This study investigated the effects of modulated respiration on blood pressure and autonomic balance to develop a healthcare application system for stabilizing autonomic balance. Thirty-two participants were asked to perform self-regulated tasks with 18 different respiration sequences, and their electrocardiograms (ECG) and blood pressure were measured. Changes in cardiovascular system functions and blood pressure were compared between free-breathing and various respiration conditions. Systolic and diastolic blood pressures stabilized after individual harmonic breathing. Autonomic balance, characterized by heart rate variability, was also stabilized with brief respiration training according to harmonic frequency. Five machine-learning algorithms were used to classify the two opposing factors between the free and modulated breathing conditions. The random forest models outperformed the other classifiers in the training data of systolic blood pressure and heart rate variability. The mean areas under the curves (AUCs) were 0.82 for systolic blood pressure and 0.98 for heart rate variability. Our findings lend support that blood pressure and autonomic balance were improved by temporary harmonic frequency respiration. This study provides a self-regulated respiration system that can control and help stabilize blood pressure and autonomic balance, which would help reduce mental stress and enhance human task performance in various fields. In recent years, people have frequently been exposed to mentally stressful situations at their workplaces, in which cognitive mechanisms in the human brain simultaneously process numerous pieces of information. It is very important to control mental workload or stress while performing work or daily activities under a variety of circumstances ,7,8,9,10Many studies have found that controlling respiration alone can reduce the symptoms of major disorders , enhanceAutonomic balance and respiration have been found to be closely correlated . These aGiven this relationship, a control method can be developed whereby controlling respiration and autonomic balance could conclusively manipulate blood pressure. The primary purpose of the control is to manipulate the respiration frequency and, by doing so, manipulate the autonomic balance frequency to the same or similar frequency. With two identical frequencies, the amplitude doubles as the frequencies construct with each other. A few papers already have studied and found the optimal frequency, which is known as the “Natural Harmonic Frequency,” of the arterial baroreflex that initiates this phenomenon and its effects . The natWritten informed consent was obtained from each participant prior to the experiment. The Institutional Review Board at Sangmyung University in Seoul, Republic of Korea approved all the protocols used in this study. Thirty-two participants, sixteen women and sixteen men, with ages ranging from 23 to 32 years (mean: 26.43 years), voluntarily participated in the study; incentives of USD 40 were offered to encourage their participation. Only participants with no history of any disorders, particularly cardiovascular diseases that could have affected their heart rates, were included in this experiment. One day prior to the experiment, to minimize possible variations in cardiovascular responses, participants were prohibited from smoking and consuming alcohol or caffeine. Additionally, they were recommended to have a full night of sleep. Before the experiment, participants were informed of the experimental protocols and procedures, except its purpose.The room designed for the experiment included a chair and a screen placed in front of the chair. The participants sat on a chair during all trials of the experiment. Before the respiratory experiment, each participant was given a 5 min break to eliminate external influences on both autonomic balance and blood pressure ,30. AfteAs mentioned before, previous studies have proved that the natural harmonic frequency averages at approximately 0.1 Hz . HoweverTo help participants easily follow each breathing pattern, a video of a pump was played on the screen; the pump gage was filled and emptied according to the corresponding breathing cycle for inhalation and exhalation processes. Each participant’s blood pressure was measured before the breathing cycle; for comparison, blood pressure was also measured after the breathing cycle. Respiration (RSP) was measured with an RSP sensor, a band that goes around the participant’s chest, to observe and check if they were correctly following the breathing pattern. After each breathing cycle, a short break was provided to normalize the participants’ physiological signals. An illustration of the experimental procedure is shown in ECG signals were recorded at a 500 Hz sampling rate from Lead-I type, and the R-peaks were detected using QRS detection algorithms given by Pan and Tompkins . The R-pSuccessive RRI values in normal range were converted to a time series by resampling at 2 Hz. The resampled data were processed using a fast Fourier transformation (FFT). HRV spectra (0–0.4 Hz) were then obtained. The HRV spectrum was used to identify individual harmonic respiration frequencies and autonomic balance. An overview of the signal processing is shown in An individual’s harmonic respiration frequency was defined as the highest amplitude value of the LF band (0.04–0.15 Hz) in the HRV spectrum band (0–0.4 Hz). All respiration tasks , excluding the free respiration condition, were extracted from the LF band. The dominant amplitude in the LF band was then compared with that in the other respiratory conditions. The highest amplitude value among the respiratory conditions was determined as the individual’s harmonic respiration frequency, as shown in Zone 1: High parasympathetic/low sympathetic.Zone 2: High parasympathetic/normal sympathetic.Zone 3: High dual autonomic tone.Zone 4: High sympathetic/normal parasympathetic.Zone 5: High sympathetic/low parasympathetic.Zone 6: Normal sympathetic/low parasympathetic.Zone 7: Low sympathetic and parasympathetic.Zone 8: Low sympathetic/normal parasympathetic.The normalized HRV technique evaluates autonomic balance based on the sympathetic and parasympathetic nervous systems. The HRV spectrum was categorized into two frequency bands: the LF (0.04–0.15 Hz) and HF (0.15–0.4 Hz) bands. The power spectrum values (LF and HF) were converted into natural logarithms (assuming ln), and nine zones (zones 1–8 plus a reference zone) were created to categorize the autonomic balance  ,34,36, aRSP was measured to identify breaths per minute. During the respiration task, RSP signals were recorded at a 500 Hz sampling rate from the thoracic region. This signal was processed using the FFT, and the frequency of the dominant peak was obtained. These values were then compared for each respiratory condition. It was also used to set a standard for task performance to determine the task performance accuracy of each participant. If a subject could not concentrate on the respiration task where the respiratory data did not match the controlled respiratory rates, such data were excluded from this experiment.The ECG sensor used in the experiment was an SS29L multi-lead ECG cable  and was operated using Lead-I. The RSP sensor was a TSD201 respiration transducer (BIOPAC System Inc.), which measured the thoracic expansion and contraction. The ECG and RSP signals were recorded using an ECG 100C and RSP 100C amplifier system (BIOPAC System Inc.) and digitalized using NI-DAQ-Pad9205 (BIOPAC System Inc.) at a rate of 500 Hz. Signals were processed using an MP150 data acquisition unit, the AcKnowledge analysis software v 4.1 (BIOPAC System Inc.), and the LabVIEW 2010 software . An HEM-780  was used to measure blood pressure.α = 0.05/n); thus, α = 0.007  was used. The effect size, based on Cohen’s d (parametric), was calculated to confirm the practical significance of the findings. For Cohen’s d, standard values of 0.20, 0.50, and 0.80 for the effect size are generally regarded as small, medium, and large effects, respectively [The individual harmonic frequency of each participant was determined by comparing the HRV spectra  between the respiration tasks. To identify the effect of the breathing rate, the optimized breathing rate  was compared with other breathing conditions, including free respiration. Variations in autonomic balance and blood pressure caused by the breathing rate condition were measured. All the data were recorded before and after the respiration task. However, because the optimized breathing rate differed among participants, the personalized harmonic frequency breathing rate was compared with free breathing using SPSS 17.0 . Autonomic balance was evaluated based on nine domains . Systolic and diastolic blood pressures were measured. To compensate for multiple comparisons, Bonferroni correction was performed for the derived statistical significances ,37,38. Sectively .d) = 0.8 (large effect size). (3) α = 0.01. (4) 1 − β = 0.95. The recommended sample size was obtained at 32 from G*Power software v.3.1.9.7, and a total sample size in this experiment  was tenable to achieve acceptable statistical power.The required sample size for our experiment design was determined using G*Power software v.3.1.9.7  with the following parameters: (1) tails = two tailed test. (2) effect size  and paired t-tests were conducted. For the resonance frequency condition, systolic blood pressure in the post-task condition was significantly reduced compared with that in the pre-task condition (t(31) = 4.438, p < 0.001, Cohen’s d = 0.785, indicating a medium effect size) as shown in t(31) = 3.679, p = 0.001, Cohen’s d = 0.650, indicating a medium effect size) as shown in t(31) = 0.650, p = 0.521) or diastolic blood pressure (t(31) = 0.906, p = 0.372) of the participants.All participants had different harmonic frequencies; therefore, the free-breathing condition was used as a control for comparison. The effects of the harmonic frequency on the free-breathing cycle were compared for all participants. While the participants’ blood pressures were not within the optimal range during free respiration, the blood pressure was stabilized to the optimal range during the harmonic breathing cycle. As shown in Breathing at the harmonic frequency also stabilized the autonomic balance of the participants, as the values of autonomic balance fell within the reference zone while other respiratory cycles failed to do so. As shown in During free-breathing cycles, nearly all participants’ autonomic balances were in zones 4 and 5. These zones describe the sympathetic nervous system as highly active and parasympathetic, with little or no activity. Some participants also had autonomic balances residing in zones 2, 3, 6, and 8, but none were in the reference zone during free respiration, as shown in p > 0.05) and paired t-tests were conducted. Paired t-tests indicated that ln LF in the resonance frequency condition significantly decreased (t(31) = 10.814, p < 0.001, Cohen’s d = 1.912, indicating a high effect size) and ln HF power significantly increased relative to those of the free respiration condition (t(31) = 7.046, p < 0.001, Cohen’s d = 1.246, indicating a high effect size) as shown in The normality assumption was tenable (p > 0.05) and paired t-tests were conducted. The paired t-tests showed that the time domain parameters of cardiac activity in the resonance frequency condition were significantly higher than those in the free respiration condition: SDNN , rMSSD , and pNN50 . The mean (M) and standard deviation (SD) values were as follows: SDNN , rMSSD , and pNN50 , as shown in As for the time domain data of cardiac activity, normality assumption was tenable , implying that no significant differences were found by chance. Five machine learning algorithms (logistic regression (LR), linear discriminant analysis (LDA), decision tree (DT), random forest (RF), and linear kernel support vector machine (LSVM)) were used to classify the two opposite factors of the biomarkers. The significant features were trained using the algorithms on 32 participant datasets with five-fold cross-validation. Classification performances were compared based on the receiver operating characteristic (ROC) curve and area under the curve (AUC) derived from confusion matrix indices . Python 3.9.2  was used to conduct the classification and cross-validation. As for the Python code used, see The significant biomarkers demonstrated in this study  were classified using machine learning algorithms to develop a mobile healthcare application for harmonic respiration. Before the biomarkers were trained and classified, resampling-based permutation tests were performed to further verify that significant differences would not be observed by chance. One-thousand permutations