in the dominant forearm and positioned a NIRS probe at the top of the flexor digitorum superficialis (FDS) muscle and verified the correct placement of the probe visually. A pneumatic cuff was placed around the arm 5 cm proximal to the antecubital crease, with its tube connected to an automatic inflation system  capable of reaching a manually predefined pressure in less than 0.5 s. To ensure that there were no differences in hydrostatic pressure due to the position of the forearm during measurement and that no correction factor was needed, we restrained the forearm in a plastic frame at an angle of 135° in relation to the upper arm and placed the NIRS probe at the same level as the right atrium7, we first inflated the cuff to 50 mmHg for 120 s, according to Halliwill’s technique13, to ensure equilibrium between the cuff pressure (Pcuff) values and intravascular pressure (Pi) and achieve their equivalence14. Then we decreased Pcuff by 5 mmHg down to 0 mmHg, with each step lasting 20 s (10 data points). The five [Hb]tot values preceding each Pcuff drop of 5 mmHg were manually averaged into 1 value from 50 to 0 mmHg, obtaining 10 steady volume values to generate P–V curves. In both methods, it is believed that applying a pressure P with a cuff to the arm generates an extra downstream pressure and blood volume increase that overcomes the baseline venule pressure (P0) (i.e. the mean systemic filling pressure).In this study, unlike in previous onesHealthy participants were asked to perform maximal voluntary contraction (MVC) with a digital hand grip  recording the force in kilograms.After a first set of measurement at rest, two additional sets of measurements were performed during isometric exercises by clenching the handgrip at 10% and at 20% MVC, and maintaining the force for 3 min. The isometric muscle contractions were separated by a resting period of 3 min. During contractions, the cuff was inflated to a pressure of 50 mmHg and then deflated following the same framework used for the first set of measurements performed at rest.Measurements were performed on patients at rest. All patients received treatments established by the doctor on charge and NIRS measurements were performed before and after changes in vasoactive agents infusion rate or fluid administration.u, Vs) and venular compliance.Both methods are based on the cuff pressure and venular volume measurements. Assuming that these variables are correctly measured, we compared two independent methods of calculation to derive the MSFP, venular volume partitioning , the intermediate and steeper part as vascular bed recruitment induced by the increase in Pi, and the lower portion of the curve as blood volume changes that occur at a Pi lower than that needed to recruit the venular bed.Based on the evidence that venous compliance is not linearPi < 50 mmHg, C is compliance, P is intravascular pressure, V is blood volume, and i is an index value from 1 (corresponding to 0 mmHg) to 10 (corresponding to 45 mmHg). In this model, the breakpoint pressure (bP), which separates the intermediate phase from the low-pressure phase, was determined by the Pi corresponding to the highest value of compliance. To calculate MSFP, we extrapolated the measurements of the steeper P–V segment using linear regression from the bP to the blood volume measured before occlusion  on the pressure axis. This corresponds to the Pi within venules and small veins in the presence of blood flow and was thus deemed to represent the MSFP.To avoid any assumption about the shape of the P–V curve, the relationship was calculated as the numerical derivative (2-point difference derivative) of each data point using the following equation:0 in Vs and Vu, we calculated Vs as the volume included in the MSFP taking into account the steeper P–V segment from the bP7.In order to partition the V16 and that the oxygen saturation of [Hb] at baseline corresponds to that measured following venous occlusion at a low Pcuff. Since light absorption at baseline is the result of deoxy-[Hb] plus the percentage of [HbO2] in tissue blood, we could calculate the [MbO2] contribution to V0. Then, we obtained Vu by subtracting [MbO2] contribution from Vs7.As NIRS makes no distinction between [Hb] and [Mb], we assumed that at rest, Mb is totally oxygenated17, by adapting the model proposed by Van Vo et al.18. As an analogy with the electric scheme, the current, difference in electric potential, resistances, and capacitance represented blood flow, pressure difference, vascular resistance, and vascular compliance, respectively . Above this Pv value, the vascular bed is fully recruited and venular compliance (C2) reflects the vessel wall elasticity.We modeled the vascular compartment between the arteries and veins upstream of the pneumatic cuff. The initial and final pressures on our circuit were represented by the arterial pressure V0 and Pcuff, which is reported in Fig. Pcuff is lower than the MSFP (P0) venular volume equals the sum of Vu and Vs, which is the baseline volume (V0), namely, the volume attained when the Pcuff is not applied. Above P0, venular volume increases as a result of the Pcuff values increase, showing two different slopes corresponding to the vascular bed recruitment and vessel wall elasticity. Calculations and relationships between the variables and details on the model are reported in supplementary methods Based on this premise and by assuming the blood flow upstream and downstream venular compartment in the steady state as a constant, we derived a relationship between the Variable values calculated with the model fitted with NIRS were analyzed using generalized nonlinear regression with R software .From preliminary results comparing P–V values calculated by the two methods, a slope of the linear regression line of 0.95 and 0.97 respectively with a standard deviation (SD) of the regression errors of 0.88 and 0.17 were showed for patients, whereas for healthy participants a slope of 0.70 and 0.98 with a standard deviation of 0.91 and 0.18. These data entail that a sample size of 4 measurements for patients and 10 measurements for healthy participants would be adequate to detect a difference between methods in the order of magnitude previously assessed, with a statistical power of 80% and an alpha error of 0.05 .p-value less than 0.05 was considered to indicate statistical significance. Data were analyzed with the software program MedCalc .All data were expressed as mean ± SD. The Kolmogorov–Smirnov test was used to assess normal data distribution. We used the analysis of variance (ANOVA) for repeated measurements for testing values differences within the same group. The Bland and Altman test was used to compare the two methods of calculation plotting the differences between data measured by method 1 and 2 and against the averages for the two methods. We calculated the mean difference between two methods of measurement (the “bias”), and 95% limits of agreement as the mean difference (± 1.96 SD). Pearson’s correlation coefficient (r) and regression analysis were used to test data linearity of the two methods. A Of the 10 healthy participants, 7 had measurements at baseline, at 10% and 20% MVC. Two participants were excluded from measurements at 20% MVC because of an unreliable NIRS signal, and for 1 participant we only included the measurement at baseline. We performed 18 measurements on the six patients , before and after all changes in fluid balance, norepinephrine infusions, or airway pressures.P–V relationship . In contrast, the volume values matched those previously reported7. ANOVA showed significant changes in MSFP (p < 0.001) when comparing sets of measurements at rest and during exercise, showing a progressive increase in MSFP from rest to 10% and 20% MVC. The changes in the shape of the P–V curve due to exercise resulted in no change in volume (p = 0.440). Thus, calculations revealed a decrease in the Vs compliance (p = 0.010).At rest, the MSFP calculated in healthy participants by method 1 yielded values higher than those reported in our previous studies  qualitatively and quantitatively reproduced the values obtained by NIRS , and in patients   Fig. a,b.FigurThe two regression lines showed different values for intercepts and slopes, with values concentrated mainly within a small range in both groups of participants. The Bland–Altman test selected one value out of those in the range of ± 1.96 SD for healthy participants and one for patients Fig. c,d.Vu + Vs) showed a linear correlation between values calculated using methods 1 and 2, both in healthy participants  and in patients .Measurements of the volumes in venules 21. Since IMP is typically identified as a measurement of fluid pressure, including the contribution of the interstitial fluid22, it is reasonable to suppose that a force-related IMP increase affects pressure inside venules. This simulates an interstitial fluid pressure higher than normal, as observed during inflammation. Our results confirmed the incremental MSFP values by varying muscle efforts, providing evidence of the sensitivity of NIRS technology to changes in interstitial pressure.The values of MSFP and venular volumes obtained by our NIRS methodology, in contrast to those of the mcfp obtained with the arterial flow limitation maneuvers, conform to the physiologic knowledge on venous return and the hydrostatic pressure1.Higher MSFP values measured at rest in healthy participants by method 1 when compared to those previously reported can be explained by a small change we introduced in the calculation of method 1. It included the estimation of the lower part of the P–V curve, the low-pressure phase. In this revised method, we extrapolated the steeper P–V segment in the intermediate phase to the pressure axis. The rationale behind this change relies on the reasoning that P–V data, resulting from the change in vascular compliance at the beginning of vascular bed recruitment, should