Studies have reported that cerebral hypoxia occurs after cardiac arrest in the absence of hypoxemia or hypotension. To obtain preliminary information on the degree to which PbtO2 is responsive to changes in the common target variables for PbtO2-guided care in conditions without hypoxemia or hypotension, we investigated the relationships between the common target variables for PbtO2-guided care and PbtO2 using data from an experimental study in which the animals did not experience hypoxemia or hypotension after resuscitation. We retrospectively analyzed 170 sets of MAP, ETCO2, PaO2, PbtO2, and cerebral microcirculation parameters obtained during the 60-min post-resuscitation period in 10 pigs resuscitated from ventricular fibrillation cardiac arrest. PbtO2 and cerebral microcirculation parameters were measured on parietal cortices exposed through burr holes. Multiple linear mixed effect models were used to test the independent effects of each variable on PbtO2. Despite the absence of arterial hypoxemia or hypotension, seven (70%) animals experienced cerebral hypoxia (defined as PbtO2 <20 mmHg). Linear mixed effect models revealed that neither MAP nor ETCO2 were related to PbtO2. PaO2 had a significant linear relationship with PbtO2 after adjusting for significant covariates (P = 0.030), but it could explain only 17.5% of the total PbtO2 variance . In conclusion, MAP and ETCO2 were not significantly related to PbtO2 in animals without hypoxemia or hypotension during the early post-resuscitation period. PaO2 had a significant linear association with PbtO2, but its ability to explain PbtO2 variance was small.Brain tissue oxygen tension (PbtO Brainn injury , 12.2) monitoring is performed by placing an oxygen sensor within brain tissue through a burr hole. This technique is an established method for direct real-time monitoring of cerebral oxygenation. It has been used as a neuromonitoring modality in the management of patients with severe traumatic brain injury. In patients with severe traumatic brain injury, low PbtO2 levels have been shown to increase the risk of hypoxic-ischemic brain injury and the likelihood of poor outcomes [2-guided care, a therapeutic strategy to treat or prevent cerebral hypoxia through modifying determinants of cerebral oxygen delivery, including PaO2, end-tidal carbon dioxide (ETCO2), and MAP, has been introduced in post-cardiac arrest care [2 levels after cardiac arrest is needed before PbtO2-guided care can be trialed or widely implemented in clinical post-cardiac arrest care. In several studies using PbtO2 monitoring, despite maintaining adequate arterial oxygenation and perfusion pressure, episodes of cerebral hypoxia frequently occurred after resuscitation from cardiac arrest [2 levels [2 and/or MAP on PbtO2 levels in non-hypoxemic, non-hypotensive cardiac arrest patients during the early post-resuscitation period.Tissue oxygen tension, the partial pressure of oxygen within the interstitial space of a tissue, has been measured in various clinical and laboratory settings to assess the adequacy of tissue oxygenation. Currently, two types of oxygen sensors are widely used to measure tissue oxygen tension: polarographic electrodes and optical sensors. Polarographic electrodes measure oxygen tension based on the electrical current produced when an anode and cathode submerged in an electrolyte solution come into contact with oxygen . Opticaloutcomes –18. Receest care –21. Althc arrest –22. It i2 levels –26. Howe2-guided care, including PaO2, ETCO2, and MAP, are related to PbtO2 in the early post-resuscitation period using data from an experimental study conducted using a pig model of cardiac arrest in which the animals did not experience hypoxemia or hypotension during the early post-resuscitation period. The results of this analysis would provide preliminary information on the degree to which PbtO2 is responsive to changes in the common target variables for PbtO2-guided care and, thus, would help identify an optimal management protocol for PbtO2-guided care. We hypothesized that in conditions without hypoxemia or hypotension after cardiac arrest, PaO2, ETCO2, and MAP would be closely related to the PbtO2.In this study, we sought to determine the extent to which the common target variables for PbtOThis study was a post-hoc analysis of data derived from a previous study investigating the effects of pralidoxime administration during cardiopulmonary resuscitation (CPR) on hemodynamics and cerebral microcirculation after ROSC in 20 healthy Yorkshire/Landrace cross pigs weighing 24.7 ± 1.7 kg . In this2O; inspiratory/expiratory ratio, 1:2; and fraction of inspired oxygen (FiO2), 0.3. ETCO2 was monitored using a sidestream capnography monitor , and the respiratory rate was subsequently adjusted to maintain normocapnia. A 6.0-F introducer sheath was advanced through the right external jugular vein for pacemaker wire insertion and right atrial pressure monitoring. A 7.0-F saline-filled catheter was advanced through the left femoral artery for arterial pressure monitoring and blood sampling. Another 7.0-F saline-filled catheter was inserted into the left internal jugular vein and advanced toward the skull base for jugular venous blood sampling. After subcutaneous infiltration of 2% lidocaine solution, a scalp incision was made to expose the right and left parietal bones. A 10-mm diameter burr hole was drilled bilaterally through the parietal bone . The dura underneath the burr hole was opened to visualize the pial vessels. Three adhesive electrodes were applied on limbs to record the electrocardiogram. Normal saline was infused to maintain a mean right atrial pressure of 5–10 mmHg. Throughout the experiment, the rectal temperature was maintained at 38°C using a heating blanket.The animals were fasted overnight, but they were given water ad libitum. After an intramuscular injection of ketamine (20 mg/kg) and xylazine (2.2 mg/kg), they were placed in a supine position, and their trachea was intubated with a 7.0-mm internal diameter tracheal tube. The animals were anesthetized using an anesthesia machine with a 70/30 mixture of nitrous oxide/oxygen and sevoflurane. During surgical intervention, sevoflurane was titrated to maintain adequate anesthetic depth, measured by the absence of reflex withdrawal and no change in heart rate, arterial pressure, or respiratory rate. They were mechanically ventilated in a volume control mode with the following settings: tidal volume, 10 ml/kg; respiratory rate, 14 breaths/min; positive end-expiratory pressure, 5 cmHAfter baseline measurements were obtained, an electrical current  was applied through the pacemaker wire placed in the right ventricle to induce ventricular fibrillation (VF). Mechanical ventilation was discontinued immediately after the onset of VF. After 5 min of untreated VF , externa2 of 1.0; the other ventilator settings were unchanged. Fifteen minutes after achieving ROSC, the ventilatory rate was adjusted to maintain an ETCO2 of 45 mmHg. Normal saline (10 ml/kg/h) was intravenously infused to maintain normovolemia during the 60-min period, but no hemodynamic drugs were given during this period. We predetermined the humane endpoints for euthanasia , but none of the animals reached the endpoints until completion of the experimental protocol. Immediately after completing the experimental protocol, the animals were euthanized with a rapid bolus of 40 mEq potassium chloride under general anesthesia.After ROSC, the animals were observed for 60 min in a simulated intensive care setting. General anesthesia with sevoflurane was provided throughout the 60-min period. Immediately after ROSC, mechanical ventilation was resumed with an FiO2 and cerebral microcirculatory blood flow were assessed in the right and left parietal cortices. The measurement site (right or left) was randomized and counterbalanced. PbtO2, the study primary outcome, was measured using an optical oxygen sensor , which was placed directly