of the group variables were randomly generated for each blood pressure and heart rate variability indicator. As shown in A respiration training system with individual harmonic frequencies was developed using Visual C++ 2013  and OpenCV 3.0.0 , as shown in The primary purpose of this study was to investigate the effect of individual harmonic breathing frequencies on blood pressure and the autonomic nervous system. The harmonic frequencies for each participant were determined using the highest LF power among the 17 respiratory conditions, and significant effects were observed. The study clearly showed that temporarily controlled respiration positively influenced blood pressure and the autonomic nervous system, controlling respiration to match the harmonic-frequency-stabilized blood pressure, whether it was high or low, to the optimal range, and the autonomic nervous system to the reference zone. Overall, our findings can be summarized into two significant statements: (1) blood pressure was stabilized to the optimal range, and (2) autonomic balance was stabilized to the reference zone with brief harmonic frequency respiration training.2 levels [While this study focused on the effects of harmonic frequency breathing on blood pressure and autonomic balance, several studies have investigated how respiration affects other functions from a physiological or psychological perspective ,44,45,462 levels . These sThis study found that breathing to harmonic frequencies not only stabilizes the blood pressure, but also the autonomic nervous system. This was due to alterations in the volumetric flow of the heart, which were induced by modifications in respiration. A previous study showed that depending on the respiratory effort, cardiac output was altered by changes in heart rate and/or stroke volume . TherefoOur study suggested the easiest way to stabilize autonomic balance and blood pressure through temporary harmonic respiration. Harmonic frequency can be defined as the frequency of the arterial baroreflex system ,28,33. BThis study found that matching breathing rates to an individual’s harmonic frequency had a positive effect on the body by balancing blood pressure and autonomic balance. These significant findings provide evidence that blood pressure and autonomic balance can be continuously stabilized solely through harmonic frequency breathing. Respiration is a voluntary process that controls other involuntary functions. Moreover, this study focused only on people with no pre-existing health conditions. Consequently, it cannot be concluded that the method of breathing with harmonic frequency can alleviate hypertension or cardiovascular diseases, but it may contribute to the prevention of these disorders. Therefore, future studies should be directed towards determining the effects of harmonic frequency breathing in patients with hypertension and other cardiovascular diseases.


The current guidelines recommend the administration of vasopressors in addition to fluids to maintain arterial pressure when life-threatening hypotension occurs in order to prevent the risk of organ failure, especially acute kidney injury. However, different vasopressors exert variable effects on the kidney, depending on the nature and dose of the substance chosen as follows: Norepinephrine increases mean arterial pressure both via its α-1-mediated vasoconstriction leading to increased systemic vascular resistance and its β1-related increase in cardiac output. Vasopressin, through activation of V1-a receptors, induces vasoconstriction, thus increasing mean arterial pressure. In addition, these vasopressors have the following different effects on renal hemodynamics: Norepinephrine constricts both the afferent and efferent arterioles, whereas vasopressin exerts its vasoconstrictor properties mainly on the efferent arteriole. Therefore, this narrative review discusses the current knowledge of the renal hemodynamic effects of norepinephrine and vasopressin during hemorrhagic shock.During hemorrhagic shock, blood loss causes a fall in blood pressure, decreases cardiac output, and, consequently, O Hemorrhagic shock may cause arterial hypotension and, consecutively, acute circulatory failure. Together with the control of the source of bleeding, fluid resuscitation and transfusion of blood products are recommended by the current guidelines . Norepin2 transport [During hemorrhagic shock, blood loss causes the fall of blood pressure, decreases cardiac output, and, consequently, Oransport . Howeverransport . Under tIn the second phase of hemorrhagic shock, once control of bleeding has been obtained, the patient may develop a sepsis-like response induced by the ischemia/reperfusion (I/R) sequence comprising oxidative and nitrosative stresses  as well 2 delivery, and microcirculatory perfusion [During hemorrhagic shock, several mechanisms may induce acute kidney injury (AKI): (1) The fall of MAP and the consecutive decrease in CO are associated with reduced renal blood flow (RBF), Oerfusion ,9,10  Through the hormonal activity, i.e., the above-mentioned activation of the sympathetic system, redistribution of blood to the “vital2 partial pressure (PμvO2) declines much earlier in the kidney than in other organs [2 supply with redistribution of PμvO2 away from the cortex and outer medullar [μvO2 drops immediately, and renal O2 consumption (VO2R) becomes dependent on renal O2 delivery (DO2R) [μvO2 [2R and lactate uptake despite the increased renal PμvO2 [(3) Within the renal parenchyma, RBF is redistributed at the expense of the renal cortex and outer medulla ,12. Sincr organs , AKI witr organs . In the medullar , ultimatmedullar ,16  . Both LeR) [μvO2 ,9. In adal PμvO2 . 2 supply.While hemorrhagic shock situation per se may be responsible for the development of AKI, resuscitation therapies may also contribute to kidney injury as follows: restoration of blood flow due to the resuscitation procedure may induce renal I/R-injury as a result of oxidative and nitrosative stress . MoreoveWithin the normal MAP range, RBF and GFR are auto-regulated as follows: in fact, in conscious mammals, RBF and GFR remained unchanged above the MAP thresholds of 65 and 80 mmHg, respectively ,19,20. RThe myogenic response is related to vascular smooth muscle cells’ contraction in response to stretching force . In the The tubuloglomerular feedback leads to vasoconstriction of the renal afferent arteries in response to an increase in sodium chloride concentration in the macula densa in the early distal tubule . An incrTherefore, a decrease in MAP will decrease tubular flow through a decreased glomerular filtration . This wiIn this way, the nature and amount of chloride among resuscitation fluids became the object of many controversies in the setting of critically ill patients. No trial found improved mortality nor renal outcomes with the use of balanced fluids when compared to sodium chloride 0.9% .However, below these critical thresholds of mean renal artery pressure, both RBF and GFR decreased and became MAP dependent. Norepinephrine increases systemic vascular resistance through α-1 receptor activation. Furthermore, through β-1 activation, norepinephrine increases CO , and botIn a model of a hemorrhagic pig, RBF was preserved between the range of 60 and 100 mmHg of MAP . During In healthy humans, norepinephrine infusion has been reported to reduce RBF ,39,40,41To summarize, the severity and ischemia-reperfusion stress during hemorrhagic shock both contribute to the loss of kidney autoregulation. Therefore, these results suggest a rationale for the use of norepinephrine to target MAP within physiological ranges in hemorrhagic shock states in order to maintain glomerular perfusion pressure. As mentioned above, during hemorrhagic shock, norepinephrine induces veno-constriction, which may help to mobilize the unstressed blood venous compartment in order to increase the circulating blood volume ,39. VariμvO2 to pre-shock levels [2.In a dog model of hemorrhagic shock, norepinephrine-related titration of MAP values above 100 mmHg was associated and did not allow for restoring renal Pk levels . HoweverIn rats undergoing hemorrhagic shock with MAP ~30 mmHg over 60 min, resuscitation with fluid resuscitation alone  was compared with a pre-established limited fluid volume  plus norepinephrine both aiming at a MAP target of 50–55 mmHg. At day 1 or 3 post-shock, neither renal function nor markers of renal tissue injury showed any inter-group difference . MoreoveIn a pig model of combined hemorrhagic shock (25–30 mL/kg of blood loss over 30 min) and blunt chest trauma, Prunet et al. reported lower urine output in the group resuscitated to a MAP of 70 mmHg with combined norepinephrine and fluids when compared to fluids alone . HoweverIn another model of porcine hemorrhagic shock, resuscitation to a systolic arterial pressure target of 80–90 mmHg with norepinephrine in combination with fluid administration restored kidney microcirculation and oxygenation, as well as renal function in a manner comparable to fluid resuscitation alone. However, at 48 h post-shock, additional norepinephrine administration led to a fluid volume-sparing effect with less hemodilution and, subsequently, an attenuated drop of hemoglobin concentration, as compared with fluid-alone resuscitation . In summary, norepinephrine, in combination with fluids, probably does not alter the renal microcirculation and function during resuscitation hemorrhagic shock and allows the sparing fluids . HoweverVasopressin is synthesized in the hypothalamus and stored in the post-pituitary gland. Vasopressin secretion is regulated by plasma osmolarity as well as by blood volume and pressure. Vasopressin has well-known specific renal effects through the activation of V2 receptors located on the basolateral surface of renal tubular cells in collecting ducts. There, vasopressin induces aquaporine-2 recruitment, leading to increased permeability of the epithelial membrane to water and, consecutively, allowing water reabsorption . In addiVarious experimental studies are available on the renal effects of vasopressin on the kidney during hemorrhagic shock , vasopressor requirements, secondary complications, and mortality at day 30) showed any significant intergroup difference. Of note, albeit not significant either (p = 0.19), AKI was less frequent in the AVP-treated patients  when compared to the control group  [These experimental findings prompted the authors’ group to perform the so far single clinical study that investigated the impact of vasopressin on renal function in patients with hemorrhagic shock. In a randomized, double-blind, placebo-controlled trial in a total of 100 patients with trauma, who had received at least 6 units of blood products, the authors tested the hypothesis of whether vasopressin  vs. other vasopressors and titrated to target a MAP ~65 mmHg would reduce the total volume of blood product transfused. Patients who received AVP indeed required significantly fewer blood products, while none of the other secondary end points  ,67. During hemorrhagic shock, arterial vascular resistances are increased, and cardiac output is low as well. The use of norepinephrine alone may theoretically worsen the hemodynamics, may induce excessive vasoconstriction, and may further induce ischemic injuries. Experimental studies, due to their short-term assessment, do not allow to answer this concern, and in a clinical setting, there is no data on patients with hemorrhagic shock treated with vasopressor alone.Furthermore, there is a theoretical risk of lowered cardiac output through higher cardiac afterload induced by arterial vasoconstriction with norepinephrine use. This was not reported in the literature. This may be explained by the beta1 effect of norepinephrine. The European guidelines recommend the administration of vasopressors in addition to fluids to maintain the target arterial pressure in the presence of life-threatening hypotension . These rTo date, no randomized studies compared the outcome of patients with hemorrhagic shock resuscitated with fluids alone vs. fluids with vasopressor. Moreover, no randomized study compared the choice of vasopressor used in this situation. In this mini-review, we highlighted the importance of this unanswered question and the utmost importance of renal hemodynamic effects of vasopressors in the setting of hemorrhagic shock. Nevertheless, according to the current knowledge, we might suggest that vasopressor treatment could be used during hemorrhagic shock in association with fluid therapy. Norepinephrine administration appears to be a safe approach, as it does not threaten kidney function and allows a fluid-sparing effect. To date, there is not enough data to evaluate and conclude the impact of vasopressin on kidney hemodynamics and/or function.