reasonably reflect the force that the vascular bed exerts to oppose its recruitment. We were able to verify in monitored patients that this new MSFP calculation gave rise to MSFP—central venous pressure gradients in accordance to the patient’s patho-physiologic condition2 observed in the MSFP overall values of healthy participants and patients could be justified by the flattering of the curve shapes during muscle contractions, which could have a significant impact on the calculation by the two methods. On the contrary, patients at rest despite having a wider range of MSFP and volume values, showed a more homogeneous curve shape.The lower R7. In these studies, the evaluation of changes in the venular compartment was crucial for understanding the effects of volume loading and extracorporeal pump on tissue perfusion. In addition, we collected unpublished data on patients with trauma or sepsis that highlighted the importance of in vivo monitoring of the venular compartment for comprehending the effects of treatments.It is important to clarify the available evidence that justifies the utility and relevance of the data. The answer is derived from the results of two studies in which the NIRS methodology was applied in critically ill patients and in those who had undergone cardiac surgeryP–V curve. The final consequential element of construct validation is determined by judging the social acceptability of consequences that occur as a result of using a study’s findings, measures, or inferences. To fulfill this last point, we need to conduct further research and perform studies that possibly demonstrate the validity of NIRS variables in different contexts of clinical practice.Another critical issue comprised determining the consequences of data errors in terms of clinical implications. Although no measurement can be completely free from uncertainties and errors, the possibility of incorrectly recording venular pressures and volumes may theoretically lead to consideration of giving fluids or vasoactive agents to a patient when it is not necessary or, on the contrary, refraining from giving them when needed. However, as venular values vary according to variables measured in macrocirculation, the validity of NIRS variables results from their consistency with data from the macrocirculation as well as from changes in therapy. An effective way to account for possible errors in measurements is to look at the shape of the Vs and Vu. This relates to the inability to extrapolate the Vu using method 2. Another limitation is the possible inaccuracy in the absolute Vu value calculated using method 1, due to the overlapping light absorption spectra of Hb and Mb. This makes identification of Mb non-feasible. Notwithstanding, the percentage of the NIRS signal due to Mb in the skeletal muscle is lower and contributes modestly to the calculation of Vu using method 1. Additionally, since the Mb concentration and its saturation remained unchanged over several days, we considered the Vu changes in the same participant to be reliable. In order to collect more data for the P–V curve, we performed measurements with a 2-mmHg drop. However, because of the difficulty in manually setting such a small variation in the Pcuff and obtaining stable [Hb] values, we excluded these measurements from the results in view of potential inaccuracies.Our study has several limitations. The first possible limitation is that we compared the total venular volume with the two methods without categorizing it into In this study, we added mathematical consistency to our previous construct, based on P–V curves analysis, to validate with two independent methods of calculation the NIRS methodology for the assessment of venular bed without flow interruption. The methodology was tested in healthy volunteers at rest and during exercise and in patients and variables results were in conformance with the physiological principles with regard to microcirculation, as hypothesized. Further research will be required to confirm the utility and relevance of this method in cardiovascular diagnosis and treatment.Supplementary Information 1.Supplementary Information 2.


Preeclampsia is a serious complication of pregnancy that threatens the safety of the fetus and mother. We assessed the relationship between systolic blood pressure (SBP) in the early pregnancy stage (12 weeks) in patients with preeclampsia and the development of severe eclampsia and birth weight.Patients were categorized based on the quartiles of the prenatal first SBP level. Logistic regression analysis was performed to assess whether prenatal first SBP was a risk factor for low birth weight and severe preeclampsia. The area under the receiver-operating characteristic curve (AUC) of sensitivity and specificity were used to predict the risk of low birth weight and severe preeclampsia.p = 0.025), prenatal first SBP (p = 0.029), S-preeclampsia (p = 0.003), gestational age (p < 0.001), total cholesterol (TC) (p < 0.001), and low-density lipoprotein (LDL) (p < 0.001) were independent risk factors for low birth weight. Multiple logistic regression analysis showed that prenatal first SBP (p = 0.003), TC (p = 0.002), and B-type natriuretic peptide (BNP) (p < 0.001) were independent risk factors for severe preeclampsia. Compared with Group I (SBP ≤ 119 mmHg), the incidence of low birth weight for patients in groups III (131 ≤ SBP ≤ 138 mmHg) and IV (SBP ≥ 139 mmHg) was significantly higher. Even after correcting for age, gestational age, and biochemical indices, the difference remained statistically significant. The risk of diagnosed severe preeclampsia for patients in Groups IV (SBP ≥ 139 mmHg), III (131 ≤ SBP ≤ 138 mmHg), and II (120 ≤ SBP ≤ 130 mmHg) was significantly higher than that in Group I (SBP ≤ 119 mmHg). The AUC of the prenatal first SBP for predicting low birth weight and severe preeclampsia was 0.676  and 0.727 , respectively, in patients with preeclampsia.A total of 333 patients with preeclampsia were enrolled. There were 162 (48.6%) patients with severe preeclampsia and 270 (81.08%) cesareans. Group I patients with a prenatal first SBP ≤ 119 mmHg prenatal had a higher birth weight. Multiple logistic regression analysis showed that serum creatinine (Prenatal first SBP was associated with birth weight and severe preeclampsia. Higher prenatal first SBP in patients with preeclampsia can predict low birth weight and severe preeclampsia. Preeclampsia is a serious complication of pregnancy that threatens the safety of the fetus and mother. Preeclampsia and eclampsia, which vary greatly from region to region, cause approximately 50,000 maternal deaths worldwide every year . AlthougBlood pressure is an important indicator for the diagnosis of preeclampsia. Blood pressure higher than 160/110 mmHg is characteristic of the diagnosis of severe preeclampsia . CurrentThis study protocol was approved by the ethics committee of the First Affiliated Hospital of Fujian Medical University. All patients provided written informed consent to participate in this study. Patient inclusion criteria included providing written informed consent, aged >18 years, and diagnosed with preeclampsia between June 2015 and July 2021. Patients with infection, trauma, mental illness, hypertension, connective tissue disease, kidney disease, nervous system diseases, multiple pregnancies, congenital anomalies, preterm premature rupture of membrane, diabetes, and those who needed antibiotics, corticosteroids, or immunosuppressive agents within a month were excluded. Of the 362 patients, six were excluded due to connective tissue disease and use of corticosteroids or immunosuppressive agents, eight due to infection or antibiotic use within a month, nine due to chronic kidney disease, and six due to hypertension. Finally, a total of 333 individuals were included.Clinical data were recorded, including the history of the disease, concomitant disease (kidney disease and hypertension), medications, prenatal first blood pressure, prenatal blood pressure, laboratory data, and delivery model. The primary endpoints were birth weight and severe preeclampsia. Severe preeclampsia was defined by any of the findings of severe features based on the American College of Obstetricians and Gynecologists (ACOG) 2013 criteria: blood pressure ≥ 160/110 mmHg (on two occasions at least 4 h apart), thrombocytopenia , progressive renal insufficiency , new-onset cerebral or visual disturbances, and pulmonary edema (2+), phosphate(P3+), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, albumin (Alb), hemoglobin (Hb), B-type natriuretic peptide (BNP), fibrinogen, uric acid (UA), and lactate dehydrogenase (LDH) were measured in all patients.Blood samples were collected before the delivery. Blood biochemical indices, including average values of calcium . A logistic regression analysis was performed to assess whether prenatal first SBP was a risk factor for low birth weight and severe preeclampsia. The area under the receiver-operating characteristic (ROC) curve (AUC) of sensitivity and specificity was used to predict the risk of low birth weight and severe preeclampsia. Statistical significance was set at p < 0.05. SPSS 15.0  was used for all statistical analyses and figures.The Kolmogorov–Smirnov test was used to estimate the Gaussian distribution of the data, and p < 0.001). The values of Hb, Scr, ACR, and 24 h protein urine were higher in Groups III and IV than that in Group I. Intravenous antihypertensive drugs were used more frequently in groups III and IV. There were no significant differences in LDL, HDL, fibrinogen, and BNP levels between the groups.Among the 333 patients with preeclampsia, the mean age was 32.00 ± 5.03 years, and the median birth weight was 2,800.00  g. There were 162 (48.6%) cases of severe preeclampsia and 270 (81.08%) cesarean sections. Based on the quartiles of prenatal first SBP, the patients were divided into four groups: group I had a