on the surface of the parietal cortex. To assess the responsiveness of PbtO2 to changes in FiO2 at pre-arrest baseline, FiO2 was increased from 0.3 to 1.0, maintained at 1.0 until the PbtO2 level reached a plateau, and then decreased to 0.3. Cerebral hypoxia was defined as PbtO2 <20 mmHg [2. Two investigators analyzed the cerebral microcirculation videos and quantitated the microvascular flow index (MFI) of vessels <20 μm in diameter (representing primarily capillaries) by consensus [2, MFI, %Capillary number, and PbtO2 were sampled at pre-arrest baseline, 1-min intervals for 15 min after ROSC, and 30, 45, and 60 min after ROSC. Arterial blood gases were measured at pre-arrest baseline and 3, 15, and 60 min after ROSC.Arterial pressure and right atrial pressure were continuously monitored  and stored on a personal computer using a data collection software . Coronary perfusion pressure during CPR was calculated from the differences in time-coincident aortic end-diastolic and right atrial pressures. PbtO<20 mmHg , and theonsensus , 31. Theonsensus . The num2-guided care, including PaO2, ETCO2, and MAP, on the PbtO2 during the 60-min post-resuscitation period. In addition, we also tested the independent effects of cerebral microcirculation variables, including MFI and %Capillary number, on the PbtO2. Since arterial blood gases were measured only at three timepoints  after ROSC, PaO2 data were not available for several timepoints at which the other target variables were sampled. In the original study [2 levels linearly increased over time during the 60-min post-resuscitation period. Thus, PaO2 values at unmeasured timepoints were derived using linear interpolation and extrapolation methods. Mixed models included each predictor variable  and time as fixed effect covariates with random effects of intercept and slope for time and each predictor variable. The hemodynamic, blood gas, and cerebral measurement data obtained at pre-arrest baseline and CPR data, including the number of electric shocks, number of epinephrine administrations, duration of CPR, and coronary perfusion pressure and MAP during CPR, were independently examined to evaluate their effectiveness in determining the PbtO2. Significant variables  were further used for covariate adjustment in the mixed effect models. Semi-partial R-squared values of the fixed effects were computed for predictor variables and time using the r2glmm package of R software. A two-tailed P-value of <0.05 was considered statistically significant.Data were analyzed using R version 3.3.3  and T&F program version 3.0 . Continuous variables, presented as mean ± standard deviation or median values with interquartile ranges, were examined for normality using the Shapiro–Wilk test. We used multiple linear mixed effect models to test the independent effects of common target variables for PbtOal study , we foun2 was 31.4 ± 6.6 torr at an FiO2 of 0.3. Increasing the FiO2 to 1.0 resulted in a marked increase in the PbtO2 to 63.8 ± 18.1 torr. All animals achieved ROSC after 4 (2–5) min of CPR and survived the 60-min observation period. Thus, a total of 170 sets of MAP, ETCO2, PaO2, MFI, %Capillary number, and PbtO2 data were collected during the 60-min post-resuscitation period  and included in the analyses. 2, PaO2, MFI, %Capillary number, and PbtO2 data during the 60-min post-resuscitation period. Immediately after ROSC, MAP increased rapidly, reaching a plateau within 5 min. It decreased progressively after 15 min, but it was maintained >65 mmHg. ETCO2 and PbtO2 progressively decreased during the 60-min period, while PaO2 progressively increased. Immediately after ROSC, cerebral cortices became hyperemic; hence, there were more perfused capillaries than those at baseline for all animals. After a brief hyperemic period, cerebral cortices turned pale and the %Capillary number and MFI decreased progressively over the next 10 min. 2 in linear mixed effect models. In the linear mixed effect models, PaO2 levels had a significant linear relationship with PbtO2 after adjusting for significant covariates , but neither MAP nor ETCO2 were related to PbtO2. Although the cerebral microcirculation variables were significantly associated with PbtO2, their ability to explain PbtO2 variance was limited. When adjusted for significant covariates, the MFI and %Capillary number explained 14.3%  and 11.3%  of the total PbtO2 variance, respectively.Pre-arrest baseline measurements were within normal limits, as shown in 2, but not MAP nor ETCO2, had a significant relationship with PbtO2. To the best of our knowledge, this is the first study to examine the relationship between key determinants of cerebral oxygen delivery and PbtO2 in non-hypoxemic, non-hypotensive conditions after cardiac arrest.Using data from an experimental study in which the animals did not experience hypoxemia or hypotension during the early post-resuscitation period, this study showed that PaO2 level ≤ 20 torr, which is a widely accepted hypoxic threshold [2 values < 20 torr in the absence of hypoxemia or hypotension. This finding indicates that a significant percentage of cardiac arrest patients may experience secondary hypoxic insults to the brain if the initial treatments are solely based on PaO2 and MAP. PbtO2 monitoring, although highly invasive, has been repeatedly reported as a safe procedure [Several studies reported the frequent occurrence of cerebral hypoxia after ROSC despite adequate arterial oxygenation and perfusion pressure –22. In ahreshold . Consistrocedure , 33, 34.2 levels [2 [2.Cerebral oxygenation can be monitored noninvasively by near-infrared spectroscopy (NIRS), which estimates regional tissue oxygenation by using light waves of near-infrared wavelength to penetrate the scalp, skull, and brain. Although NIRS is a non-invasive and easy-to-use technique for monitoring cerebral oxygenation, it measures the oxygen saturation of combined arterial, venous, and microcirculatory blood compartments in both cerebral and extracerebral tissue –37, whic2 levels , 39. Howevels [2 . Consequ2 levels on clinical outcomes in cardiac arrest patients are unavailable, several studies involving patients with severe traumatic brain injury have suggested associations between reduced PbtO2 levels and poor outcomes [2 values and outcomes in 101 comatose head-injured patients [2 values during the first 24 h after injury correlated with unfavorable neurological outcomes and death at 6 mon. Studies have also suggested that reduced PbtO2 can be a modifiable therapeutic target for neurological recovery [2-guided care, compared with standard care, reduced the duration of exposure to PbtO2 levels below the hypoxic threshold [2 monitoring, to a protocol based on ICP monitoring alone [2 plus ICP monitoring reduced the time of exposure to cerebral hypoxia, with a trend toward lower mortality and favorable neurological recovery.Although data regarding the significance of reduced PbtOoutcomes –18. In apatients , the deprecovery , 33. In hreshold . A phase2 in this study is best explained by the presence of cerebral autoregulation. In our data, the overall MAP values were above the suggested autoregulation threshold of 60–75 mmHg [2 when MAP values were below the optimal MAP, but not when MAP values were above the optimal MAP, determined using the pressure reactivity index (89 ± 11 mmHg). Our finding suggests that in non-hypotensive cardiac arrest patients, MAP augmentation may not be able to influence PbtO2 considerably. This finding is consistent with that of a recent randomized clinical trial that compared targeted low-normal (65–75 mmHg) and high-normal MAP (80–100 mmHg) in 123 comatose cardiac arrest patients [MAP is the main determinant of cerebral perfusion pressure, which is the driving force of CBF. The lack of a significant relationship between MAP and PbtO–75 mmHg , 41, 42.