HGS was independently and inversely associated with AIx in patients with type 2 diabetes. Patients with diminished HGS should be subjected to intensive exercise therapy for reducing the risk of arterial stiffness and cardiovascular disease.Handgrip strength (HGS) is a measure of overall skeletal muscle strength and is used to identify risks for cardiovascular disease and mortality. Furthermore, HGS is an indicator of arterial stiffness that leads to atherosclerotic cardiovascular disease. This study aimed to examine the relationship between HGS and augmentation index (AIx) in patients with type 2 diabetes. A cross-sectional study was conducted to examine patients with type 2 diabetes whose HGS and AIx were measured in our hospital. AIx was measured noninvasively using an applanation tonometer, and multiple regression analyses were conducted to assess the independent relationship between HGS and AIx. This study included 404 patients. After adjusting for age, gender, body mass index, duration of diabetes, smoking and exercise habit, biochemical parameters, and physiological parameters related to arterial stiffness, HGS was found to be independently and inversely associated with AIx (β = − 0.270, Trial registration: UMIN000023010. A 10-year follow-up of the Look AHEAD  study has shown that low cardiorespiratory fitness is associated with an increased risk of atherosclerotic cardiovascular disease (hazard ratio (HR) = 1.94; 95% confidence intervals (CI), 1.12–3.35) in patients with T2DM4. On the other hand, cardiorespiratory fitness is positively associated with muscle strength measured by handgrip test in women5. Albin et al.6 reported that individuals with high cardiorespiratory fitness and strong handgrip strength (HGS) had a lower prevalence ratio of arterial stiffness  than those with low cardiorespiratory fitness and weak HGS. Therefore, HGS may be an indicator for arterial stiffness that leads to atherosclerotic cardiovascular disease. HGS is a simple method for evaluating overall skeletal muscle strength and is also a useful tool for identifying risks for T2DM7, cardiovascular disease (CV), hospitalization, and mortality9, which provides important information on a variety of health outcomes in clinical practice.Type 2 diabetes (T2DM) has become a pandemic, which is a serious problem worldwide. Patients with T2DM show lower cardiorespiratory fitness10. AIx is considered a vascular parameter showing the deleterious effect on cardiac workload of increased wave reflection related to arterial stiffness11. Previous studies have reported that AIx is higher in subjects with diabetes13 and hypercholesterolemia14, and predicts myocardial ischemic threshold in patients with coronary artery disease15. Moreover, a 10% increase in AIx is associated with all-cause mortality  and CV mortality  in patients with end-stage renal failure16. Not brachial-ankle pulse wave velocity (PWV) but heart rate-adjusted AIx is reduced by hemodyalysis, suggesting that AIx reflects large artery stiffness more precisely than PWV17.The augmentation index (AIx) is a measure of systemic arterial stiffness and risk factor for CV19 and few studies have investigated it in a T2DM population. If HGS has a significant relationship with AIx in patients with T2DM, HGS could also be a useful indicator for large artery stiffness. Thus, the present study aims to examine the associations of HGS with AIx in patients with T2DM.To date, there have been several studies that examine the association between HGS and AIx; however, the results are controversialWe conducted a cross-sectional study in patients with T2DM who were treated at the National Center for Global Health and Medicine Kohnodai Hospital. A total of 406 individuals whose HGS and AIx were measured at the medical examination (the same consultation day) were included. Trained technicians at the Clinical Research Center of the National Center for Global Health and Medicine at Kohnodai Hospital asked participants at the outpatient clinic about the subjects’ history of CV events, smoking habit, and exercise habit such as resistance training and walking. Patients with type 1 diabetes (n = 2) were excluded. The opt-out method of obtaining informed consent was used as this study was a retrospective analysis of the existing data. The study protocol was approved by the Medical Ethics Committee of the National Center for Global Health and Medicine (Reference No. NCGM-G-002052), and the study was performed in accordance with the Declaration of Helsinki.75) were measured noninvasively using an applanation tonometer . Patients put their left forearm on the elbow placement board of the device in a sitting position. Left radial pulse waves and left brachial blood pressures were automatically recorded. After recording the radial and aortic pulse waveforms, cSBP was automatically estimated using a linear equation by the device20.Height was measured using a rigid stadiometer . Weight was measured using calibrated scales . Body mass index (BMI) was calculated as body weight in kilograms divided by the square of body height in meters. Waist circumference was measured at the umbilical level at the end of exhalation in a standing position. HGS was measured using a Smedley analog hand dynamometer  twice, using both hands in a standing position. We utilized the average HGS in kilograms. Peripheral arterial stiffness was examined by measuring the PWV using a pulse pressure analyzer , and central systolic blood pressure (cSBP) and the AIx corrected for a heart rate of 75 bpm  using the revised equation adjusted for the Japanese population24.We measured plasma glucose (PG), hemoglobin A1c (HbA1c), B-type natriuretic peptide (BNP), serum high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels. Recent studies identified LDL-C-to-HDL-C ratio (LDL-C/HDL-C) as a better biomarker to predict both atherosclerosis progression and CV than HDL-C or LDL-C alonehttps://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower). Effect size was set at 0.02 according to Cohen’s definition25. The number of predictors was assumed to be 10 , the one-tailed alpha level is 0.025, and the sample size calculation indicated that at least 395 subjects were needed for a power of 0.8. This suggests that our sample size had sufficient power to detect the association between HGS and AIx.Sample size calculation was performed using G*Power (75 (dependent variable). The regression modeling was performed in three steps with age, gender, BMI, smoking habit, and duration of diabetes being included as possible confounders in the model 1, and further adjustments for exercise habit, HbA1c, and LDL-C/HDL-C (model 2), and finally, further adjustments for eGFR, BNP and cSBP (model 3). In addition, p values of < 0.05 determined by performing a two-sided test were considered as indicating statistical significance.Statistical analyses were performed using SPSS version 25 . All numerical variables are expressed as the mean ± standard deviation. Pearson’s correlation coefficient was calculated to analyze the associations of HGS with the clinical data. Mann–Whitney U test or Student’s t test, depending on the normality test results (Shapiro–Wilk test), was performed to detect significant differences between men and women, as appropriate. χ2 test was also performed to identify significant differences in categorical variables between men and women. Multiple regression analysis was performed to test independent associations between HGS (independent variable) and AIx2. Sixty patients (14.9%) had a history of CV. Eighty-six patients (21.3%) were current smokers. Two-hundred and three patients (50.2%) engaged in habitual exercise. Two-hundred and sixty-seven patients (66.1%) received glucose-lowering drugs, one hundred and twenty-three patients (30.4%) received statins, one hundred and twenty-four patients (30.7%) received renin-angiotensin system inhibitors, and fifty-eight patients (14.4%) received antiplatelet drugs. Demographic, anthropometric, and clinical data are listed in Table This study enrolled 404 patients (231 men and 173 women) with T2DM. The mean age and duration of diabetes of study participants were 63.1 ± 14.3 and 11.2 ± 11.8 years, respectively. The mean BMI was 25.7 ± 5.7 kg/m75; on the other hand, women had lower HGS than men. The number of smokers and cigarettes per day were larger in men than in women.Table p < 0.001), duration of diabetes , HDL-C , PWV , AIx75  . In contrast, HGS was positively correlated with BMI , waist circumference , eGFR , and LDL-C/HDL-C .HGS was inversely correlated with age .The adjusted associations between HGS and AIxp = 0.009).Furthermore, HGS was significantly lower in subjects with a history of CV than in subjects without  6, IL-8, IL-15, and myostatin) are altered in human skeletal muscle cells cultured from patients with T2DM39. A recent study showed that aerobic exercise training increased a myokine, irisin secretion, which was associated with improvement of arterial stiffness in rats with obesity40. To elucidate the common mechanism for decline in muscle fitness and progression of arterial stiffness, further investigations are required. However, given that muscle strength is a modifiable risk factor for CV, exercise therapy aiming to increase muscle strength can be effective for reducing the risk of atherosclerotic CV in patients with T2DM41.AIx measures the augmentation of central aortic pressure by a pulse wave reflection42 and N-terminal pro BNP levels in patients with peripheral artery disease43. We also observed the positive correlation between AIx75 and BNP  in this study. A possible mechanism explaining this relationship is that arterial stiffness has an impact on diastolic dysfunction44. The progression of arterial stiffness increases pulse wave velocity generated by left ventricular contraction, which enhances the early return of wave reflection to the heart and the augmentation of central aortic pressure. As a result, the cardiac afterload increases and then may cause diastolic dysfunction and/or left ventricular hypertrophy42. Considering that the prevalence of left ventricular diastolic dysfunction in patient with T2DM is significantly high (35%)45, the relationship among HGS, arterial stiffness, and BNP that is a prognostic marker for heart failure should be further investigated. Both HGS and BNP are predictive for CV events in patients with T2DM46. As mentioned above, skeletal muscle has been recognized as an endocrine organ that secretes myokines with a favorable effect on metabolism47. Irisin increases myocardial cell metabolism48. Fibroblast growth factor 21 increases adiponectin levels, which has a cardioprotective effect, and attenuates cardiac remodeling after myocardial infarction49. Myokines are promising for cardioprotective effects and may be the key to reveal the effect of skeletal muscle on arterial stiffness.The inverse correlation between HGS and BNP levels is intriguing. Previous studies showed that AIx was positively associated with the elevation of BNP levels in patients with paroxysmal atrial fibrillation50 reported that AIx was 77 ± 12% in men and 86 ± 12% in women, which is approximately equal to the result of the present study. The authors argued that the