prenatal first SBP ≤ 119 mmHg renatal f; group II had a prenatal first SBP between 120–130 mmHg, group III had a prenatal first SBP between 131 and 138 mmHg, and group IV had a prenatal first SBP ≥ 139 mmHg prenatal. HR] = 0.380, 95% CI 0.163–0.884, p = 0.025), prenatal first SBP , S-preeclampsia , gestational age , TC , and LDL  were independent risk factors for low birth weight , TC , BNP  were independent risk factors for severe preeclampsia  (Compared with patients in group I (≤ 119 mmHg), the risk of low birth weight for patients in group III (120–130 mmHg) and IV (≥ 139 mmHg) were significantly higher. After correcting for age, gestational age, and biochemical indices, the difference remained statistically significant. For patients in group IV (≥ 139 mmHg statistic), the risk of low birth weight significantly increased by 271.8% compared with that in Group I (≤ 119 mmHg hat in Gr) (< 0.001) .Among the patients who were diagnosed with severe preeclampsia, the risk of severe preeclampsia diagnosed in Group IV (≥ 139 mmHg), III (120–130 mmHg), and II (120–130 mmHg) was significantly higher than that in Group I (≤ 119 mmHg); this difference remained statistically significant even after correcting for all potential confounding factors .CI 0.618–0.733, p < 0.001) and 0.727 , respectively, in patients with preeclampsia, which showed that prenatal first SBP had a high accuracy for predicting low birth weight and severe preeclampsia. A cut-off value of 121.5 and 123 mmHg yielded good sensitivity and specificity for predicting low birth weight  and severe preeclampsia   , 2.in vitro fertilization, and maternal physical conditions, such as hypertension, diabetes, chronic kidney disease, and obesity.Preeclampsia and eclampsia seriously threaten the safety of pregnant mothers and fetuses. The incidence rate of hypertensive disorders in pregnancy, such as preeclampsia and eclampsia, pregnancy with hypertension, and chronic hypertension, is 5.5% . PatientThe ACOG divides gestational hypertension into four categories: preeclampsia and eclampsia, chronic hypertension, chronic hypertension combined with preeclampsia, and gestational hypertension. In this study, patients with preeclampsia had no history of chronic hypertension before pregnancy, and their blood pressure was monitored and recorded at the first follow-up of prenatal examination at 12 weeks. At 12 weeks, even if the blood pressure was within the normal range, the proportion of patients with severe preeclampsia and low birth weight was significantly higher in the SBP ≥ 120 mmHg group than in the SBP ≤ 119 mmHg group. The risk of low birth weight was 2.604–3.718 times and severe preeclampsia was 5.109–6.125 times. These abnormalities in women with preeclampsia suggest that the mechanisms that contribute to placental ischemia are set into motion very early in pregnancy. Thus, the concept of defective placentation and failure to transform uterine spiral arteries has emerged to be central to the pathogenesis of preeclampsia , Correlation among FABp4, PTEN, and gestational diabetes mellitus , and the Obstetrics and Gynaecology Division of the First Affiliated Hospital of Fujian Medical University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Treatment of chronic myeloid leukaemia (CML) is based on tyrosine kinase inhibitors (TKI), whose introduction in 2001 improved the survival rate after 5 years from 40 to 90%. The longevity increase has been accompanied by a higher incidence of cardiovascular events (CVE) that can be explained due to the sum of cardiovascular risk factors (CVRF) together with the secondary effects of the TKI. The effect of the TKI over the blood pressure control is still unknown. An observational cross-sectional study of patients with CML under treatment with TKI  was conducted. Blood pressure was analyzed through sphygmomanometer and 24-h ambulatory blood pressure monitoring (ABPM). A total of 73 patients were included, 57 treated with a single line of treatment. 32.9% of the total of individuals under this study showed uncontrolled blood pressure according to the ABPM. The factors related to uncontrolled BP were overweight, dyslipidemia, alcohol use, pulse wave velocity a high/very high cardiovascular risk. The subjects who received treatment with nilotinib did present worse control of their blood pressure in ABPM than those treated with imatinib and dasatinib (p = 0.041). This finding could indicate that an uncontrolled blood pressure is implied in the pro-inflammatory and pro-atherogenic mechanism underlying the development of the cardiovascular disease in those patients under treatment with nilotinib. The ABPM is a useful tool in the diagnosis and treatment of HT, being the reason why it should be included in the assessment of patients with CML whose HT diagnosis proves uncertain. With this drug, survival after 5 years in patients newly diagnosed with CML increased from 40 to 90%, with a life expectancy similar to healthy controls paired to age2. Second generation TKI, initially indicated for cases resistant to imatinib, showed subsequently an induction towards a quicker and deeper molecular response. For this reason, nilotinib and dasatinib were also indicated as first line treatment5. Bosutinib (second generation TKI) and ponatinib (third generation TKI) were introduced afterwards, being the latter designed specifically to be combined with BCR-ABL, having a very high potential to inhibit a wide range of mutations that confer resistance against other TKI (including the T315I)6.Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasia caused by the clonal proliferation of a tyrosine kinase BCR-ABL-1. It was the first neoplasia treated successfully with the inhibitors of the tyrosine kinase (TKI), especially with imatinib10. In a recent study by Shallis et al., it was concluded that the average age in the diagnose of this population was 59 years11. It has been observed in other studies13 that CVRF frequently coexist in this age range. Besides, the TKI have been related directly with the production of metabolic secondary effects (nilotinib and dyslipidemia), as well as the development of cardiovascular disease . All this has led current guidelines14 to recommend adapting the choice of TKI to the comorbidities of the patient15. It is therefore essential to know the CVRF and the total cardiovascular risk (CVR) of the subjects even before initiating the treatment.The increase in survival rate in CML patients with TKI came associated with an increase in CVE. The risk of developing a CVE in patients with CML is determined by an aggregation of the classic CVRF and the secondary effects of the TKI16, although there are few data about the prevalence of the CVRF17 in the different TKI. Uncontrolled HT can pose a higher risk of CVE. ABPM allows an accurate diagnose and classification of BP, as well as the diagnose of the white coat HT, masked HT and blood pressure pattern. Patients with masked HT present a higher incidence of target organ damage than those without hypertension.Regarding hypertension (HT) as a CVRF in patients with CML, in the existing literature there only exists clear evidence regarding the use of ponatinibObservational study of patients diagnosed with CML under active treatment with TKI corresponding to the University Hospital Virgen de las Nieves in Granada, Spain. Out of the 74 subjects diagnosed in the province, 73 accepted to participate in the study.ITK's selection was made as follows: In elderly patients or patients with a short life expectancy, patients with many comorbidities or highly polymedicated, the first choice for TKI was imatinib. In young patients or those with high desires for future discontinuation, the first choice was a second generation TKI (2GTKI). The choice between a 2GTKI or another in first line was based on patient's comorbidities. The use of nilotinib was avoided in patients with established CV events or large CVRF. Dasatinib was avoid in patients with a history of pleural effusions or manifest fluid retention. To date, the use of bosutinib in the first line for CML in Spain is not authorized.The patients were evaluated in a specific cardiovascular risk consultation, in which the cardiovascular history, blood and urine analysis, electrocardiogram, ankle-brachial index, pulse wave velocity and 24-h ABPM was analysed. The study was approved by the Ethical Committee of Investigation for the Province of Granada (Spain) (verification code 5c07f325e14f4a852ee4d0047025daf9baaa41c7). All patients signed the informed consent before participating in the project. All methods were performed in accordance with the relevant guidelines and regulation. The data collection was carried out between May 2018 and May 2019.18. In order to carry out the ABPM, the oscillometric model SpaceLabs 90207 19 was chosen. The normality values used were the latest recommended by the ESC/ESH Guidelines for the management of arterial hypertension (2018)20. Uncontrolled blood pressure  was defined as ABPM ≥ 130/80 mmHg. The ankle-brachial index was calculated through the Microlife WatchBP Office ABI system21, considering as pathological those quotients ≤ 0.9. For the assessment of the arterial stiffness it was performed the indirect measurement of the pulse wave velocity (PWV), using the validated system Mobil-O-Graph22. The reference values were determined by normalised charts estimated according to age, height, weight and central blood pressure. Regarding the target organ damage, it was considered microalbuminuria if the ratio albumin/creatine was higher than 30 mg/g in two measurements23. The assessment of left ventricular hypertrophy was carried out following the electrocardiographic criteria of Sokolow-Lyon24 and Cornell25.Blood pressure measurement in consultation was performed according to the recommendations of the European Society of Hypertension using a validated oscillometric blood pressure monitor (OMRON M3 IT—HEM-7131U-E)For the comparative analysis among TKI, patients who had treatment changes during the evolution of the disease were removed from the study, classifying the patients in a first group formed by subjects who had been treated with imatinib and dasatinib and a second group determined by those treated with nilotinib.This project was approved by the Provincial Ethics Committee of Granada, Spain.A population of 73 patients diagnosed with CML and under active treatment with TKI was analysed. 