–75 mmHg , 43. In –75 mmHg , MAP waspatients , in whic2 influence CBF considerably [2, a non-invasive surrogate of PaCO2, is widely used to guide ventilator management in critically ill patients and is also related to CBF [2 response curves for middle cerebral artery blood flow velocity  in 31 normal subjects showed that ETCO2 was well correlated with the middle cerebral artery blood flow velocity [2 was preserved in patients resuscitated from cardiac arrest [2 for 24 h after intensive care unit admission in 10 comatose out-of-hospital cardiac arrest patients [2 change (3.6 ± 2.9%) was comparable to that reported in healthy subjects [2 and PbtO2. The reason for this lack of a significant relationship between ETCO2 and PbtO2 is unclear, but it may be due to the blunted cerebrovascular reactivity occurring in the early post-ischemic period. Several studies have suggested that cerebrovascular reactivity to PaCO2 is markedly blunted in the early post-ischemic period [2 to changes in PaCO2 over time in patients with severe head injury [2 was initially abolished, but it recovered within the first two days after sustaining an injury.Under physiological conditions, changes in PaCOiderably . ETCO2, d to CBF . A studyvelocity . Previouc arrest , 48. In subjects . Howeversubjects , 48, ourc period , 51. In c period . In a std injury , the rea2-guided care that we investigated, only PaO2 had a significant relationship with PbtO2 in this study. This finding is consistent with that reported in other studies [2 increased with an increase in FiO2; however, it did not respond to increasing MAP with epinephrine infusion [2 in non-hypoxemic, non-hypotensive cardiac arrest patients, care should primarily focus on increasing PaO2 rather than increasing ETCO2 or MAP. However, the following points make the therapeutic efficacy of increasing PaO2 questionable. Although the PaO2 level had a significant linear association with the PbtO2 level, it explained only 17.5% of the total PbtO2 variance. This finding suggests that the extent to which one can increase PbtO2 by increasing PaO2 may not be high enough to be clinically useful. Its limited ability to explain the PbtO2 variance may be related to impaired cerebral microcirculation, as evidenced by the reduced MFI and number of perfused capillaries during the post-resuscitation period. In several studies, the response of PbtO2 to supplemental oxygen diminished in the presence of reduced CBF [2 to induced hyperoxia in 83 patients with traumatic brain injury showed that the increase in PbtO2 induced by hyperoxia was smaller when regional CBF was < 20 ml/100 g/min than when it was > 20 ml/100g/min [2 response to supplemental oxygen, it would be difficult to treat cerebral hypoxia by increasing FiO2 without exposing the patients to arterial hyperoxemia, which has repeatedly been linked with poor outcomes after cardiac arrest [Among the common target variables for PbtO studies , 34. In infusion . Our fininfusion , 34, suguced CBF , 54. A s100g/min . In the c arrest , 56.2 variance. The limited capability of the MFI and %Capillary number to explain PbtO2 variance, in addition to that of PaO2, suggests that factors other than cerebral perfusion and blood oxygenation affect the PbtO2 level. Recent studies have suggested that the diffusion limitation of oxygen delivery resulting from extensive perivascular edema and endothelial swelling is a plausible mechanism for cerebral hypoxia [2 gradient with cerebral perfusion pressure in 14 comatose cardiac arrest patients showed that increased cerebral perfusion pressure was associated with a decrease in the jugular venous oxygen tension-PbtO2 gradient in patients without cerebral hypoxia (PbtO2 > 20 mmHg) [2 ≤ 20 mmHg) exhibited an increased jugular venous oxygen tension-PbtO2 gradient unrelated to varying cerebral perfusion pressure, suggesting diffusion limitation of oxygen delivery as a mechanism for cerebral hypoxia in those patients.In this study, the perfusion of cerebral capillaries, which serve as the ultimate exchange vessels for oxygen and vital substrates, explained only a small proportion of PbtO hypoxia , 57. A s20 mmHg) . However2-guided care significantly reduced the time of exposure to cerebral hypoxia in patients with severe traumatic brain injury [2 treatment protocol consisted of multiple physiological interventions to improve cerebral oxygen delivery, including increasing PaO2, PaCO2, and/or MAP, decreasing ICP, and performing red blood cell transfusion. However, our findings together with those of the aforementioned studies suggest that nonspecific interventions such as increasing FiO2 alone are not likely to sufficiently increase the PbtO2 level in cardiac arrest patients with cerebral hypoxia secondary to impaired cerebral microcirculation or diffusion limitation physiology [2 level itself, as well as the response of PbtO2 to supplemental oxygen. We are planning future investigations on the effect of therapeutic strategies that target diffusion limitation physiology and/or impaired cerebral microcirculation on cerebral microcirculation parameters and PbtO2, These studies could illuminate why the PaO2 had a limited capacity to explain PbtO2 variance in the present study, and also help identify effective treatments for treating post-ROSC cerebral hypoxia.In the randomized trial by Okonkwo et al. in which adding PbtOn injury , the Pbtysiology , 53, 54.2 after cardiac arrest should be addressed prior to clinical implementation of PbtO2-guided care. First, the impacts of varying MAP, PaO2, and ETCO2 on PbtO2 levels in other cerebral regions, or on global cerebral oxygenation, must be investigated. Since the cerebral measurements were restricted to a small area of the cerebral cortex in our study, our results cannot be extended to the entire brain. Experimental studies in rats have reported marked regional differences in CBF and cerebral oxygenation after cardiac arrest [2 levels in immature rats subjected to 9 min and 12 min asphyxial cardiac arrest [2, and ETCO2 on cerebral oxygenation should be studied in different cardiac arrest models, specifically regarding the duration and etiology of cardiac arrest. In the study by Manole et al. [2 was greater, and the PbtO2 response to supplemental oxygen was less pronounced, after a longer duration of asphyxia cardiac arrest. In addition, several studies have reported significant differences in patterns of CBF reperfusion and cerebral injury between VF and asphyxial cardiac arrest [2 and cerebral metabolic and neurophysiological markers after cardiac arrest are warranted. Additionally, further studies to determine the effects of correcting cerebral hypoxia on histopathological and functional neurological outcomes after cardiac arrest are crucial.Many further questions regarding the PbtOc arrest , 58. Manc arrest , and repe et al. , the redc arrest , 60. Thic arrest –18, 33, c arrest , 22. The2. Third, the data were obtained from a study conducted in a well-controlled experimental setting. Variation in factors related to cardiac arrest and resuscitation, including arrest etiology and duration of arrest, in the clinical setting may result in different results. Fourth, other factors influencing PbtO2, including ICP and oxygen consumption, could confound the relationship between the common target variables and PbtO2, but they were not included in our study.Our study has several important limitations. First, data were obtained from anesthetized animals free of an underlying disease. Despite similarities in neuroanatomy between pigs and humans, direct extrapolation of our findings to human cardiac arrest patients cannot be assumed. Second, we retrospectively analyzed data derived from a previous study. Our study could not determine causal relationships between the common target variables and PbtO2 were not significantly related to PbtO2. The PaO2 level had a significant linear association with the PbtO2 level, but its ability to explain PbtO2 variance was small.In the post-hoc analysis of data from an experimental study in which the animals did not experience hypoxemia or hypotension during the early post-resuscitation period, MAP and ETCOS1 MovieIt shows changes in cerebral cortical microcirculation during the first 15 min of the post-resuscitation period.(MP4)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.S1 File(DOC)Click here for additional data file.