change in sex hormones in postmenopausal status might affect arterial stiffening in women. Indeed, the mean age of female subjects in this study was 63.7 years, and 81.6% of the women were 50 years and older. The higher AIx75 in women than men can be explained by the effect of postmenopausal status on arterial stiffness51.The gender difference in AIx was consistent with the finding of a previous study. Rosenbaum et al.52. In the present study, AIx75 was positively correlated to age ; however, AIx75 was inversely associated with the duration of diabetes in the multiple regression models. As such, we divided study subjects by the median value of the duration of diabetes and reanalyzed the differences in clinical data between groups. Then, we found that the subjects with a long (≥ 8 years) duration of diabetes had more exercise habits  and lower BMI  compared with subjects with a short duration of diabetes (< 8 years). No significant difference between groups in glycemic control, lipid profile, blood pressure, and the smoking habit was identified. The indicators of obesity, including BMI, have a positive relationship with arterial stiffness53. Excess adipose tissue is a key determinant of the development of hypertension, endothelial dysfunction, and arterial stiffness54. Moreover, regular exercise improves arterial stiffness measured by carotid intima-media thickness and PWV in patients with T2DM55. Even short-term, aerobic exercise effectively decreases arterial stiffness in radial, femoral, and carotid arteries in patients with T2DM57. Therefore, regular exercise habits and less body fat in subjects with longer duration of diabetes could contribute to a decrease AIx in this study population.Generally, arterial stiffness measured by AIx progresses with aging58 and Duran et al.59 reported that skeletal muscle mass was inversely correlated with HDL-C levels, on the other hand, higher HGS was related to higher HDL-C levels in a middle-aged population60. In this study, we observed inverse correlations of HGS with HDL-C levels and LDL-C/HDL-C. Excess adiposity is responsible for low HDL-C levels61; thus, obesity could probably explain this inconsistency. HGS is a useful tool for evaluating overall muscle mass; however, there is yet no consensus on how HGS should be used in clinical practice62. For example, there have been studies showing that not absolute but relative HGS such as HGS/BMI that takes the influence of obesity into consideration might be a better indicator for muscle weakness and the risk of cardiometabolic diseases64. Then, we re-analyzed the associations between HGS/BMI and clinical data. The associations of HGS/BMI with HDL-C  and LDL-C/HDL/C  were not significant. In addition, the adjusted associations between HGS/BMI and AIx75 were as follows: model 1, β = − 0.140, p = 0.025; model 2, β = − 0.201, p = 0.009; model 3, β = − 0.223, p = 0.022, respectively. There were still significant and inverse associations between HGS/BMI and AIx75 in model 1, 2, and 3. Meanwhile, the ability of HGS to predict health outcomes may not be different between absolute HGS and relative HGS65. How HGS should be used in clinical studies has been disputed8, and further validation studies will be needed.The relationship between skeletal muscle mass/strength and HDL-C levels is controversial. Pietrobelli et al.75 may not prove the presence of large artery stiffness. However, Betge et al.66 reported that measuring AIx was suitable for detecting atherosclerosis as compared to undergoing coronary angiography. The lower HGS in subjects with a history of CV in the present study and the strong evidence that HGS was associated with an increased risk of CV events8 suggests that HGS could be a non-invasive indicator for arterial stiffness. Additionally, König et al.27 recently showed that low HGS and increased arterial stiffness are closely tied to each other. HGS could still be a precise measurement for arterial stiffness.There are several limitations need to be addressed. First, this study is a single-center study, and the results may not be generalized to other populations. Second, the cross-sectional design cannot be used to infer causality. A prospective study is warranted to clarify the mechanisms regarding the relationship between HGS and the progression of arterial stiffness. Third, medications used to treat T2DM, hypertension, and dyslipidemia may intricately influence AIx and cardiovascular parameters. The possibility that medications affect the relationship between HGS and AIx cannot be excluded. Fourth, AIx is a surrogate marker for systemic arterial stiffness; thus, the inverse relationship between HGS and AIxIn conclusion, HGS was independently and inversely associated with arterial stiffness represented as AIx in patients with T2DM. This finding will shed a light on the mechanism behind the increased CV mortality in T2DM patients who have lower skeletal muscle mass/strength compared with healthy individuals. Although, there is yet no standard method for using HGS in clinical practice, T2DM patients who have lower HGS could be targeted by an intensive exercise therapy to reduce the risk of arterial stiffness and CV.


Surgically treated calcaneal fractures have a high risk of postoperative wound healing complications and a prolonged length of hospital stay (LOS). The aim of this study was to identify predictor variables of impaired wound healing (IWH) and LOS in surgically treated patients with isolated calcaneal fractures.This retrospective cohort study analyzed data on patients aged 18 years or older who were admitted to a level I trauma center with isolated calcaneal fractures between 2008 and 2018. Multivariable regression models were used to identify predictor variables.β = − 0.16 days/degree, 95% CI , p = 0.004) and MIA  reduced the LOS. A longer time-to-surgery  and IWH increased the LOS . In a subsequent multivariable regression analysis, two variables, open fractures  and overweight (BMI > 24) , increased the risk of IWH.In total, 89 patients  were included. In 68 of these patients, low-profile locking plate osteosynthesis was performed, and a minimally invasive approach (MIA) (percutaneous single screws/K-wire or low-profile locking plating via a sinus tarsi approach) was applied in 21 patients. Multivariable regression analysis revealed that a higher preoperative Böhler’s angle (Advanced treatment algorithms for open fractures are needed to reduce the risk of IWH.The online version contains supplementary material available at 10.1007/s00068-021-01863-1. Fractures of the calcaneus are of major socioeconomic importance, as individuals of working age (30–60 years) are the highest at-risk group . Intra-aAfter osteosynthesis of closed calcaneal fractures, wound healing complications are common, affecting up to 25% of patients , 4. The The aim of this study was to identify predictor variables of impaired wound healing (IWH) and prolongation of LOS in surgically treated patients with isolated calcaneal fractures.This retrospective case–control study was approved by the institutional review board of RWTH Aachen University . The study protocol was registered a priori at the Center for Translational & Clinical Research of the RWTH Aachen Faculty of Medicine (registration no. 19-048).Surgically treated isolated fracture of the calcaneusAge ≥ 18 yearsAvailability of data regarding the treatment modalityTreatment between 2008 and 2018Data on adults with isolated calcaneal fractures were retrospectively obtained from the hospital information system of a German academic level I trauma center in Aachen , Germany. The inclusion criteria were Fig. as followEarly hospital releaseThe exclusion criteria were as follows:Information on the coding of the variables can be found in Supplement 1.Fixation by implantation of low-profile locking plate osteosynthesis using an extensile lateral approach was defined as ORIF. Closed reduction and minimally invasive internal fixation using single screws/K-wires or minimally invasive plating via a sinus tarsi approach was defined as MIA. Overweight was defined as a body mass index (BMI) of > 24. Böhler’s angle was determined as described previously . FracturThe decision of whether surgery was done through an ORIF or MIA was made by clinical criteria. Criteria for the use of a MIA were multifactorial and the decision to use or not to use MIA was made by a specialist. Criteria included soft tissue swelling, obesity, pre-existing conditions, compliance, and preexisting conditions . The timing of ORIF was determined based on periodic soft tissue assessments  by a specialist. Follow-up treatment included unloading of the injured extremity for 10 weeks in a fracture orthosis boot. From the start of the 11th week, patients began step-by-step loading in a fracture orthosis boot (Settner’s orthosis) in the following 4 weeks until full load. The diagnosis of IWH was made by a medical staff member with specialist standard at the Department of Orthopaedics, Trauma and Reconstructive Surgery.χ2 test and Wilcoxon’s rank-sum test, respectively. The significance level was set at α = 0.05 . All statistical analyses were performed using the Statistical Package for Social Sciences .Continuous values are presented as mean, standard deviation (SD), and median, where applicable. Differences in categorical and continuous variables were evaluated by a α = 0.05. The significance of each regression coefficient was analyzed by a t-test. The significance level was set at α = 0.05. The results are reported as odds ratios (ORs) with their 95% confidence intervals (CIs). CIs were generated using the bootstrap method (1000 replications). R2 was calculated as a measure of the goodness of fit of the models.We fitted a full multivariable logistic regression model, using LOS as the dependent endpoint. To identify independent variables for inclusion in the multivariable linear regression model, univariable linear regression analyses of multiple variables were conducted (Supplement 2). The variables explored included age, sex, time-to-surgery (TTS), open fracture, MIA, IWH, Böhler’s angle, ASA physical status classification system, and overweight. Coding and the cases per variable are presented in Supplement 1. The accepted level of statistical significance in the multivariable regression was set at α = 0.20. The statistical significance of each regression coefficient was tested by the Wald test. The significance level was set at α = 0.05. CIs were generated using the bootstrap method (1000 replications). The goodness of fit was measured using ROCAUC and the Hosmer–Lemeshow test (X2).The binary logistic regression model was fit using the dichotomous variable “IWH” as the dependent endpoint. As with model A, univariable binary logistic regression analyses of multiple variables were conducted to identify independent variables for inclusion in the logistic regression model (Supplement 3). The variables included age, sex, TTS, open fracture, MIA, active smoker, alcohol abuse, drug addiction, arterial hypertonia, anticoagulation, and overweight (Supplement 2). The significance level was set at AUC of the model in the validation cohort. Validation of the linear regression was performed by analyzing Pearson’s correlation between the results of model B and the patient’s LOS.We studied one additional data set for validation: all patients with an isolated calcaneal fracture treated in the same academic level I trauma center from 2019 to 2021 (Supplement 4). This cohort was selected due to a change in personnel of the senior surgeon, so a corresponding bias could be excluded. Validation of the multivariable binary logistic regression model was performed by computing the ROCThe demographics of the 89 patients included in the study cohort are displayed in Table The univariable analyses identified the preoperative Böhler’s angle, TTS, surgical treatment method, and IWH as independent variables in Model A (Supplement 2).