39 patients were treated in first line with imatinib 400 mg daily, 24 with nilotinib 300 mg twice daily and 10 with dasatinib 100 mg daily. 16 patients required a change to a second line of treatment  and one to a third line with dasatinib. Mean age was 56.47 ± 15.19 years. The average duration of the treatment was 74.04 ± 54 months. 46 of the subjects were male (63.01%). The complete description of the cardiovascular risk factors appears in Table The factors related to hypertension according to ABPM were analysed. In the group with arterial hypertension in ABPM there existed significant differences regarding age, overweight, dyslipidemia, pulse wave velocity, established cardiovascular disease and high/very high cardiovascular risk. No relationship was observed between TKI and HT, although it was identified a statistical trend with nilotinib Table .Table 2A multivariate analysis was carried out, considering those variables with a p < 0.20. The variables which had influence over ABPM ≥ 130/80 mmHg were overweight, dyslipidemia, alcohol use, high pulse wave velocity and high cardiovascular risk (Table 26 (61.40%) and a second one with patients who had received nilotinib21 (38.60%). The average duration of the treatment was 85.31 ± 56.58 months in the first group and 42.73 ± 33.66 months in the second. Most of the patients developed hypertension after starting treatment (69.2%). Specifically, by treatment groups, 53.85% of the patients in the imatinib + dasatinib treatment group developed hypertension after the initiation of TKI treatment, while in the nilotinib group, the number increased to 84.62% of the patients. There were no statistically significant differences between the onset of TKI and the development of hypertension between the two groups, although there was a statistical trend. 96.15% of hypertensive patients were taking antihypertensive drugs. The mean number of drugs was 1.35 ± 0.98 drugs per patient. Table For a deeper analysis of the factors related to blood pressure control and TKI, it was decided to only include those patients who had received a single drug during their oncological history. Out of the 73 initial patients, the sample was reduced to 57: imatinib 26 45.6%), nilotinib 22 (38.6%) and dasatinib 9 (15.8%). They were divided into two groups: a first group with patients who had been treated with imatinib and dasatinib5.6%, nil27. The increase in survival rate has been accompanied by a higher incidence of cardiovascular disease, produced by the presence of CVRF and cardiometabolic toxic effects of the very TKI. The cardiovascular toxic effects produced by the TKI can be explained due to the fact that the inhibition of the tyrosine kinase BCR-ABL1 is not selective, thus being able to also affect other kinases, including those which act on the vascular biology10, such as the receptors of the vascular endothelial growth factor (VEGF) 1 to 3, TIE-2, receptors A and B derived from platelet growth (PDGFRAα/β) and fibroblast growth factor receptors (FGFR) 1 to 428.With the development of the different generations of tyrosine kinase inhibitors, CML has entirely changed its prognosis, evolving from a fatal disease in a few months to a chronic pathology, with a life expectancy similar to that of the general population8. Dasatinib presents a non-haematological safety profile similar to imatinib, except for the development of pleural effusion29. There are contradictory data regarding the production of pulmonary hypertension31. Nilotinib has been related to the development of dyslipidemia, coronary disease, cerebrovascular disease and peripheral arterial occlusive disease. It has not been related to thromboembolic disease32. No cardiovascular complications with bosutinib have been described. Ponatinib is related to the apparition of hypertension, venous thromboembolic and arterial disease, which can rapidly develop after exposure to the drug33.Knowledge of the TKI cardiovascular profile is paramount in order to attain the most favourable treatment for these patients. Imatinib presents a favourable metabolic and vascular profile. Although at the beginning of its development it was suggested that it could cause cardiomyopathy, this suspicion was never confirmed afterwards. It has been observed a lower incidence of CVD with imatinib compared to nilotinib16. It has been described that ponatinib inhibits VEGFR, therefore producing a decrease of the angiogenesis, vascular rarefaction, lower production of nitric oxide and an increase in endothelin. No increase of HT incidence has been described in patients treated with imatinib, dasatinib or nilotinib.Regarding HT as a cardiovascular risk factor in patients with CML, it has only been clearly related to the use of ponatinib12. In Spain, the prevalence of HT in the adult population fluctuates between 33.3% and 42.6%34, 13.8% of diabetes mellitus35, 50.5% dyslipidemia36, 39.3% overweight and 21.6% obesity37. The percentage of patients with high blood pressure and overweight in our population is higher than the national average, with similar results with respect to the rest of CVRF.As per our study, the population included has a mean age and male sex prevalence similar to that described in other series of patients with CML40, being statistically significant the results for age (uncontrolled blood pressure patients are significantly older), overweight , dyslipidemia, alcohol use, pulse wave velocity  and established cardiovascular disease. Besides, patients with uncontrolled blood pressure had a higher cardiovascular risk. The long-term analysis of the ENESTnd  study revealed that the CVR calculation according to the Framingham Risk Score predicted the development of CVE during treatment with nilotinib42. These data, together with the results of our study, would make us carry out a stricter monitoring and tighter control of the CVRF in those patients with worse blood pressure control.Regarding the factors associated to hypertension in ABPM, they are similar to those of the general populationRegarding the analysis in order to evaluate the relationship between arterial hypertension in ABPM and TKI, it was decided to remove the patients who had been treated with two or more types of TKI during the evolution of the illness. Out of the 73 initial patients, the sample was reduced to 57. Most patients developed hypertension after initiating treatment with TKI (69.2%). Although there were no significant differences between the two groups, there was a trend in the nilotinib group. There were no differences between the number and class of antihypertensive drugs in the two groups. The statistical analysis showed a trend towards relevance in the prevalence of hypertension and ABPM (BP ≥ 130/80 mmHg) in those patients under treatment with nilotinib compared to those who were not. Statistically significant differences were found between the values of clinical diastolic blood pressure, systolic blood pressure in the 24 h period and systolic blood pressure in the daytime period. Patients in treatment with nilotinib presented worse blood pressure control in ABPM than the patients in the group with imatinib/dasatinib, showing a higher incidence of cardiovascular events.43 with higher levels of inflammatory cytokines, TNF-alpha and IL-6, as well as an increase in expression of proatherogenic endothelial adhesion molecules , which could contribute to the atherosclerotic process. The results of our study, in which patients treated with nilotinib presented a worse control of blood pressure in comparison with those treated with imatinib and dasatinib, make us consider the hypothesis that hypertension could also be involved in the development of the atherosclerotic mechanism affecting those patients treated with nilotinib44.Nilotinib produces dyslipidemia in 50% of the subjects treated, besides potentially generating ischemic cardiopathy and cerebrovascular disease. However, the mechanism through which nilotinib produces CVE is not well known. It has been observed that the patients treated with nilotinib present a higher inflammatory state than the patients treated with imatinib and dasatinib, due to an increased level of low density lipoproteins (c-LDL), which could lead to a pro-oxidative and pro-inflammatory stateWe are aware of the limitations of our work since it consists of an observational uncontrolled study. Besides, we are dealing with a rare disease, which determines the small size of the sample. Nevertheless, this is a pioneering study in the field of cardiovascular risk in CML, and we believe that it serves as a reference for further studies.As far as we know, this is the first study analysing clinical BP and 24-h ABPM in patients with CML treated with TKI. It has been observed that our population presents a higher prevalence of HT than the national average of the general population. Besides, those patients treated with nilotinib showed a higher percentage of patients with uncontrolled blood pressure than the group with imatinib and dasatinib. This leads us to consider the hypothesis that uncontrolled hypertension could be involved in the pro-atherogenic mechanism of nilotinib underlying the development of cardiovascular disease in those patients. 24-h ABPM has proved useful in order to improve the diagnose and treatment of HT in patients under TKI, especially for those treated with nilotinib and ponatinib. It can also help clarifying the pro-atherogenic mechanisms of the TKI.