Background: Chemotherapy regimens for breast cancer treatment can promote vascular dysfunction and lead to high cardiovascular risk.Purpose: To investigate the cardiovascular burden and vascular inflammation in metastatic breast cancer patients receiving CDK 4/6 inhibitors or everolimus in addition to standard hormonal treatment.Methods: 22 consecutive female patients with metastatic breast cancer were enrolled. Relative wall thickness (RWT) and left ventricle mass (LVM) measurements by transthoracic echocardiography were obtained followed by 24-h ambulatory blood pressure monitoring, and 18F-fluorodeoxyglucose positron-emission tomography/computed tomography imaging. Uptake of the radiotracer in the aortic wall was estimated as tissue-to-background ratio (TBR). Each patient was assessed for the aforementioned parameters before the initiation and after 6 months of treatment.Results: At follow up, patients assigned to CDK 4/6 treatment demonstrated increased 24-h systolic blood pressure (SBP) (p = 0.004), daytime SBP (p = 0.004) and night time SBP (p = 0.012) (Group effect). The 24-h mean arterial pressure measurements were also higher in CDK 4/6 population, in comparison to everolimus that displayed firm values . Additionally, 24 h diastolic blood pressure recordings in CDK 4/6 therapy were higher opposed to everolimus that remained consistent (Interaction effect- p = 0.010). In CDK 4/6 group, TBR aorta also increased significantly, whereas TBR values in everolimus remained stable (Interaction effect-p = 0.049). Both therapeutic regimens displayed statistically significant damaging effect to RWT and LVM.Conclusion: CDK 4/6 inhibitors and hormonal treatment can lead to increased vascular inflammation, and higher blood pressure compared to the combination of everolimus and hormonal treatment. Moreover, both treatment strategies promoted left ventricle remodeling. Breast cancer has been established as the commonest diagnosed type of cancer in women and a prominent cause of mortality among cancer patients, globally , 2. UntiEven though hormonal treatment has been studied extensively through the past decades, the crucial role of CDK4/6 pathway inhibition in moderating breast cancer cells propagation and the progress of the disease began to arise in 2015 . Many raEverolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and specifically of the mTorc1 complex. The mTOR axis is essential in cell multiplication, differentiation, and angiogenesis in breast cancer. Its widespread use in clinical practice emerged after BOLERO 2-3 clinical trials established its efficacy in combination with an aromatase inhibitor in postmenopausal metastatic breast cancer patients , 13. ComBoth types of therapy might also impair cardiovascular health by means of endothelial injury and vascular dysfunction/inflammation , 14–19. n = 31, patients meeting exclusion criteria n = 9). All subjects received hormonal treatment and of those, 10 received everolimus and 12 received therapy with CDK 4/6 inhibitors . All patients were free of major cardiovascular events for the past 6 months. Evaluation of left ventricle remodeling, 24 h arterial blood pressure and the inflammation of the aortic wall were performed at baseline and before the initiation of treatment and 6 months after ongoing therapy for both groups. Patients demonstrating increased arterial blood pressure values at baseline measurements were treated according to 2017 ESC/ESH guidelines on arterial hypertension. Hypertensive patients already under treatment before the initiation of chemotherapy continued their standard medication throughout the study protocol.This single center prospective observational study included 22 consecutive female patients with metastatic breast cancer that expressed estrogen and/or progesterone receptor and were HER2-negative in a 12 month period. The study protocol was approved by the Alexandra General Hospital review board and ethics committee and each patient provided written consent before the enrollment. Patients with active infection, chronic autoimmune disease, and history of chemotherapy for the metastatic disease and/or adjuvant chemotherapy during the past 3 years were excluded ]} + 0.6g (IVSd = interventricular septum diameter).Complete transthoracic echocardiography (TTE) study was performed using a GE Vivid E9 ultrasound system. The estimation of left ventricle geometry and mass was conducted by 2 experienced operators after careful examination of the acquired images. Relative wall thickness (RWT) was calculated by using the formula: RWT = 2*posterior wall diameter (PWd)/left ventricle end diastolic diameter (LVEDD) while left ventricle mass (LVM) was evaluated using Cube's formula as LVM = 0.8{1.04[ was conducted during a usual working day and each patient was advised to act and work normally. Spacelabs 90217 ambulatory blood pressure monitoring  system was used with a previously described standard protocol .All participants underwent FDG-PET/CT imaging after fasting for at least 12 h prior to the study. None of the patients had blood glucose levels >180 mg dL-1 before injection. FDG was injected intravenously (5MBq/Kg) and scanning was performed at 120 min post injection for vascular tracer uptake assessment. Patients were encouraged to void before imaging and images of the thorax and abdomen were obtained by a hybrid PET/CT scanner . A low dose computed tomography (CT) scan in supine position was obtained, with patients' arms placed above their heads when possible. No CT IV contrast was administered. CT images were acquired with 30 mA, 130 KV, axial slice thickness of 5 mm and table feed rotation of 27 mm per tube rotation. CT radiation exposure was estimated in the region of 5 mSV. PET scanning followed immediately over the same pre-defined body region and the images were reconstructed with a standard Iterative Ordered-Subset Expectation Maximization (OSEM) algorithm using 4 Iterations and 8 subsets. FDG-PET radiation exposure was in the region of 7 mSV for an injected activity of 10 mCi (370 MBq).Aortic FDG uptake was assessed by using previously described validated and reproducible methodology without knowledge of patients' data or laboratory values . In briet-test and the non-parametric Mann-Whitney U test as appropriate. Comparisons of continuous paired variables  were performed utilizing paired t-test and Wilcoxon Signed Ranks test as appropriate. To test for changes within and differences between treatment groups after 6 months of treatment, repeated measurement analysis of variance (RMANOVA) was performed with the changes in parameters of ambulatory BP monitoring, echocardiography and PET-scan as dependent variables, and time, treatment group and baseline measurements as fixed parameters. The statistical tests were two-tailed and performed at the 5% level of significance. All statistical analysis was performed using SPSS .Data are expressed as mean ± 1 standard deviation (S.D.) for continuous variables and as percentages for categorical data. The Kolmogorov-Smirnov test was used in order to assess the normality of distributions. Comparisons of baseline variables between groups of treatment were performed utilizing Student's unpaired p < 0.001. The interrater agreement was strong with a 95% confidence interval from 0.884 to 0.992, p < 0.001. Concordance correlation coefficients (CCCs) with 95% confidence intervals were calculated to test the intraobserver variability (2-way random effects model with absolute agreement), and also to assess interobserver agreement (2-way mixed effects model with absolute agreement) for TTE measurements regarding LVM and RWT assessment. The average