β = − 0.163 days/degree, 95% CI , p = 0.004), and MIA  were independent variables reducing the LOS. A longer TTS  and IWH were independent variables increasing the LOS  (Table R2 = 0.562).In the multivariable regression analysis, a higher preoperative Böhler’s angle .p = 0.030) and overweight (BMI > 24)  were independent variables increasing the risk of IWH .The models were tested in a validation data set comprising 25 patients (characteristics: Supplement 4). The models showed consistent predictive validity , our study ultimately lacks power regarding this risk factor and is subject to a reasonable degree of statistical uncertainty. Due to the small number of cases in the center, a reliable estimation of the influence of diabetes will only be possible by a meta-analysis or a multicenter study.Our findings on the association of BMI with wound infections and IWH were in accordance with those of Su et al. . HoweverIn summary, IWH was identified as a major risk factor for prolongation of LOS in our study. Two variables, open fractures and overweight, were risk factors for wound healing disorders. Improved management approaches for open fractures and validation of these approaches in randomized trials as well as a more profound understanding of the influence of a high BMI on wound healing are urgently needed.In terms of strengths, against the background of a satisficing rather than an optimizing concept, our models can be considered to have excellent clinical applicability and sufficient statistical validity . In addiA prolonged hospital stay after a calcaneal fracture has significant consequences for patients in terms of hospital costs and time off work. The single most important factor responsible for an extended LOS is IWH. Overweight and open fractures predispose patients to wound healing disorders, regardless of the surgical procedure performed. Improved management approaches for open fractures and validation of these approaches in randomized trials, as well as a more profound understanding of the influence of overweight on wound healing, are urgently needed.Supplementary file1 (DOCX 35 KB)Below is the link to the electronic supplementary material.


Introduction:  In this investigation, we aimed to explore the relationship between the triglyceride-glucose (TyG) index and the non-dipping blood pressure (BP) pattern in newly diagnosed hypertensive patients.Methods: In this retrospective study, 216 consecutive newly diagnosed hypertensive patients who had undergone 24-hour ambulatory blood pressure (ABPM) monitoring and had not received anti-hypertensive drugs were included. Non-dipping status was evaluated by a 24-h ABPM monitoring in all patients. We categorized the patients into two groups as; dippers (n=104 cases) and non-dippers (n=112 cases). The TyG index was derived from the fasting triglyceride and fasting glucose levels using the formula; ln[fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Results: Non-dipper group had a higher TyG index than the dipper group. The TyG was an independent predictor of non-dipping BP in hypertensive individuals, according to multivariable analysis. The TyG index was negatively associated with a decrease in both systolic and diastolic BP during the nighttime. The ideal cutoff value of the TyG index in detecting non-dipping status was≥9.01 with 74.1% sensitivity and 71.2% specificity. A ROC comparison indicated that the area under the curve value of TyG index was superior to fasting triglyceride, fasting glucose, and homeostasis model assessment of IR (HOMA-IR) in detecting non-dipping BP. Conclusion: The TyG index was an independent predictor of non-dipping status in newly diagnosed hypertensive patients who had undergone 24-hour ABPM monitoring and had not received anti-hypertensive drugs. As a simple and easily obtained parameter, the TyG index can be used to detect such pattern among these patients. Dipper-pattern (DP) blood pressure (BP) is described as a both systolic and diastolic BP fall of more than 10% during the nighttime compared to daytime.3 Moreover, the association of IR with hypertension had been established in previous studies, and a higher prevalence of non-DP was found in patients with IR.4 Triglyceride-glucose (TyG) index has emerged as a useful marker of IR that is calculated based on fasting glucose and triglyceride.5 The TyG index is found to be superior to the homeostasis model assessment of IR (HOMA-IR) for assessing IR.6 The association of the TyG index with cardiovascular diseases, including coronary artery disease, hypertension, arterial stiffness, and carotid atherosclerosis, was reported in previous studies.9 However, no prior study has evaluated the association of the TyG index with the circadian pattern of BP. Thus, the goal of this study was to assess if there was a link between the TyG index and non-DP in newly diagnosed hypertension patients who were not on antihypertensive treatment. Insulin resistance (IR) is a pathological status in which insulin has a lower biological effect than expected. IR is thought to be a risk factor for heart disease.1 Patients with a high clinical BP who underwent a 24-hour ABPM were included in the study. The exclusion criteria were as the followings; patients who were diagnosed with hypertension previously and/or used anti-hypertensive treatment and those who were treated with anti-hyperlipidemic or anti-hyperglycemic drugs, had diabetes mellitus, coronary artery disease, heart failure, creatinine level above 1.5 mg/dL, hepatic disease, acute or chronic infectious disease, inflammatory disease, and malignancy. The current study was carried out in accordance with the Declaration of Helsinki, version 2008. In all, 216 newly-diagnosed treatment-naive hypertensive patients who had both clinical and 24-hour ABPM assessments at the cardiology outpatient clinic between January 2015 and March 2020 were included in this retrospective, cross-sectional study. Hypertension was defined as two or more measures of systolic blood pressure (≥140 mmHg) and/or diastolic blood pressure (≥90 mmHg). on separate days and the mean 24-hour ABPM SBP ≥ 130 mmHg and/or the mean 24-h ABPM DBP ≥ 80 mmHg or the mean daytime 24-hour ABPM SBP ≥ 135 mmHg and/or the mean daytime 24-hour ABPM DBP ≥ 85 mmHg as recommended in a recent guideline published by European Society of Cardiology.7 HOMA-IR was calculated as; HOMA-IR = fasting insulin (microU/L) x fasting glucose (mg/dL)/405.10 After a 12-hour overnight fast, all blood samples were taken in the morning. The Coulter LH 750 analyzer  was used to assess the total blood count parameters. The following formula was used to determine the TyG index; TyG index = ln (fasting triglyceride (mg/dL) x fasting glucose (mg/dL)/2). The BP measurement of each patient was performed two or more times on separate days after at least 10 minutes of rest at the cardiology outpatient clinic. Patients with high clinical BP (mean SBP ≥140 mmHg and/or mean DBP ≥90 mmHg) underwent 24-hour ABPM.11 A 24-hour ABPM , which recorded BP and pulse rate in the non-dominant arm at 15-minute intervals in the daytime and at 30-minute intervals at nighttime, was performed in patients with high BP. The daytime was referred to the time interval between 06:00 A.M. and 10:00 P.M., and the nighttime was referred to the time interval between 10:00 P.M. and 06:00 A.M. In patients whose acceptable measurements in daytime and nighttime were below 70%, second 24-hour ABPM was conducted. DP was accepted as a 10% or more decrease in BP during the nighttime period compared to daytime, whereas non-DP was accepted as less than a 10% decrease in BP in that period. All analyses were performed using R-Studio Version 4.0.3 .th interquartile range). The statistical differences in continuous variables between the groups were calculated using an independent Student’s t-test or a Mann-Whitney U test. To compare categorical variables, the chi-square test or Fisher’s exact test were used, as applicable. The independent determinants of non-DP status were determined using univariate and multivariate logistic regression analysis. The model in the multivariable logistic regression analysis was created with the variables that were statistically significant in the univariable logistic regression analysis. To avoid multicollinearity and interaction, fasting glucose, fasting triglyceride, and fasting insulin were not included in the multivariate model with TyG index and HOMA-IR. There were no additional variables with multicollinearity in the model. Receiver operating characteristic (ROC) curve analysis was employed to detect the optimal cutoff value for the TyG index in detecting patients with non-DP status using the Youden index. ROC curve comparisons were computed using the DeLong test between TyG index, triglyceride, glucose, and HOMA-IR to compare the discrimination ability of those variables for non-DP in hypertensive patients. Spearman rank-correlation analyses were performed to determine the associations between the TyG index and the declines of both SBP and DBP from daytime to nighttime. We calculated a-priori required minimum total sample size as 98 with an effect size of 0.57 with 80 % power and 0.05 alfa error probability by calculating the effect size based on a previous report.12 Thus, we conducted this study with 216 patients. A post-hoc study power was calculated as 99% with 0.98 effect size for our study. Statistical significance was defined as a two-sided P value < 0.05. The normality of the data was determined using the Kolmogorov-Smirnov test. Categorical variables were presented as numbers and percentages. Quantitative variables with a normal distribution were reported as mean (standard deviation) and those without normal distribution as median  and with non-DP . The non-DP group had higher fasting glucose, triglyceride, TyG index, clinical SBP and DBP, low-density lipoprotein (LDL) cholesterol, fasting insulin, HOMA-IR, and red cell distribution width (RDW) compared to the DP group. The other characteristics of patients were given in P < 0.001, P < 0.001, P = 0.035), triglyceride (P = 0.029), and glucose (P = 0.036). 