The results of the present study suggest that the severity of alopecia areata may be associated with an increased risk of atherosclerosis.Alopecia areata is an autoimmune, inflammatory form of non-scarring hair loss that may affect any hair-bearing area. Recently, an increased risk of cardiovascular disorders has been described in patients with alopecia areata. The aim of the study was to evaluate the serum concentrations of proinflammatory proteins associated with atherosclerosis , and cardiovascular risk  in patients with alopecia areata without symptoms or prior cardiovascular disease in comparison with healthy controls. Sixty otherwise healthy patients with alopecia areata and twenty control subjects matched for age, gender, and body mass index (BMI) were enrolled in the study. No significant differences in the serum levels of MPO, IL1RL1, CCL4, CCL7, SORT1, and GDF15 were detected between patients with alopecia areata and healthy controls. A positive correlation was found between the serum concentration of CCL7 and the severity of alopecia areata (r = 0.281,  Numerous systemic conditions are associated with future cardiovascular events. Well-established risk factors for the development of cardiovascular diseases include diabetes, hypertension, dyslipidemia, and a positive family history as well as non-independent risk variables, such as smoking and being overweight. Chronic inflammation was also postulated to play an important role in the development and propagation of cardiovascular conditions .Alopecia areata is an autoimmune type of non-scarring hair loss . The preAlopecia areata has been considered as an organ-specific disorder limited to the hair follicles. However, numerous studies indicate that alopecia areata is associated with a systemic immune activation and the dysregulation of multiple proinflammatory cytokines, including Interleukin 1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) . It has Numerous novel proinflammatory proteins are associated with atherosclerosis and cardiovascular risk, including chemokine C-C motif ligand 4 (CCL4), chemokine C-C motif ligand 7 (CCL7), sortilin (SORT1), myeloperoxidase (MPO), interleukin 1 receptor-like 1 (IL1RL1), and growth differentiation factor 15 (GDF15) , may sugThe aim of the study was to evaluate the serum concentrations of proinflammatory proteins associated with atherosclerosis  and cardiovascular risk  in patients with alopecia areata without symptoms or prior cardiovascular disease in comparison with healthy controls.Patients diagnosed with alopecia areata (41 women and 19 men) who consulted in our department between March 2021 and May 2021 were screened for inclusion in this study. The following inclusion criteria were determined: patients aged 18 years and above diagnosed with alopecia areata. Exclusion criteria were: symptoms of cardiovascular disease, autoimmune diseases other than alopecia areata, malignancy, pregnancy, breastfeeding, chronic coronary artery disease, a history of acute coronary syndrome or coronary revascularization, heart failure with reduced ejection fraction, a cardiac condition requiring surgery, a history of stroke, a transient ischemic attack or vascular revascularization, severe grade II or III arterial hypertension, diabetes, and dyslipidemia. The control group comprised healthy individuals matched for age, gender, and body mass index (BMI) with the same exclusion criteria.2 (m) [Demographic data and clinical variables, such as age, gender, smoking, a family history of cardiovascular disease, weight, and height, were collected in all individuals. The BMI was calculated as weight (kg)/height2 (m) . Additio2 (m) . Subsequ2 (m) .The serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL cholesterol) cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), triglycerides, and fasting glucose were measured in both groups.Venous blood was collected using a 19G needle and centrifuged to obtain the serum, which was stored at −80 °C. The serum concentrations of MPO, IL1RL1, CCL4, CCL7, SORT1, and GDF15 were measured using a commercially available ELISA kit , according to the manufacturer’s instructions.p < 0.05 were considered statistically significant.The Shapiro–Wilk test was used to evaluate data for the normality of distribution. Normally distributed variables were presented as the mean ± standard deviation (SD). Non-normally distributed variables were shown as the median and interquartile range (IQR). Categorical data were compared with the chi-squared test and presented as a number of cases and percentages. The Student’s t-test and the Mann–Whitney U test were used to analyze parametric and nonparametric continuous variables, respectively. The correlation coefficient Spearman’s rank test was used to assess possible linear associations between two continuous variables. To compare the variables according to the disease activity, one-way ANOVA was used to analyze normally distributed variables and the Kruskal–Wallis test was used for variables that were not normally distributed. The values of All statistical analyses were performed with STATISTICA 13.1 .The study protocol conformed to the principles of the World Medical Association’s Declaration of Helsinki and was approved by the Medical University of Warsaw Review Board for Ethics in Human Research (KB/142/2020). Written informed consent was obtained from all participants.Sixty patients with alopecia areata and twenty control subjects were enrolled in the study. The groups did not differ with respect to age, sex distribution, and BMI. No differences were revealed as regards smoking, a family history of cardiovascular diseases, lipid profile, and fasting glucose. No significant differences in the serum concentrations of MPO, IL1RL1, CCL4, CCL7, SORT1, and GDF15 were detected between patients with alopecia areata and healthy controls .p = 0.03) (p < 0.0001)  A. In add 0.0001) B.The comparison between patients with a SALT score < 50% and healthy subjects revealed no significant differences in the serum levels of various atherosclerosis and cardiovascular markers .Moreover, no significant differences were observed between patients with a SALT score ≥ 50% and the healthy controls .No significant differences in the serum levels of MPO, IL1RL1, CCL4, CCL7, SORT1, and GDF15 were present between patients with active, stable, and remitting alopecia areata. However, a decreased serum level of HDL cholesterol was identified in patients with active and stable alopecia areata compared to individuals with remitting hair loss .Alopecia areata is an autoimmune inflammatory condition. Thus, it was hypothesized that it might be associated with an increased risk of cardiovascular disorders . HoweverSeveral biomarkers have been identified as useful in the diagnosis, management, and prognostic stratification of patients with cardiovascular diseases. Only a limited number of studies have been published as regards cardiovascular biomarkers in patients with alopecia areata to date. Troponin I is an important marker of cardiomyocyte injury. However, it may be also elevated in individuals with subclinical cardiac involvement. Wang et al.  reportedCCL7, also known as monocyte chemotactic protein-3, belongs to the monocyte chemotactic protein subfamily of C-C chemokines. It is a potent chemoattractant for a variety of leukocytes, including monocytes, eosinophils, basophils, dendritic cells, natural killer cells, and activated T lymphocytes . The rolGDF15 belongs to the transforming growth factor-β (TGF-β) cytokine superfamily, which has been shown to regulate the inflammatory and angiogenesis pathways. GDF-15 exhibits various and even contradictory functions under various circumstances, including proapoptotic/antiapoptotic, proangiogenetic/antiangiogenetic, and proinflammatory/anti-inflammatory properties . It has The primary limitation of our study is a relatively small sample size, leading to the lack of statistical power to show the differences in the serum concentrations of proinflammatory markers between patients with alopecia areata and the controls. For example, patients with alopecia areata were characterized by nominally higher concentrations of CCL4, compared to the controls, which might become significant in a larger cohort. Finally, the study did not show a direct association between the serum concentrations of proinflammatory biomarkers and cardiovascular events in patients with alopecia areata, which would require a long-term observation period . Altogether, the presented results are hypothesis generating and need to be verified in further trials.The results of the present study suggest that the severity of alopecia areata may be associated with an increased risk of atherosclerosis. Further studies are necessary to evaluate atherosclerosis and cardiovascular risk in patients with alopecia areata.