measure intra-class correlation coefficient (CCC) was 0.998 with a 95% confidence interval from 0.996 to 0.999, p < 0.001.In a cohort of 22 consecutive female patients with metastatic breast cancer, 10 received hormonal therapy with everolimus, and 12 received hormonal therapy with CDK 4/6 inhibitors. Baseline characteristics did not differ significantly between two groups, including blood pressure, body mass index (BMI), and TBR . Intra-cp = 0.004), daytime SBP (p = 0.004), and night time SBP (p = 0.012) (Group effect). The 24-h MAP measurements were also higher in CDK 4/6 population, in comparison to everolimus that displayed firm values . Additionally, 24-h DBP recordings in CDK 4/6 therapy were higher opposed to everolimus that remained consistent (Interaction effect: p = 0.010). Profile plots from ambulatory BP monitoring are presented in Figure 2. Regarding FDG uptake in the aorta, TBR measurements increased significantly in CDK 4/6 group whereas TBR values in everolimus remained stable at follow up as presented in p = 0.049). Results of repeated measurement analysis of variance are presented in At follow up, patients assigned to CDK 4/6 treatment demonstrated increased measurements of 24-h SBP .Both therapeutic regimens displayed statistically significant damaging effect with regards to the following echocardiographic variables: RWT and LVM . On the CDK 4/6 treatment strategy promoted vascular inflammation by means of increased TBR values, higher blood pressure values as recorded by 24 h ABPM and induced left ventricle remodeling. CDK4/6 inhibitors function as ATP competitive inhibitors, while they intervene in the phosphorylation and inactivation of retinoblastoma, a key tumor suppressor fundamental in cell cycle and the inactivation of FOXM-1. Thus, moderation of breast cancer cells proliferation occurs, without directly causing their apoptosis, and enhance their capacity to present antigen and stimulate cytotoxic T cells , 15.CDK inhibition has been found to trigger interferon production and indirectly moderate cytotoxic T cells activation against tumor cells proliferation . CDKs arHypertensive response as a result of an inflammatory process has been described extensively , 19, 30.The increased RWT and LVM values recorded in the group of CDK4/6 inhibitors can be interpreted as a result of ventricle remodeling and in the context of an inflammatory induced hypertensive state. Many studies have proposed the role of cytokines such as TNF-a, IL-1, and IL-6 in alterations of left ventricle geometry and progressive diastolic and systolic functional impairment –36. ConcThe group that received Everolimus did not demonstrate significant alterations at follow up in TBR and 24 h ABPM recordings. Everolimus interacts exclusively with the mTORC1 compound (direct inhibition) and promotes phosporylation of P70 ribosomal S6 protein kinase. Furthermore, it blocks HIF-1 expression and moderates angiogenesis with an impact on VEGF and smooth muscle and endothelial cells propagation. As an anticancer agent it does not promote direct cardiotoxicity; its impact on vasculature stems from hyperglycemia, hyperlipidemia and hypertension that it might induce –14.In the present study however, RWT and LVM were increased at 6 months follow up. Despite the fact that established hypertension was not apparent in this group, the above findings support the theory of concentric remodeling of the left ventricle in the context of possible microvascular dysfunction induced by Everolimus treatment  and an oThe present study exhibits the results of a single center observational report including a relatively limited number of patients. Secondly the study protocol did not include the measurement of inflammatory markers.The findings of the present study suggest that both treatment strategies might impair cardiovascular function. Specifically, CDK 4/6 inhibitors and hormonal treatment promotes vascular inflammation, hypertensive response, and alters left ventricle geometry. On the contrary, Everolimus and hormonal treatment does not have such a compounding impact on cardiovascular burden, by means of TBR and 24 h ABPM measurements, although left ventricle concentric remodeling was noted in TTE at 6 months of follow up.To our knowledge, this is the first study to assess the cardiovascular impact of contemporary anti-neoplasmatic treatment in metastatic female breast cancer patients with HR-positive HER2-negative phenotype, using a combination of different techniques including PET-CT imaging. Taking into consideration the above findings, the authors have the notion that close monitoring with TTE and ABPM at baseline and during treatment would be a reasonable approach in this subgroup of breast cancer patients. Moreover, long term consequences of increased vascular inflammation might be accessed further with the implementation of peripheral vascular imaging and/or aortic and peripheral arteries functional alterations, assessed by well-established methods such as IMT (intima media thickness), ABI , and/or PWV (pulse wave velocity), respectively, especially in cases with emerging signs and symptoms of cardiovascular dysregulation. Both cardiologists and oncologists, ought to be alert and in close collaboration for the prompt detection of cardiovascular toxicity when treating breast cancer patients receiving either CDK 4/6 inhibitors or Everolimus.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Alexandra General Hospital Review board and Ethics committee, Athens, Greece. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.FZ reports honoraria for lectures and has served in an advisory role for Astra-Zeneca, Daiichi, Eli-Lilly, Merck, Novartis, Pfizer and Roche. MD reports consulting fees, lecture fees, and honoraria from Janssen, Amgen, Celgene, and Takeda; research funding from Janssen, Amgen, Takeda, and Genesis Pharma; and consulting fees from Bristol-Myers Squibb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Associations found were significant only for subjects older than 50 years . The present results suggest that a decreased capacity to excrete sodium during daytime is more prevalent as age increases and that it impacts nighttime blood pressure and nocturnal dipping in older subjects.The circadian rhythm of urinary sodium excretion is related to the diurnal blood pressure regulation (BP) and the nocturnal dipping pattern. The renal sodium excretion expressed as daytime/nighttime ratio impacts BP, but a limited number of studies have investigated this topic to date. In this cross-sectional study, we aimed to investigate the impact of different daily patterns of sodium excretion (comparing low with high ratios) on BP and nocturnal dipping and to explore the relationship with age. Twenty-four-hour ambulatory BP monitoring and daytime and nighttime urinary sodium collections were used to assess 1062 subjects in Switzerland. Analyses were performed according to the day/night urinary sodium excretion ratio quartiles (Q1–Q4) and by age group (≤50 and ≥50 years). Subjects in Q1 can be considered low excretors of sodium during the daytime since the rate of sodium excretion during the daytime was 40% lower than that of subjects in Q4. Quartiles of the day/night urinary sodium excretion ratio showed that subjects in Q1 were 7 years older and had respectively 6 and 5 mmHg higher nighttime systolic and diastolic BP and a higher nocturnal dipping compared with subjects in Q4 ( Excessive dietary sodium intake represents a pathogenic determinant and a key modifiable environmental risk factor for hypertension . HoweverPrevious findings have suggested that BP represents the primary determinant of sodium excretion during the night, indicating that an impaired capacity to excrete sodium during the daytime is linked to increased nocturnal BP in order to promote sodium excretion, thus resulting in a typical non-dipping pattern ,8,9. NevAt present, what is known is that the diurnal pattern of sodium excretion