24-hour ABPM results were demonstrated in  The results of the current study showed that the TyG index was higher in non-DP patients than in DP patients with newly diagnosed drug-naive hypertensive patients. Clinical SBP, RDW, LDL cholesterol, 24-hour mean BP, HOMA-IR, and TyG index were independent predictors of non-DP among these patients. The TyG index was negatively associated with the decrease of both SBP and DBP from daytime to nighttime. Furthermore, the AUC value of the TyG index was superior to fasting triglyceride, fasting glucose, and HOMA-IR in detecting non-DP status.13 Especially, this risk increases in correlation with an increase in BP.14 Compared to clinic BP measurements, much information could be obtained by 24-hour ABPM, including mean BP level, diurnal variation, and BP variability. Within a 24-hour circadian cycle, 24-hour ABPM can discriminate hypertensive patients based on DP and non-DP.15 Non-DP BP is more closely associated with cardiovascular events than DP BP.17 Non-DP BP has been shown to be associated with several clinical conditions such as autonomic dysfunction, chronic kidney disease, connective tissue disease, malignancy, hypothyroidism, and chronic inflammation.18 Non-DP was also found to be more common among patients with older age, high salt intake, high stress, poor sleep quality, obesity, and metabolic syndrome.19 Hypertension is a well-recognized risk factor for cardiovascular disease, stroke, and target organ damage.20 It is noted that the presence of IR is associated with an increased risk of hypertension.21 The pathologic link between the development of hypertension and IR might be explained by impaired endothelium-dependent vasodilatation, enhanced response to endogenous vasoconstrictors, sympathetic nervous system activation, increased sodium reabsorption in kidneys, and anti-diuretic effect of insulin.22 Diabetic patients are at a higher risk for developing non-DP BP.23 Tartan et al reported that patients with a higher metabolic syndrome score had more frequent non-DP. Similarly, Mea et al showed that patients with non-DP BP tend to have higher IR, which was assessed by HOMA-IR and adiponectin levels, than patients with DP BP.24 The detection of IR plays a pivotal role in the prevention of hypertension and as well as in considering therapy modalities for hypertension.25 HOMA-IR, insulin level, and insulin-to-glucose ratio were used to evaluate IR, all of them were found positively correlated with the risk of hypertension.26 We showed in this study that non-dipper patients had higher HOMA-IR, which was detected as an independent predictor of patients with a non-DP in the current study. IR, which is considered as the major pathologic underlying mechanism of metabolic syndrome, may have a key role in the link between hypertension and metabolic diseases.8 In a meta-analysis consisting of eight observational studies, Wang et al reported that patients with a high TyG index had a 1.53-fold increased risk of developing hypertension.27 TyG index was reported to be associated with subclinical arterial stiffness.28 Furthermore, the TyG index was also superior to HOMA-IR in predicting the incidence of carotid atherosclerosis. 29 Similarly, the TyG index was found superior to HOMA-IR in detecting non-DP in our study. Sanchez-Inigo et al reported that the TyG index was related to the development risk of cardiovascular events.30 In accordance with this study, Wang et al reported that the TyG index was independently correlated with adverse events after acute coronary syndrome in diabetic patients.31 In this study, we identified a statistically significant difference in TyG index between patients with and without DP BP. The TyG index was also independently linked with non-DP in hypertensive patients. According to our results, the TyG index appears to be an effective marker for detecting non-DP BP in hypertensive patients. TyG index has been widely investigated as a marker of IR in the literature and its association with cardiovascular diseases and adverse events has been evaluated in previous studies. Jian et al concluded that the TyG index was found to be significantly related to the risk of hypertension.32 The relationship between inflammation and non-DP was presented in a previous report.33 Ozcan et al reported that RDW was an independent predictor of non-DP, which was similar to our results.34 There were contradictory reports on the association of dyslipidemia with the non-DP. Sunbul et al reported that hyperlipidemia was an independent predictor of non-DP.35 In contrast, Chotruangnapa et al could find an independent relation between dyslipidemia and non-DP.36 LDL-cholesterol was independently correlated with non-DP in our study, which might suggest the link between metabolic syndrome and non-DP. RDW and LDL-cholesterol were also found as independent predictors of non-DP in our study. RDW, which is the heterogeneity in the measure of erythrocytes, reflects enhanced inflammation and has been suggested as a prognostic indicator in cardiovascular diseases. Our study results are valuable for daily clinical practice. Since detecting hypertensive patients who are at high risk is crucial for initiating preventive treatment besides anti-hypertensive treatment, an easily calculable TyG index could provide to identify hypertensive patient’s cardiovascular risk as a better marker of IR than HOMA-IR. Non-DP patients with higher TyG index levels might be more prone to cardiovascular adverse events than those with lower TyG index. The major limitations of our study were retrospective design and a single-center study. Due to the cross-sectional study design, there was a lack of inference of causality of results. The other limitation was that fasting blood glucose, fasting triglyceride, and TyG index were measured once at baseline, and we could not get information about the effect of changes in these variables by the follow-up on 24-hour ABPM measurements. The results of the study may have been misestimated because only patients with high clinical BP who underwent 24-hour ABPM were taken and those without 24-hour ABPM were excluded. Finally, this study was conducted in one regional area. Thus, our findings might not be applicable to other areas. In this investigation, we found that the non-DP patients had a higher TyG index, and it was an independent predictor of non-DP among these patients. Additionally, the AUC value of the TyG index was superior to fasting glucose, fasting triglyceride, and HOMA-IR in the discrimination of non-DP BP. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This research was approved by the ethics committee of Van Training and Research Hospital . The authors have no conflict of interest to declare.


Markers used in everyday clinical practice cannot distinguish between the permanent impairment of renal function. Sodium and potassium values and their interdependence are key parameters in addition to volemia for the assessment of cardiorenal balance. The aim of this study was to investigate volemia and electrolyte status from a clinical cardiorenal viewpoint under consideration of renal function utilizing artificial intelligence. In this paper, an analysis of five variables: B-type natriuretic peptide, sodium, potassium, ejection fraction, EPI creatinine-cystatin C, was performed using an algorithm based on the adaptive neuro fuzzy inference system. B-type natriuretic peptide had the greatest influence on the ejection fraction. It has been shown that values of both Na+ and K+ lead to deterioration of the condition and vital endangerment of patients. To identify the risk of occurrence, the model identifies a prognostic biomarker by random regression from the total data set. The predictions obtained from this model can help optimize preventative strategies and intensive monitoring for patients identified as at risk for electrolyte disturbance and hypervolemia. This approach may be superior to the traditional diagnostic approach due to its contribution to more accurate and rapid diagnostic interpretation and better planning of further patient treatment Renal dysfunction is a common finding in patients with primary and secondary heart disease, and the most common reason for repeated hospitalizations is cardiac decompensation and hypervolemia. It is also known that the therapy used to correct congestion and improve the pumping function of the heart also affects kidney function ,2. ThereCurrent research in the field of knowledge-based systems known as synthetic intelligent systems and software algorithms is based on establishing a diagnosis of chronic kidney disease or estimating the time it takes for kidney function to deteriorate using equations for estimating the GFR in pre-dialysis or transplant patients. In some studies, a system was created to monitor the deterioration of kidney function in combination with risk factors that affect the progression of chronic kidney disease. Risk factors for the occurrence of heart diseases were also analyzed and adverse cardiovascular events during percutaneous coronary interventions were evaluated in some studies ,20,21. SThe aim of our paper was to analyze volemia, electrolytes, and renal function in heart failure, using an algorithm based on the ANFIS, an intelligent approach to renal and heart function monitoring ,23,24,25The work is structured in five sections. This is a prospective cross-sectional study comparing subjects with associated renal and heart failure or with the existence of a “de novo” or previously diagnosed, clinically manifested cardiovascular disease and with the existence of AKI or the presence of chronic kidney disease at different stages of evolution. The study group included 90 subjects older than 18 years of both sexes with heart and kidney damage; 52 men (57.77%) and 38 women (42.22%).® Indianapolis, IN, USA analyzer with reference values for Na+ 135–150 mmol/L and for K+ 3.5–5.5 mmol/L. Plasma BNP concentration was determined by enzymatic immunoassay quantitative chemiluminescent microparticle immunoassay (CMIA) technology on an Abbott Laboratories® Germany apparatus. Antiserum-NT-proBNP microparticles were added to the plasma sample, and the reaction was determined as the ratio of the amount of NT-proBNP to the relative light units (RLU). NT-proBNP concentration is expressed in pg/mL. The limit value for NT-proBNP is 300 pg/mL was used as a reference in patients with GFR less than 15 mL/min/1.73 m2 calculated using CKD-EPI cystatin C formula. A reference NT-proBNP cutoff value of less than 100 pg/mL was used in patients with GFR if CKD-EPIcystatin C > 90 mL/min/1.73 m2. Serum cystatin C (CysC) was determined in plasma using a commercial ELISA (the enzyme-linked immunosorbent assay) kit. Determination of serum cystatin C-based GFR was performed using a reference formula using a calculator [® Tokyo Japan device with a multifrequency phase array transducer 2.0–4.5 MHz transthoracic approach in compliance with all recommendations of good clinical practice [All patients who had malignant disease of any etiology, acute and chronic inflammatory diseases of other organ systems and clinical manifestations of thyroid disease, were excluded from the study. Blood samples for routine hematological analysis and biochemical analysis after centrifugation for 15 min at 1000 rpm and 5 mL of serum were analyzed by a standard method with commercially available tests. Na+, K+ electrolyte values were measured on a Roche Diagnostics Corporation 9181lculator . Echocarpractice . This repractice .In this paper, we wanted to assess the impact of the occurrence of an imbalance of serum electrolytes , BNP, ejection