Evidências demonstram que a tradicional avaliação casual da PA no consultório médico não é, na maioria dos casos, a melhor ferramenta para o diagnóstico, assim como para a tomada de decisão clínica em indivíduos com PA elevada ou mesmo no seguimento do tratamento da HA.        –,,,Recentes diretrizes têm preconizado o uso mais amplo das medidas ambulatoriais e residenciais da PA na avaliação inicial de pacientes com PA elevada, assim como no acompanhamento de pacientes hipertensos.        ,Na literatura e prática médica clínica internacional, são descritas duas modalidades de avaliação da PA fora do consultório: a monitorização ambulatorial da pressão arterial (MAPA), em que o equipamento é programado para realizar medidas automáticas em intervalos programados nas 24 horas; e a medição domiciliar da PA, em que cada indivíduo realiza as medidas livremente em horários determinados ou não, e os valores são registrados manualmente. No Brasil, embora realizemos a MAPA como em demais países, a medição domiciliar da PA é usualmente feita de duas maneiras distintas. Uma delas é a forma não estruturada, que denominamos de automedida da PA (AMPA), e a outra é uma forma peculiar de registro, comum em nosso meio, que é a medida residencial da PA (MRPA), em que equipamentos semiautomáticos armazenam as medições e, segundo protocolo estabelecido em diretrizes, são capazes de emitir laudos estruturados.        Esta edição dos Arquivos Brasileiros de Cardiologia traz o artigo original “Hipertensos Tratados e Avaliados por Telemonitoramento Residencial da Pressão Arterial. Estudo TeleMRPA”, de Barroso et al.,        ,Embora não existam estudos comparativos entre AMPA e MRPA, estima-se que o método estruturado (MRPA) seja mais reprodutível, embora a avaliação livre (AMPA) tenha os benefícios do melhor custo e possibilidade de ser realizado habitual e frequentemente como aliado do seguimento.        Um estudo realizado em Ohasama, no Japão, revelou originalmente que a PA domiciliar tinha maior valor preditivo para mortalidade do que a PA casual de consultório na população geral.        ,Considerando a maior precisão diagnóstica e sua capacidade prognóstica, a PA residencial desempenha também um importante papel no seguimento do tratamento da HA, pois é superior à PA casual em condições como o efeito do avental branco e a hipertensão não controlada mascarada em pacientes tratados, assim como na titulação de fármacos.        Systolic Blood Pressure Intervention Trial (SPRINT) utilizou uma metodologia que incluía um período de repouso prévio e adotou a média de múltiplas leituras em cada visita. O protocolo incluía ainda uso de manguito de tamanho apropriado, posicionamento adequado do paciente, apoio para as costas, pés apoiados no chão, braço apoiado no nível do coração e manguito instalado em braço nu, com as medições realizadas na forma de automedições sob vigilância dos pesquisadores.Diante de tantas restrições à medida casual e na tentativa de apurar a acurácia da medição da PA no consultório, o estudo         2, observou-se que os valores médios de PA sistólica foram 6,6 mmHg  e de PA diastólica, 4,4 mmHg  maiores que na medida casual. Também, comparativamente, a taxa de controle da HA foi de 61,3% pela MRPA, sendo este percentual maior que o encontrado na medida casual . O estudo demonstrou ainda uma prevalência de efeito avental branco de 15,4% e de hipertensão mascarada não controlada de 11,1% da população avaliada.No estudo de Barroso et al.,        Uma publicação anterior preliminar do mesmo banco de dados, envolvendo 1.273 participantes com pré-hipertensão e HA estágio 1, havia encontrado hipertensão do avental branco em 21,9% e hipertensão mascarada em 11,4%, além de discordância com o diagnóstico de HA por PA casual em 33,3% pacientes        Diante das evidências da importância do monitoramento da PA, é necessário refletir sobre os emergentes dispositivos de medição da PA fora do consultório, muitos dos quais são vestíveis, ofertando possibilidades de ilimitados registros, além de armazenamento e de análises digitais. Novos monitores digitais, agora disponíveis até mesmo sem a necessidade do uso de braçadeiras, oferecem maior comodidade e já vêm sendo empregados em ensaios clínicos randomizados, embora muitos ainda estejam em processo de validação. Além disso, o advento da inteligência artificial amplia as possibilidades de análise desse grande número de registros de PA fornecidos por tais dispositivos, que, em conjunto com outras variáveis, propiciarão uma verdadeira revolução do conhecimento acerca da PA em um futuro muito próximo.                 ,Hypertension (HTN) is the leading preventable risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide.            ,Accuracy in blood pressure (BP) measurement is essential for the diagnosis, risk stratification, and adequate treatment of HTN. The evidence shows that the traditional casual assessment of BP in the doctor’s office is not, in most cases, the best tool for diagnosis or clinical decision-making in individuals with high BP, or even for monitoring response to antihypertensive treatment.            –,,,Recent guidelines have advocated the broader use of outpatient and home BP measurements in the initial assessment of patients with high BP, as well as in the follow-up of patients with known HTN.            ,In the literature and international clinical medical practice, two broad types of out-of-office BP assessment are described: ambulatory blood pressure monitoring (ABPM), in which the device is programmed to obtain automatic measurements at preset intervals over a 24-hour period; and home BP measurement, in which patients themselves obtain measurements at predetermined or random times and BP values are manually recorded. In Brazil, although ABPM is done as in other countries, household BP measurement is usually done in two different ways: one unstructured, which we call self-measurement of BP (SMBP), and a peculiar form of recording quite common in our country, home blood pressure monitoring (HBPM), based on the use of semi-automatic sphygmomanometers which stores measurements and, according to a protocol defined in clinical guidelines, must be capable of issuing structured reports.            This issue of ABC Cardiol carries the original article “Treated Hypertensive Patients Assessed by Home Blood Pressure Telemonitoring. TeleMRPA Study”, by Barroso et al.,            ,Although there are no head-to-head comparisons of SMBP and HBPM, the structured method (HBPM) is believed to be more reproducible, although freeform measurement (SMBP) is less costly and can be performed habitually and frequently as an adjunct to follow-up.            A study carried out in Ohasama, Japan, originally revealed that home BP had greater predictive value for mortality than casual BP in the general population.            ,In view of its greater diagnostic accuracy and prognostic capacity, home BP measurement also plays an important role in the follow-up of antihypertensive treatment, as it is superior to casual BP in conditions such as white coat hypertension and masked uncontrolled hypertension in treated patients, as well as for monitoring response to drug titration.            Systolic Blood Pressure Intervention Trial (SPRINT) used a method that included a rest period before each measurement and averaged multiple readings obtained at each visit for analysis. The protocol also included the use of an appropriately sized cuff, proper patient positioning, back support, feet flat on the floor, arm supported at heart level and cuff placed on a bare arm, with self-measurement performed under the supervision of the investigators.Given these many restrictions on casual measurement and in an attempt to ascertain the accuracy of office BP measurement, the             2), mean systolic BP values were 6.6 mmHg (p<0.001) higher and diastolic BP 4.4 mmHg higher (p<0.001) than on casual measurement. Comparatively, the prevalence of controlled HTN was 61.3% by HBPM versus 57.0% by casual BP measurement (p<0.001). The study also showed a 15.4% prevalence of the white coat effect and 11.1% prevalence of uncontrolled masked hypertension in the evaluated population.In the study by Barroso et al.,            A previously published interim analysis of the same database, involving 1273 participants with prehypertension and stage 1 HTN, had found white coat hypertension in 21.9% and masked hypertension in 11.4%, as well as disagreement with the diagnosis of hypertension by casual BP measurement in 33.3% of patients.            By revealing the reality of HBPM in our country, this study makes an important contribution to the body of evidence that demonstrates the benefits of this method in evaluating the response to HTN treatment, highlighting the need for broader use of this tool in the follow-up of hypertensive patients.            Given the evidence of the importance of monitoring of BP, it is necessary to reflect on the emerging devices of BP measurement outside the office, many of which are wearable, providing the possibility of unlimited recording, storage, and digital analysis. New digital monitors, which now even dispense the use of inflatable armbands or cuffs, offer greater convenience, and although many have yet to be validated, these are already being used in randomized clinical trials. In addition, the advent of artificial intelligence expands the possibilities of analysis of the enormous body of BP records provided by such devices, which, together with other variables, should bring about a true revolution in knowledge about HTN in the very near future.