can be reversed or altered by hypertension . The finSeveral factors could contribute to an impairment in sodium excretion capacity, among which reduced renal function , increased tubular sodium reabsorption  and specific hormonal effects are the most relevant .Moreover, experimental models have shown that the capacity of the kidney to manage sodium intake  and to produce an adequate pressure natriuresis decreases with aging ,14. An iPrevious findings have suggested that an impaired renal capacity of sodium excretion during the daytime could be relevant in determining a BP increase at night, resulting in a non-dipping pattern ,16.Nevertheless, studies that support this hypothesis have been mainly conducted in a selected patient population  or in a larger sample of subjects in selected geographic regions.Several previous epidemiological and interventional studies showed a dose–response association between BP and sodium intake ,18. In tHowever, studies to investigate the difference in daytime/nighttime urinary sodium excretion ratio in the general population and its impact on blood pressure are still lacking.On the basis of all the above-mentioned concepts, it is conceivable to hypothesize that daytime/nighttime urinary sodium excretion ratio could have a peculiar pattern in the general population and most likely a different impact on ambulatory 24 h BP (ABPM). For this purpose, we analyzed the data of a large sample of subjects in Switzerland, including both normotensive and hypertensive, from whom separate daytime and nighttime urine samples and 24-h ABPM recordings were collected. In the present study, we aimed to investigate the impact of the different daily patterns of sodium excretion (low vs. high daytime excretion) on BP and nocturnal dipping and to assess whether different associations occur according to age.The present analysis is based on data from a population-based cross-sectional study conducted between 2017 and 2018 in Southern Switzerland to explore determinants of arterial stiffness and cardiovascular risk factors of the resident population. The design and methodology have been detailed previously [The study was carried out in accordance with the Helsinki Declaration and was approved by the local Swiss ethics committee. All participants provided informed written consent. Data and analyses are presented in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) . ParticiAll study participants underwent two consecutive visits at the hospital’s research unit of the internal medicine department of the teaching hospital of Bellinzona and Valli (Switzerland).All individuals were investigated while on their usual diet. Twenty-four hour urine collections were performed on the same day as ABPM. Two separate collections of urine were performed: one for the daytime period and another one for the nighttime. Study participants visited the hospital’s research unit of the internal medicine department at the Regional Hospital of Bellinzona (Switzerland) in the morning and received detailed instructions explaining the study procedure. During the first visit, participants were given two containers for 2 L urine collection, marked as “daytime urine” and “nighttime urine”, and a plastic beaker to transfer the urine to the urine collection containers. Daytime and nighttime were defined according to each participant’s self-reported bedtime and wake-up time. A urine collection diary was also provided in which each participant marked (i) the starting diurnal hour of urine collection, (ii) the starting hour of nighttime urine collection and (iii) the hour of the last urine sample collected. All urine during the following 24 h was collected and the first urine of the waking period was added to the night urine collection. The next day, the participants visited the hospital’s research unit a second time and the collected urine containers were transferred to the Biochemistry Laboratory of Ente Ospedaliero Cantonale, Regional Hospital of Bellinzona, for the analyses.Urinary sodium and potassium concentrations were measured by a non-ion-selective electrode method .Urinary albumin concentration and creatinine were determined using a Behring Nephelometer  and a Hitachi 717 device , respectively. All urine assessments of the daytime and nighttime periods were performed separately.The validity of the 24-h urine collection was assessed through a combination of self-reported urine loss and the 24-h urine volume . The amount of excreted 24-h urine sodium and potassium was calculated by multiplying the total volume of the collected urine by the concentration of measured sodium.For each study participant, a device for twenty-four hour ambulatory BP monitoring (ABPM) was programmed to register BP every 30 min during the daytime and every hour during the nighttime. A validated, automated non-invasive oscillometric device  was used. BP recordings were performed on working days, and the patients were instructed to maintain their usual activities. Appropriate cuff sizes were used. The 24-h ambulatory BP was recorded simultaneously with the collection of 24-h urine. Hypertension was defined on the basis of a previously reported personal diagnosis of hypertension or the current use of antihypertensive medication with a previous diagnosis of hypertension. All BP parameters provided by ABPM were recorded. Daytime and nighttime periods were pre-defined. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and pulse pressure (PP) were recorded for the daytime and nighttime periods.2) and neck circumference (cm). Blood pressure (BP) in the office was measured during the first examination using a validated automatic oscillometric device following standardized procedures .During the first visit, a medical examination and a standardized interview were performed in which information on socio-demographic characteristics, comorbidities and traditional cardiovascular risk factors  were collected. A detailed drug anamnesis  was also performed. The following parameters were assessed: height (cm), weight (kg), waist circumference (cm), hip circumference (cm), body mass index  and used for the measurement of serum glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, magnesium, creatinine and cystatin C.Data are expressed as the median  for continuous variables and numbers (percentages) for categorical variables. The data were analyzed according to the daytime/nighttime urinary sodium excretion ratio quartiles . Participants were divided into two groups for analysis: younger subjects (age <50 years) and older subjects (age ≥50 years). Differences among urinary sodium excretion and age groups were investigated. Specific quartiles of the daytime/nighttime urinary sodium excretion ratio for each age group were calculated, corresponding to the following values: Q1 <0.91; Q2 0.91–1.23; Q3 1.24–1.74; Q4 ≥1.75 for the age group under 50 years; and Q1 <0.83; Q2 0.83–1.10; Q3 1.11–1.46; Q4 ≥1.46 for the age group over 50 years.The chi-square test and Wilcoxon rank-sum test were conducted to evaluate differences in categorical and continuous variables between the two age groups and to evaluate trends across the day/night ratio of urinary sodium excretion quartiles.To explore the association between the daytime/nighttime urinary sodium excretion ratio and, the 24-h blood pressure parameters and the nocturnal dipping effect (measured as the day–night change between ABPM parameters), linear regression models were constructed. The following dependent variables were used: daytime and nighttime BP values and differences between daytime and nighttime values  for systolic (SBP), diastolic (DBP) and mean blood pressure (MBP) and pulse pressure (PP).The association between the daytime/nighttime urinary sodium excretion ratio and the 24-h blood pressure parameters was also explored considering daytime/nighttime urinary sodium excretion ratio quartiles, with Q1 used as the reference group. All models were adjusted for