fraction (EF), and CKD-EPIcystatin C equations for GFR (glomerular filtration rate) on further monitoring or hospitalization of the patient ,30,31.To analyze the given problem, we used the ANFIS-network type, which is supervised learning with fuzzy logic that is similar to Takagi and Sugeno’s approach. The process of learning a neural network with phase logic, shown in 2) in back propagation (BP), as shown in + on the ++ and K+ are assigned to the phase of the rule (fuzzy rule) of the form: We used the structure of the ANFIS network, which we based on the connection of input parameters: BNP (pg/mL), Na+ (mmol/L), and K+ (mmol/L) with one output parameter EF (%) or CKD-EPIcystatin C , the sum of which determines the value of the outputIn the fifth layer, the final value of one output parameter is determined during training as the sum of the values of the fourth layer,+ and K+ leads to the accuracy of the formed network during training, checking on test data  where checking is quite consistent and varies in accuracy values of approximately 15% [The selection of the output parameter is reduced to one and represents either the CKD-EPIcystatin C or EF parameter. The structure of ANFIS requires that the training time of the network is realistic during training in 1000 epochs with a tolerance error for a mean square error (MSE) of 0.0005. This specifically selected structure with the parameters NT-proBNP, Nately 15% ,41. We bThe learning algorithm of ANFIS leads to the formation of a model by connecting the given input and output parameters of the respondents. The ANFIS system formed in this way encourages the use of neural networks in the earlier stages of disruption of individual parameters and indicates the need for faster clinical processing of individual subjects cases. p = 0.286). No statistically significant difference was found in the values of electrolyte status parameters shown in p < 0.001) and cystatin C (p < 0.001) values was found between healthy subjects and subjects with heart and kidney damage (Mann–Whitney U test).In this study, an ANFIS model based on a neural network with fuzzy logic was applied to predict renal function and hydro electrolyte disturbance in patients with heart damage. The usual statistical methods did not find a statistically significant difference in age between healthy subjects who had an average age of 69.55 ± 32.01 years and subjects with heart and kidney damage who had an average age of 70.72 ± 9.26 years (p < 0.001) and CKD-EPIcystatin C equation (p < 0.001) by analysis of healthy and diseased subjects (Mann–Whitney U test).Evaluation metrics are presented in To obtain more accurate results, we used AI to classify the collected data. The central tenet of AI techniques is to computationally automate logical judgment by extracting general rules and patterns from large datasets. The wide range of soft computing techniques are frequently used in system modeling and solving. Cardiorenal syndrome is a complex syndrome characterized by salt and water retention and activation of various neurohumoral mechanisms. Kidney and heart are interconnected by regulatory mechanisms that are important for maintaining homeostasis in the body . DisordeType B natriuretic peptide (BNP) is a marker of neurohumoral stimulation whose activity is associated with inhibition of sympathetic nerve activity and the renin angiotensin system axis. NT-proBNP in healthy individuals, even in the case of dietary salt intake, has a protective role for kidney and heart function, while in the early stages of heart and kidney disease it induces natriuresis and diuresis, and in advanced stages of the disease this neurohormone becomes ineffective in regulating hypervolemia. The explanation lies in the fact that at the renal level, NT-proBNP at physiological concentrations acts by increasing the strength of glomerular filtration and directly inhibits the tubuloglomerular feedback response, which first inhibits sodium resorption at the distal tubule, and then at the proximal tubule, reduces intrarenal vascular resistance, but has no effect on the permeability of intrarenal blood vessels . The conWe have described the typical (and) most common problems in the clinical model of cardiorenal syndrome. Despite the high dynamic nature of progression of cardiorenal syndrome, our model can accurately determine the presence of electrolyte disbalances and hypervolemia. In our study, NT-proBNP was a useful biomarker for assessing the progression of cardiac and renal dysfunction in our subjects with cardiorenal syndrome. The results of our study showed that the overall trend of data verification in the network with NT-proBNP, Na, and K that we formed is approximately 15%, with which subjects can be classified according to the severity of hypervolemia, electrolyte disturbance and renal function . ElectroThe way in which high values of EPIcistC and EF indicate the risk of adverse events is shown in To identify the risk of occurrence, the model identifies a prognostic biomarker by random regression from the total data set. This research did not include patients with cardiorenal syndrome who would require additional data preprocessing . They reSerum potassium disturbances are associated with advanced heart failure and reduced prognosis. The cardiorenal syndrome is used for the estimation of heart failure and kidney disease. There are numerous factors that contribute to the maintenance of disturbed values of potassium in cardiorenal syndrome. Cardiorenal syndrome is definitely independent of many influences, and the balance of serum potassium is more important than sodium in cardiorenal syndrome. In this study, the potassium balance in cardiorenal syndrome was analyzed by the ANFIS. ANFIS is suitable for nonlinear systems with highly redundant data. Although there are encouraging advances around this unsolved clinical problem, further investigation should consider the progressive inclusion of patients with advanced renal impairment to allow a better understanding of the cardiorenal syndrome.Our work aims to fill a gap by presenting a specific systematized predictive tool for high-risk patients with associated heart and kidney damage. After rigorous validation, this tool will help to predict serious adverse events before they occur and thus improve the treatment outcome of these patients. The predictions obtained from this model can help optimize preventive strategies and intensive monitoring for patients identified as at risk for electrolyte disturbance and hypervolemia.


Although sodium glucose co-transporter type 2 (SGLT-2) inhibitors were initially introduced as glucose-lowering medications, it was later discovered that cardiorenal protection is the most important treatment effect of these agents. A triad of landmark trials consistently showed the benefits of SGLT-2 inhibitors on kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD), irrespective of the presence or absence of Type 2 diabetes (T2D). Furthermore, finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that safely and effectively improved cardiorenal outcomes in a large Phase 3 clinical trial program that included >13,000 patients with T2D and a wide spectrum of CKD. These two drug categories have shared and distinct mechanisms of action, generating the hypothesis that an overadditive cardiorenal benefit with their combined use may be biologically plausible. In this article, we describe the mechanism of action, and we provide an overview of the evidence for cardiorenal protection with SGLT-2 inhibitors and the nonsteroidal MRA finerenone in patients with CKD associated with T2D. T2D is 2 . In cont2 . Lifesty2 ,7. Pharm2 ,7. DespiIn this article, we discuss recent advances in the management of CKD associated with T2D, providing an overview of the evidence for cardiorenal protection through the use of sodium glucose co-transporter type 2 (SGLT-2) inhibitors and the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone . These tSGLT-2 inhibitors were originally approved for improving glycemic control in patients with T2D . However2, severely increased albuminuria (UACR of >300 to 5000 mg/g), and were receiving he standard-of-care treatment with maximally tolerated doses of an RAS blocker [In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial , 4401 pa blocker . The pri blocker . Patient blocker .2 with or without albuminuria and at least one additional cardiovascular risk factor. SCORED was originally designed to explore the non-inferiority of sotagliflozin relative to a placebo in improving ischemic cardiovascular events as well as the superiority of sotagliflozin vs. a placebo with respect to HF events [In the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial , 10,584 F events . HoweverF events . DespiteF events . HoweverF events .2 and moderately to severely increased albuminuria (UACR of 200–5000 mg/g), despite background therapy with the maximally tolerated doses of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). The primary outcome was defined as the combination of a sustained ≥50% decline in the eGFR after randomization, ESKD, or death from renal or cardiovascular causes [The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial explored the hypothesis that SGLT-2 inhibitor therapy is also effective in preserving kidney function in patients with CKD due to causes other than T2D . Accordir causes . Once agr causes . As compr causes . Subgrour causes .2 or an eGFR of ≥45 to <90 mL/min/1.73 m2 with a UACR of ≥200 mg/g. Accordingly, EMPA-KIDNEY was originally designed to include a broader spectrum of patients with CKD, such as those with nonalbuminuric CKD or patients with a lower eGFR, down to the threshold of 20 mL/min/1.73 m2. Such patients were under-represented in prior CKD trials with SGLT-2 inhibitors. The primary outcome was the combination of the progression of CKD  or death from cardiovascular causes [The recently published Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial randomized 6609 CKD patients with or without T2D to receive empagliflozin at a dose of 10 mg/day or a placebo . EMPA-KIr causes . Similarr causes . This ber causes . The lacThe treatment effect of SGLT-2 inhibitors on kidney and cardiovascular outcomes was quantified in a recent collaborative meta-analysis of 13 large Phase 3 clinical trials involving a total of 90,409 patients (82.7% were patients with T2D and 17.3% were patients without T2D) . In the Although the exact mechanistic explanation for the cardiorenal protection afforded by SGLT-2 inhibitors is not yet fully understood, there is a growing body of evidence that these agents exert pleiotropic effects to attenuate the injury to the heart and the kidney . The glyAdditional cardiorenal protective mechanisms have been proposed. For example, the glycosuric action of SGLT-2 inhibitors results in a “fasting-like” state that is characterized by a reduced insulin–glucagon ratio and enhanced ketogenesis . Increas2 should receive first-line therapy with an SGLT-2 inhibitor, with the indication of cardiorenal protection [2, unless this is not tolerated or when the patients initiate renal replacement therapy [On this basis, the 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines provided a strong Level 1A recommendation that patients with T2D, CKD, and an eGFR of ≥20 mL/min/1.73 mDespite receiving standard-of-care treatment with optimal doses of an RAS blocker and the concomitant use of an SGLT-2 inhibitor, patients with T2D and CKD remain at a high risk of adverse cardiorenal outcomes. Evidence from preclinical studies suggested that in such disease states, there is a pathophysiological overactivation of the mineralocorticoid receptor (MR) that leads to the acceleration of end-organ damage through upregulation of the inflammatory and fibrotic pathways ,27. Furt2 and evidence of diabetic retinopathy, or a UACR of 300 to 5000 mg/g and an eGFR of 25 to <75 mL/min/1.73 m2. Therefore, FIDELIO-DKD enrolled patients with T2D and predominantly advanced CKD with severely increased albuminuria. FIDELIO-DKD was originally designed to investigate the treatment effects of finerenone on a primary kidney outcome, defined as the combination of a sustained ≥40% decline in the eGFR from the baseline, ESKD, or death from renal causes [Finerenone is a novel, selective, nonsteroidal MRA that has recently received regulatory approval for improving kidney and cardiovascular outcomes in patients with CKD associated with T2D . The safl causes . This trl causes . In addil causes . Notablyl causes .Whereas finerenone improved the primary outcome by 18% vs. the placebo in the FIDELIO-DKD trial , the pla2, or patients with a UACR of 300–5000 mg/g and an eGFR of ≥60 mL/min/1.73 m2. Accordingly, FIGARO-DKD enrolled patients with less advanced CKD and moderately increased albuminuria; such patients were either excluded or under-represented in the FIDELIO-DKD trial. Unlike FIDELIO-DKD, the primary outcome of FIGARO-DKD was a combined cardiovascular outcome, defined as the time to first occurrence of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for HF [The safety and efficacy of finerenone in patients with T2D and a broader spectrum of CKD was investigated in the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial . FIGARO-2 and a median UACR of 515 mg/g were included in this combined analysis. Notably, 40% of the patients had an eGFR of ≥60 mL/min/1.73 m2 at screening; thus, the identification and recruitment of these patients was based solely on the detection of increased albuminuria. Over a median follow-up of 3.0 years, as compared with the placebo, finerenone reduced the composite cardiovascular outcome of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for HF by 14%  [The FIDELITY analysis combined individual patient-level data from the FIDELIO-DKD and FIGARO-DKD trials with the aim of investigating the safety and efficacy of finerenone more precisely relative to the placebo across the whole spectrum of CKD in patients with T2D . Overall78–0.95) . Further78–0.95) . With re78–0.95) . These dSeveral mechanisms have been proposed to explain the beneficial impact of finerenone on cardiorenal outcomes. Owing to its short plasma half-life and the lack of active metabolites , there i2, serum potassium levels are within the normal range, and there is persistent albuminuria (UACR of ≥30 mg/g), despite the standard-of-care treatment with maximally tolerated doses of an RAS inhibitor [Taking the abovementioned evidence from clinical trials into consideration, the 2022 KDIGO guidelines provided a Level 2A recommendation for the use of a nonsteroidal MRA with proven efficacy in improving cardiorenal outcomes in patients with T2D when the levels of eGFR are ≥25 mL/min/1.73 mAs illustrated above, SGLT-2 inhibitors and the nonsteroidal MRA finerenone are both guideline-directed therapies in patients with CKD associated with T2D . These tThese preliminary data provided the rationale for the design of randomized clinical trials aiming to directly investigate the potential superiority of a combination therapy with an SGLT-2 inhibitor and an MRA over each respective monotherapy. The Rotation for Optimal Targeting of Albuminuria and Treatment Evaluation-3 (ROTATE-3) was an open-label, randomized, crossover trial that explored the albuminuria-lowering effects of the SGLT-2 inhibitor dapagliflozin (10 mg/day) and the steroidal MRA eplerenone (50 mg/day), administered either individually or in combination, in 48 CKD patients with or without T2D . Short-tThe long-term safety and additive efficacy of the combination therapy is currently under investigation in the ongoing Combination Effect of Finerenone and Empagliflozin in Participants with CKD and Type 2 Diabetes Using a UACR Endpoint (CONFIDENCE) trial . CONFIDEFor almost 18 years, the standard-of-care treatment for patients with CKD associated with T2D included only improving the control of hyperglycemia and hypertension, as well as the regression of albuminuria through the administration of RAS blockers. After this long period of hiatus, there is now a new era in the pharmacological treatment of diabetic kidney disease. On the basis of strong evidence from clinical trials, the inhibition of SGLT-2 and antagonism of MR with finerenone are two guideline-directed therapeutic interventions used to attenuate the progression of CKD and improve cardiovascular morbidity and mortality in this high-risk group of patients ,7. These


We propose a consensus definition of “an exaggerated orthostatic pressor response” in subjects in whom systolic blood pressure increases ≥ 20 mmHg when going from supine to standing posture. This definition can be extended for seated to standing measurements. We reserve the term “orthostatic hypertension” for when this pressor response leads to an upright systolic blood pressure ≥ 140 mmHg. We believe this consensus definition will help in the study of the pathophysiology, clinical impact, and potential treatment of these entities, and identification of patients who are at greater cardiovascular risk. Standing imposes a major hemodynamic burden on the cardiovascular system. In healthy persons, neurohumoral reflex mechanisms, particularly the arterial baroreflex, maintain blood pressure with standing. However, the counterregulatory response overshoots in some people such that blood pressure increases with standing. This orthostatic pressor response may result in hypertensive blood pressure levels only when standing or further exacerbate arterial hypertension. The condition is often referred to as orthostatic hypertension and appears to be associated with increased cardiovascular risk , 2. Yet,exaggerated orthostatic pressor response is a sustained increase in systolic blood pressure by at least 20 mmHg when changing from the supine to the standing position regardless of absolute blood pressure while standing.An Orthostatic hypertension is defined as an exaggerated orthostatic pressor response associated with systolic blood pressure of at least 140 mmHg while standing.Our goal was to arrive at a pragmatic definition that could be utilized in the setting of mechanism-oriented studies, epidemiological surveys, and clinical trials. We are aware that the suggested definitions are based on clinical reasoning and normative data rather than cardiovascular risk estimates and that the definitions as well as blood pressure cutoff values may have to be refined in the future. While orthostatic hypertension may be associated with cardiovascular risk as outlined in the sections below, more data are required to allow for a risk-based definition.In the Malmö Preventive Project, blood pressure after 10 min in the supine position and after 1 min standing was measured in 33,346 persons aged 45.7 ± 7.4 years [An increase in diastolic blood pressure on standing can be normal. Moreover, in individuals with excessive orthostatic heart rate increases, cardiac stroke volume may decrease such that pulse pressure is narrowed. The resulting spurious diastolic blood pressure increase is difficult to interpret. The panel, therefore, suggests that systolic blood pressure may be more practical when diagnosing orthostatic hypertension.A recent publication by an expert group suggested that a systolic blood pressure increase while standing by at least 20 mmHg or above 140 mmHg in otherwise normotensive persons could serve as criteria for orthostatic hypertension . The limWhen standing, approximately 500–1000 ml blood is pooled below the diaphragm and hydrostatic pressure shifts fluids from the intravascular to the interstitial compartment. In healthy persons, compensatory autonomic reflex mechanisms withdraw cardiac parasympathetic drive and raise cardiac and vascular sympathetic activity, thereby leading to an increase in heart rate, a drop in systolic blood pressure < 20 mmHg, and a small increase in diastolic blood pressure . Small-sThe epidemiology of orthostatic hypertension and the data regarding the cardiovascular risk associated with orthostatic hypotension have been reviewed recently . BrieflyWhen diagnosing an exaggerated orthostatic pressor response or orthostatic hypertension, blood pressure measurements with a brachial cuff suffice. Pulse rate should also be recorded. Preferably, measurements should be conducted in a quiet surrounding to limit confounding of orthostatic blood pressure responses by external stimuli. Supine blood pressure and heart rate should be measured after 5 min of rest in the supine position. Then, patients should stand up actively. Upright blood pressure and heart rate should be measured after 1, 3, and 5 min, at least, to confirm the persistent character of the blood pressure change. We suggest that the measurements after 3 and 5 min be averaged to determine standing systolic blood pressure. For screening purposes, a single measurement after 3 min may be sufficient.Beat-to-beat blood pressure and heart rate recordings can be applied in selected patients but are not widely available .We recommend that repeated orthostatic testing should be conducted on a different day to confirm the diagnosis.Because supine and upright blood pressure measurements may be difficult to conduct in all patients, seated-to-upright measurements may be considered for screening purposes. Since hemodynamic changes when standing up from the seated to the standing position are less compared with standing up from the supine position, the orthostatic pressor response may be less pronounced such that the sensitivity in detecting orthostatic hypertension may decrease. Similar limitations have been observed when using seated-to-standing measurements when diagnosing orthostatic hypotension . TherefoHead-up tilt testing may be considered for persons unable to undergo an active standing test.There is no evidence that individuals with an exaggerated orthostatic pressor response and blood pressure within the normal range require antihypertensive therapy. It may be prudent to follow up these patients’ blood pressure given the increased risk for progression to arterial hypertension. In patients with isolated orthostatic hypertension in whom blood pressure is only in the hypertensive range while standing, ambulatory blood pressure monitoring may have utility in gauging the overall blood pressure load during the day and detect abnormalities in diurnal blood pressure patterns, such as extreme blood pressure dipping during the night or masked morning hypertension , 14. Pat