Conclusions: We detected no significant differences in cIMR between KD patients and controls that could confirm any evidence that KD predisposes patients to a subsequent general arteriopathy. Our results, however, need to be interpreted in the light of the low number of study participants.Background: Kawasaki Disease (KD) is a generalized vasculitis in childhood with possible long-term impact on cardiovascular health besides the presence of coronary artery lesions. Standard vascular parameters such as carotid intima–media thickness (cIMT) have not been established as reliable markers of vascular anomalies after KD. The carotid intima–media roughness (cIMR) representing carotid intimal surface structure is considered a promising surrogate marker for predicting cardiovascular risk even beyond cIMT. We therefore measured cIMR in patients with a history of KD in comparison to healthy controls to investigate whether KD itself and/or KD key clinical aspects are associated with cIMR alterations in the long-term. Methods: We assessed cIMR in this case-control study ; 13.4 (7.5); 36 controls, mean age 12.1 (5.3)) approximately matched by sex and age. Different clinical outcomes such as the coronary artery status and acute phase inflammation data were analyzed in association with cIMR values. Results: When comparing all patients with KD to healthy controls, we detected no significant difference in cIMR. None of the clinical parameters indicating the disease severity, such as the persistence of coronary artery aneurysm, were significantly associated with our cIMR values. However, according to our marginally significant findings ( Other t in 2018 , prolong in 2018 ,8 and peVascular inflammation attributable to KD can also influence the carotid’s intimal and media layers. In patients with CAA, carotid intima–media thickness (cIMT)—measured as the distance between the lumen–intima interface and media–adventitia boundary of the common carotid artery—was found to be thicker than in KD patients without coronary artery lesions ; howeverPatients with KD were recruited and examined at the paediatric cardiology department at Ludwig Maximilian University of Munich. All patients’ KD diagnoses had been verified following the American Heart Association (AHA) guidelines. The Z-score of each coronary artery was calculated according to Dallaire et al. , with a 2, blood pressure < 97 th percentile and normal echocardiography.Healthy controls were recruited among the patients′ personal contacts. The patients or parents were asked to present in a fasting state and bring along a sex- and age-identical friend or sibling to the appointment. We took a detailed medical history and carried out physical examinations, ECGs, and echocardiography in all patients and controls. The following applies to the healthy control children: absence of any cardiac, infectious, oncologic, rheumatic, neurologic or endocrine disease  to eliminate any impact on the cardiovascular system. Further inclusion criteria were: normal resting ECG (12 leads), body mass index (BMI) < 30 kg/mAfter at least 10 min in resting state, blood tests and blood pressure were taken and the cIMR ultrasound examination was performed by a pediatric cardiologist, experienced in cIMT measurement.CIMR was determined via an ECG-triggered sonographic examination. An ultrasound device from Philips (IE33) equipped with a linear transducer L11-3) was used for the measurement. All examinations were carried out according to a standardized protocol for right and left common carotid artery. In a supine position, patients turned their head 30 degrees to the opposite side to create optimal visual conditions. The common carotid artery (CCA) was visualized in the longitudinal plane, and the intima–media layer was visible as typical double lines. Two cine-loops in B-mode were recorded on each side, proximal to the carotid bulb. The first possible 10 mm section proximal to the carotid bulb of sufficient image quality was selected for analysis. To measure the CCA’s far wall, we relied on the end-diastolic and end-systolic phase of the heart cycle, defined via the top of the QRS-complex and the end of the T-wave, in order to minimize intrabeat variability. Dynamic Artery Analysis (DYARA) software was used to automatically identify the IM layers. This software has been described and validated in adult and pediatric cohorts -3 was us,15,16. TThe regression line of all cIMT values within the 10-mm segment was calculated, and the respective regression line’s deviation was determined. CIMR was calculated as the arithmetic mean of the deviation from the regression line, according to the ISO definition . The higher this deviation, the greater the roughness  Figure .t-test . Furthermore, to evaluate differences between end-diastolic and end-systolic cIMR measurements, the paired-samples t-test was applied. For correlations between clinical parameters  and cIMR, Pearson’s coefficient was assessed. The correlation analyses were conducted for all study participants together as well as stratified by KD and control patients.Statistical analysis was performed with the program R (Version R-4.0.2). Data are indicated as the mean and standard deviation (SD) unless otherwise specified. To check the homogeneity of sex distribution between patients with KD and controls, the χ2 test was applied. For the participants’ clinical characteristics , blood pressure and blood lipids determined on the day of presentation) and cIMR measurements (end-diastolic and end-systolic), we assessed differences at baseline per groups via Welch′s Multiple linear regression analysis adjusted for age, sex, weight and height was performed to study the association between KD (absence of disease (control group) = reference) and cIMR measurements. In relation to the coronary artery lesion, patients were subdivided into the following three groups: A: never had CAA, B: CAA only during acute phase of KD and C: persistent CAA. In one regression model, each group  was compared to the healthy control group . In another regression model, we compared group A to group B + C .In the second step, we evaluated the associations between clinical KD acute phase parameters and the end-diastolic and end-systolic cIMR. The following acute phase variables were used as predictors in a regression model (with either end-diastolic or end-systolic cIMR as the dependent variable): aneurysm status (groups B + C vs. group A), IVIG non-responder, duration of fever (days), C-reactive protein (CRP) levels, thrombocytes, leucocytes and hemoglobin. As before, we adjusted for age, sex, weight and height (measured at the time of our study).p-value of < 0.05 was considered significant.In all analyses, a A total of 44 patients with KD  in years: 13.4 (7.5)) and 36 healthy controls ) were included in this investigation. One patient  had to be excluded from the study due to poor image quality, as intima–media boundaries were not precise enough for analysis.2: KD 18.2 (3.7) vs. controls 18.1 (3.1). Furthermore, our assessments of blood pressure hemodynamics  in mmHg KD 117/71 (13.6/10.0) vs. controls 113/68 (8.2/9.2)) and blood–lipid values  in mg/dL: KD 104.7 (25.5) vs. controls 104(26.2)) revealed no significant differences between the two groups. A detailed comparison of baseline characteristics in patients with KD and controls is provided in The examination was carried out, on average, 8.1 years after the acute phase of KD (range: 7 months to 26.9 years). Patients with KD and controls did not differ significantly in age, sex or BMI (mean BMI (SD) in kg/mTwo loops per carotid artery side were analyzed and used to calculate mean cIMR values. Mean cIMR was calculated as the mean of all four recorded loops of both carotid arteries. For one patient, only one loop per side (left/right) could be recorded instead of two; the mean cIMR values were calculated from the available measurements. For one control person, one of the two end-diastolic cIMR values recorded on the right carotid artery had to be removed due to a measurement error. For this control person, the mean end-diastolic cIMR was thus calculated from two loops on the left and one on the right side. We also calculated end-systolic and end-diastolic cIMR values in each study participant.p-value = 0.044).No statistically significant difference appeared after comparing right-sided and left-sided cIMR values from all study participants together . However, we did observe that the mean end-diastolic cIMRs were significantly higher than the end-systolic values when taking all study participants together  (CI of the difference between end-diastolic and end-systolic cIMR), p-value = 0.012) and when taking all study participants together . However, due to the high number of tests performed overall, this result should be regarded with caution (we did not correct for multiple testing). In the patient group, VLDL (mg/dL) did not correlate significantly with end-diastolic cIMR. The full correlation results are available upon request.BMI, blood pressure and blood lipid values mostly did not correlate significantly with our cIMR measurements, except for VLDL (mg/dL), which correlated significantly with end-diastolic cIMR in the healthy control group  (CI of the difference between cIMR in patients and controls); p-value = 0.590) nor end-systolic cIMR ) (CI of the difference between cIMR in patients and controls); p-value = 0.886) differed significantly between groups . Due to the five persons with unknown CAA status, the number of KD patients in the analyses was reduced to 39 persons. Patients with KD with evidence of coronary artery involvement (Group B and C) had slightly higher mean end-systolic cIMR values than patients in Group A . For end-diastolic cIMR values, there was no clear tendency . However, according to the multiple linear regression analyses, the group differences were not statistically significant for either end-systolic or end-diastolic values see .Multiple linear regressions showed that acute phase parameters such as being a non-responder to intravenous immunoglobulins (IVIG), duration of fever (days), CRP levels, thrombocytes, leucocytes and hemoglobin were significantly associated with neither the end-systolic nor the end-diastolic cIMR (these data are not presented here but are available upon request). These regression analyses were limited to 29 patients with complete values for all the variables.In this study, we investigated cIMR as a potential surrogate marker for long-term vascular anomalies in children with a history of KD. To the best of our knowledge, the cIMR in children with KD has not been investigated until now. cIMR might reveal an intima–media anomaly more thoroughly than the thickness alone. However, we found that our KD patients’ cIMR—including both the systolic and diastolic values— failed to differ significantly from our healthy controls’ cIMR. Furthermore, 95.6% of all cIMR values of the KD patients concurred with published cIMR normative data for children ; they weFollowing the characteristics of cIMT, we found that cIMR measured during the heart cycle’s diastole was significantly higher than end-systolic cIMR. As assumed for cIMT, the most probable reason for this is the lumen diameter’s physiological expansion during systole, causing the artery’s intima–media complex to become thinner. A study from 2017 even implicates that this effect is clearly stronger in childhood than in adulthood, as they reported a cIMT increase by 8.8% (38 µm) in four-year-olds compared to only 3.8% 18 µm) in adults [ µm in adAHA guidelines recommend the acquisition of end-diastolic cIMT values for cardiovascular risk assessment . The inc17. In one case report, the cIMR in a 12-year-old boy with type 1 diabetes diminished during consequent blood glucose control from 0.048 mm to 0.036 mm  [cIMT studies in adults showed that atherosclerotic anomalies such as plaque formation or a granulated intima–media layer are linked to cardiovascular risk factors and transient ischemic lesions or stroke, and may be a major criterion for cardiovascular events ,23,24,25s: 8.2%) . Patients: 8.2%) . cIMR miApart from its effect on the coronary arteries, the evidence of KD’s long-term effect on the vascular system is inconsistent. Dalla Pozza et al.  detectedIn this study, we investigated the cIMR in patients with a history of KD in comparison to healthy controls. By recruiting groups whose anthropometric and laboratory data are similar—that is, our two groups did not differ significantly in sex, age, weight, height and laboratory data—we restricted influencing factors to a minimum. However, our data should be interpreted in the light of the low number of study participants. We had only a few patients with coronary artery aneurysms, thus weakening our statistical subgroup analysis. Furthermore, the broad range of the time since the KD diagnosis must also be accounted for. We were unable to compare our results within a clinical context as there are no cIMR normative values applying to children < 8 years, or even to adults, available.We assessed the systolic and diastolic cIMR, which differed significantly, indicating that, in future cIMR studies, clear reference to heart cycle-specific values may be useful. However, the differences are small and should be confirmed by studies including a larger sample size.In this study, cIMR did not differ in either patients with a KD history or in those with KD and a severe cardiovascular phenotype, such as persistent CAA. Therefore, our results do not support the hypothesis of a generally higher long-term cardiovascular risk in patients with KD. Nevertheless, more investigations are needed with larger study populations that investigate other known vascular parameters in association with cIMR. Nevertheless, CIMR seems to be a promising parameter in the long-term assessment of atherogenesis.