selected covariates to examine potential confounding effects. Age, gender, body mass index, smoking, use of antihypertensive medications, diuretics, previous cardiovascular diseases, dietary salt consumption, magnesium, hypercholesterolemia, diabetes and heart rate were included in the multivariate model as covariates.Based on sodium excretion in 24-h urine, we have estimated the 24-h salt consumption using the following conversion factor: 1 mmol of sodium corresponds to 0.0584 g of salt (NaCl), previously used in large epidemiological studies .All analyses were separately performed for the whole population and for both younger and older groups. The β-coefficient and confidence interval  relative to urinary sodium excretion quartile categories were calculated.p-value level of significance was set at 0.05. Statistical analyses were performed using SPSS  and Stata statistical software (STATA) version 15.1. All statistical tests were two-sided, and the The characteristics of the subjects are displayed in A different circadian pattern of sodium excretion was noted across quartiles of the daytime/nighttime urinary sodium excretion ratio. More specifically, subjects in the first and second quartiles could be considered low excretors of sodium during the daytime, since they excreted half the amount of sodium during the daytime than during the nighttime compared with subjects in Q4. On the other hand, subjects in Q4 could be considered high excretors of sodium during the daytime since the rate of sodium excretion during the daytime was about 40% higher than that of subjects in Q1.p-value 0.627). However, despite these different circadian patterns of sodium excretion, 24-h urinary sodium excretion was not significantly different across quartiles   and higher levels of creatinine  . No significant difference in the self-reported duration of nocturnal urine collection across quartiles of the daytime/nighttime urinary sodium excretion ratio was found.Low daytime sodium excretors were significantly older than high excretors: the median age of subjects in Q1, Q2, Q3 and Q4 was, respectively, 55, 52, 52 and 47 years, p-value ≤0.001). Significant differences in BP were found across quartiles of the day–night ratio of urinary sodium excretion for nighttime values. Nighttime SBP was significantly higher in Q1 and decreased across quartiles to Q4 . Despite the different circadian patterns of sodium excretion, the 24-h urinary sodium excretion was not significantly different between age groups . The self-reported duration of nocturnal urine collection did not vary between age groups   compared to high daytime sodium excretors  (< 0.001) .The difference in BP values for the daytime, nighttime and nocturnal change was more evident in older subjects compared with younger ones. We performed an analysis also considering the daytime/nighttime urinary sodium excretion ratio quartiles in order to determine which category of subjects (low or high daytime sodium excretors) had a stronger association with nighttime and nocturnal BP values.p-value ≤0.001 and 63.2 (48.6–77.7) p-value ≤0.001. The same significant increase was also noted for MBP and PP for Quartile 1: 82.5 (66.8–98.2) p-value ≤0.001 and 42.8 (29.6–56.8) p-value 0.040, respectively : 106.0 (86.2–125.9) ectively .p-value < 0.001) and 3.6 , respectively.For low daytime excretors, a significantly reduced nighttime vs. daytime difference in BP values was noted for SBP and DBP in Q1: 4.1 . Older low daytime excretors showed a significantly reduced tendency of nocturnal dipping for all BP values .Moreover, previous studies have highlighted an inverse relationship between the renin-angiotensin system activity and serum magnesium and BP and lower level of serum magnesium with increasing age ,49,50,51A number of limitations in the present study should be acknowledged, too. Firstly, it is a cross-sectional study; therefore, the long-term influence of sodium intake on nighttime BP and nocturnal BP fall was not evaluated. Moreover, nighttime and daytime urine salt measurements were performed by a single 24-h urine collection, which might not be precise enough to estimate daily salt intake, considering the inter-daily variability of sodium intake and excretion. The inter-daily variability should also be considered for BP because the assessment of only one day of ABPM represents another limitation in our study. However, the single-day assessment of both BP and urinary sodium was for its technical feasibility. The assessment of such parameters over multiple consecutive days in such a large sample of subjects was impractical to realize. Moreover, the duration of the urine collection was not standardized for the daytime and nighttime period but adapted to intra-individual subject habits, and a variation in the hours of collection could affect the results. We strove to overcome this limitation by including a large number of participants, minimizing the inter-individual variability, performing urine and BP measurements on the same day and including all participants only during weekdays.Moreover, although a single ABPM measurement might be inaccurate for its lower reproducibility, some previous studies have even highlighted a significant relationship between non-dipping BP and target organ damage using a single ABPM measurement.Last but not least, considering the observational nature of the study design, cause-and-effect relationships cannot be postulated, and therefore, we cannot resolve a major question: does the decreased daytime sodium excretion cause an increased nighttime BP and a reduced nocturnal BP fall? Or do the higher nighttime BP values cause higher excretion of sodium during the nighttime and lower daytime excretion?Considering the direction of the association found in previous experimental studies on sodium diet restriction and BP, we can speculate that it is the circadian rhythm of sodium excretion that influences nighttime BP. Moreover, we cannot exclude the possibility that some of the higher nighttime BP values are the consequence of poor-quality sleep due to the ABPM registration.In conclusion, our results suggest that the pattern of sodium excretion characterized by a decrease in daytime sodium excretion is associated with a nighttime BP increase and a decreased nocturnal BP fall in older individuals.The present findings suggest that the assessment of the individual circadian pattern of urinary sodium excretion could be useful for identifying individual variability in sodium excretory capacity, assessing salt sensitivity patterns, and potentially, detecting patients at higher risk of a nocturnal BP increase and of the non-dipping pattern.The results of the present study suggest that an abnormal circadian rhythm of urinary sodium excretion may have an effect on nighttime BP in older individuals. The assessment of daytime and nighttime urinary sodium excretion in selected subjects could help in identifying an impaired circadian rhythm of sodium excretion and salt sensitivity patterns and, eventually, in detecting patients at higher risk of high nighttime BP and nocturnal non-dipping. Further prospective interventional studies could help to assess the beneficial outcome of salt intake restriction based on individualized circadian rhythms of sodium excretion.