Background: Cardiovascular disease (CVD) is associated with morbidity and mortality in patients with type 2 diabetes mellitus (T2D). However, the role of serum uric acid as a risk factor for developing cardiovascular disease is controversial. This study investigated whether uric acid variability was associated with new-onset symptomatic CVD in patients with T2D, requiring percutaneous coronary intervention.Methods: A total of 1,071 patients were enrolled in this retrospective cross-sectional study after propensity score matching. Patients with T2D and new-onset symptomatic CVD who received percutaneous coronary intervention for the first time, and with at least three consecutive 6-monthly measurements of serum uric acid were recruited from Severance Hospital between January 2015 and December 2019. Uric acid variability was measured by average successive variability (ASV) and analyzed to evaluate a possible correlation with the risk of developing CVD.Results: The patients were divided into quartiles based on the uric acid variability. Patients in the highest quartile were older and presented lower renal function and a higher mortality from CVD. There was a linear association between a high uric acid variability and the development of CVD. Compared to the lowest quartile, patients in the higher quartiles had a higher risk of CVD .Conclusion: High uric acid variability is independently associated with an increased risk of new-onset symptomatic CVD requiring percutaneous coronary intervention in patients with T2D. Thus, maintaining serum uric acid in a narrow range by prescribing effective medications is essential to prevent new-onset CVD in patients with T2D. Nonetheless, the potential use of uric acid variability as a predictive marker of CVD in patients with T2D needs further validation. Type 2 diabetes mellitus (T2D) is a major risk factor for developing cardiovascular diseases (CVD)  and is cUric acid is an antioxidant, particularly in the extracellular environment . HoweverThe concept of long-term variability, defined as the variability in clinical measures outside the recommended range, is currently a well-accepted. Long-term glycemic variability correlates with an increased risk of macro- and microvascular complications in patients with T2D  and incrThis study investigated whether uric acid variability can predict the risk of development of new-onset symptomatic CVD in patients with T2D. By determining the importance of uric acid variability relative to CVD with view to provide evidence-based guidance to clinicians for preventing CVD by measuring and managing SUA levels in patients with T2D.This retrospective cross-sectional observational study included patients, aged ≥19 years, with T2D and at least three consecutive measurements of 6-montly SUA as well as simultaneously evaluated blood and urinary markers at the Severance Hospital, between January 2015 and December 2019. T2D was defined as follows: (1) the use of insulin or oral hypoglycemic agents or (2) HbA1c ≥ 6.5% (47.5 mmol/mol) according to the Practical Guidelines of the Korean Diabetes Association . The exc2). Cigarette smoking was self-reported, and classified as ever smokers or not. Hypertension was defined as systolic blood pressure of ≥140 mmHg or diastolic blood pressure of ≥90 mmHg, or the current use of antihypertensive medications according to 2005 Guidelines of the American Heart Association and the National Heart, Lung, and Blood Institute for Asian populations  was calculated as body weight divided by height squared  was used because of the non-normal distribution of SUA levels. ASV was defined as the average of absolute difference between successive values and was calculated using the formula |FPG and BMI .Following an overnight fast (≥8 h), morning spot urine samples were collected, and albumin, protein, and creatinine levels were quantified. Blood samples were collected, and the complete blood count, lipid profile, fasting glucose, insulin, C-peptide, HbA1c, and creatinine were measured. HbA1c was measured by immunoassay using an Integra 800 CTS analyzer . Serum glucose and creatinine were quantified using a Hitachi 7,600 analyzer (Hitachi Ltd.). Serum creatinine levels were determined using the compensated kinetic Jaffe method , in which creatinine concentration was standardized to isotope dilution-mass spectrometry. Low-density lipoprotein cholesterol (LDL-C) levels were calculated using the Friedewald equation without actual LDL-C measurements ; howeverpost-hoc analyses using Bonferroni procedure for ANOVA and Dunn procedure for Kruskal-Wallis test. The normality of continuous variables was evaluated using the Shapiro-Wilk test. Correlations between ASV and other parameters were evaluated using Pearson's correlation analysis. The independent association between ASV and CVD after adjusting for age, sex, baseline SUA, hypertension, statin use, eGFR, HbA1c, and duration of diabetes was evaluated by multiple logistic regression analysis. Survival was assessed using the Kaplan-Meier methods and Cox proportional hazard regression model and was compared using the log-rank test. To assess the predictive accuracy of uric acid variability by ASV for CVD adjusted by multiple variables, receiver operating characteristic (ROC) curves (AUC) was calculated. Differences between ROC curves were evaluated according to Delong et al.  for non-normally distributed continuous variables. Categorical variables were expressed as numbers and percentages. The baseline characteristics of the CVD group and non-CVD group were compared based on the quartiles of uric acid variability. Participants' characteristics according to quartiles of baseline uric acid variability were analyzed using one-way analysis of variance (ANOVA) or Kruskal-Wallis test to compare continuous variables, and Chi-square test to compare categorical variables, followed by g et al.  and abilg et al. . Statist2 and 5.18 ± 1.53 mg/dL, respectively. The ASV of quartiles of uric acid were 0.23 ± 0.09 (quartile 1), 0.47 ± 0.06 (quartile 2), 0.77 ± 0.13 (Quartile 3), and 1.66 ± 0.80 (Quartile 4). Patients in the highest quartile were older and presented higher baseline SUA, lower high-density lipoprotein (HDL) cholesterol, higher creatinine, lower eGFR and higher mortality from CVD and hypertension. Blood pressure, waist circumference, lipid profile, except for HDL, u-ACR, the use of angiotensin converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB), angiographic data and the prevalence of dyslipidemia and cerebrovascular disease were not significantly different across quartiles. The use of insulin and uric acid lowering agents was more common in patients in quartiles 3 and 4. In contrast, the use of metformin and statin was more common in the patient in quartiles 1 and 2. Mean fasting glucose and HbA1c were 155 mg/dL and 7.2%, respectively, but did not exhibit significant differences between the quartiles, including HOMA-β and HOMA-IR.A total of 1,071 patients  were enrolled in this study. The patients were divided into quartiles according to the uric acid variability . The meaThe ASV was positively and significantly correlated with age and creatinine levels and negatively associated with eGFR . In turnP = 0.019; quartile 4 HR = 2.89; 95% CI, 1.74–4.80; P < 0.001; n = 108, 103, and 71, respectively; P = 0.004; The association between ASV and new-onset symptomatic CVD was analyzed using logistic regression analysis . Since tP = 0.027; p for trend = 0.007; P = 0.76).During the median follow-up of 12 months, 357 patients had new-onset symptomatic CVD, of which 19 died. Kaplan-Meier curves showed a significant relationship between SUA quartiles and cumulative CVD events  is a purine derivative . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.EK and HK: conception, design, analysis, and interpretation of data, drafting and revising of manuscript, and final approval of the manuscript submitted. ML, Y-hL, B-WL, and B-SC: interpretation of data, revising of manuscript, and final approval of the manuscript submitted. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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