Results: Median CAVI was higher in diabetes and prediabetes groups compared with group without CMD . Elevated CAVI (≥9.0) was detected in 16.8% of diabetes patients, in 15.9% of those with prediabetes, and in 9.0% of those without CMD (p < 0.001). The factors affecting on CAVI did not differ in CVD groups. In logistic regression the visceral obesity, increasing systolic blood pressure (SBP) and decreasing glomerular filtration rate (GFR) were associated with a pathological CAVI in CMD patients, and age, diastolic blood pressure (DBP), and cholesterol in persons without CMD. Conclusions: the CAVI index values in the prediabetes and diabetes patients were higher than in normoglycemic persons in a population sample of the Russian Federation. Since the identified disorders of arterial stiffness in prediabetes are similar to those in diabetes, their identification is important to prevent further cardiovascular complications.The aim of this study was to evaluate Cardio-Ankle Vascular Index (CAVI) and increased arterial stiffness predictors in patients with carbohydrate metabolism disorders (CMD) in the population sample of Russian Federation. Methods: 1617 patients (age 25–64 years) were enrolled in an observational cross-sectional study Epidemiology of Cardiovascular Diseases and Their Risk Factors in the Regions of the Russian Federation (ESSE-RF). The standard ESSE-RF protocol has been extended to measure the cardio-ankle vascular index (CAVI), a marker of arterial stiffness. Patients were divided into three groups: patients with type 2 diabetes mellitus ( In patients with diabetes mellitus (DM), cardiovascular diseases are the main cause of death ,2. FurthOne of these markers is increased arterial stiffness ,6. TradiThis index reflects the stiffness of the arterial tree from the beginning of the aorta to the ankle; the CAVI principle and the formula for its calculation were described in more detail in previous publications . It is nAn increase in CAVI was noted in diabetic patients compared to healthy individuals. CAVI is associated with HbA1c levels ,15. An eimproving interMediAte RisK management (MARK) study, the level of CAVI in the healthy and pre-diabetes groups did not differ and was increased only in the presence of diabetes [Previous studies investigating the relationship between arterial stiffness and prediabetes were inconsistent ,22,23,24It can be concluded that there is no clear relationship between markers of dysglycemia and CAVI in subjects with normal glucose metabolism, prediabetes, and type 2 diabetes. The aim of this study was to evaluate the level of CAVI in the persons with pre-diabetes and diabetes mellitus in the population sample of the Russian Federation, as well as to investigate the factors associated with pathological CAVI in these subjects.The study was carried out within the framework of a multicenter observational epidemiological study ESSE-RF (Epidemiology of Cardiovascular Diseases and Their Risk Factors in the Regions of the Russian Federation) in the Kemerovo region in the period from 2012 to 2013 years . The objThe study design is shown in n = 272, of which 54 patients (19.8%) with newly diagnosed type 2 diabetes mellitus); group 2—patients with prediabetes—IFG, IGT, or their combination  with newly diagnosed prediabetes); group 3—persons without any confirmed carbohydrate metabolism disorders . In these groups, clinical and anamnestic data, anthropometric characteristics, and CAVI index were analyzed depending on the presence of carbohydrate metabolism disorders. Further, to analyze vascular stiffness and related patterns, 49 patients were excluded, who had not been tested on the VaSeraVS-1000 device and had not been identified by CAVI.The remaining 1617 people were divided into three groups: group 1—patients with type 2 diabetes mellitus  values less than 0.9 were also excluded from the analysis. Thus, the final sample for analyzing the patterns associated with CAVI was 1491 persons.Physical examination included measurement of blood pressure, heart rate, anthropometric indicators; registration of electrocardiogram (ECG) at rest in 12 leads; and taking blood for biochemical laboratory tests.2, which was calculated by the formula: weight in kg/height in m2 (Quetelet index). Waist circumference (WC) and hip circumference (HC): the measurements were carried out in a standing position, the measuring tape was placed horizontally; for WC, the measurement point was the midpoint of the distance between the apex of the iliac crest and the lower lateral edge of the ribs. Visceral obesity was defined with a waist circumference equal to or greater than 80 cm in women and 94 cm in men. Persons who smoked 1 cigarette or more per day were considered regular smokers.Blood pressure was measured on the subject’s right arm with an automatic tonometer in a sitting position, after a 5-min rest. The blood pressure was measured twice with an interval of ~2 to 3 min. The analysis included the mean of two measurements. Patients were considered to have arterial hypertension if blood pressure was 140/90 mmHg and more or they were currently receiving antihypertensive treatment in accordance with the current guidelines of the European Society of Cardiology. Measurements of height and body weight were carried out using a height meter with an accuracy of 1 cm and an outdoor electronic medical scale with an accuracy of 100 g; the subject was without shoes and outerwear. Obesity was determined at a body mass index (BMI) ≥ 30 kg/mAll blood samples were collected after overnight fasting of at least 12 h, and glucose, creatinine, cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and uric acid levels were determined. Laboratory methods were strictly standardized and performed on the same laboratory equipment using the same reagent kits in clinical laboratories. Glomerular filtration rate (GFR) was calculated from creatinine levels using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula.The cardiac screening program included a survey based on a standard questionnaire consisting of 12 subsections (modules): socio-demographic data of the respondent; food habits; physical activity; smoking; alcohol consumption; health, attitude to health, and quality of life; sleep; economic conditions and work; stress; anxiety and depression; data on medical care and disability, as well as a history of diseases: angina pectoris, myocardial infarction, arterial hypertension, diabetes mellitus, and others.Cardio-ankle vascular index was measured with the VaSeraVS-1000 device . This method is based on the estimate of the arterial stiffness index b, of the aorta and the iliac, femoral, and tibial arteries. CAVI was measured in study participants for the right and left lower extremities. The patient was resting in a supine position. Cuffs were placed approximately 2 cm above the intercubital fossa on the arms and 2 cm above the medial malleolus on the legs. The elbow and the heel were elevated on the special pillows to stabilize the pulse wave. The fixed cuffs did not touch the surface of the couch. ECG electrodes were placed a few centimeters above the wrist on each forearm. A small microphone was taped onto the chest. The measurements took no more than 10–15 min. The automatic calculation of this indicator is carried out on the basis of registration of plethysmograms of 4 limbs, ECG, phonocardiogram, using a special algorithm for calculations using Bramwell–Hill’s equation [Carbohydrate metabolism disorders were defined in accordance with the WHO diagnostic criteria for diabetes mellitus and other disorders of glycemia . Most caWhen determining prediabetes  we also used the WHO 1999–2013 criteria, which are adopted in our country, and not the more stringent criteria of the American Diabetes Association. According to WHO criteria Impaired glucose tolerance (IGT) was diagnosed with fasting plasma glucose <7.0 mmol/L and 2h glucose 7.8–11.1 mmol/L. Impaired fasting glucose (IFG) has been diagnosed with fasting plasma glucose between 6.1 and 6.9 mmol / L and (if measured) plasma glucose after 2 h < 7.8. HbA1c level up to 6.0% was considered normal, HbA1c level 6.0–6.4% corresponded to prediabetes. The term prediabetes was understood as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), or a combination of both.The study protocol was approved  by the Local Ethical Committee of Research Institute for Complex Issues of Cardiovascular Diseases (Protocol No. 20120208) and was performed in accordance with the declaration of Helsinki. Patients were included in the study after they provided written informed consent.p when comparing the three groups was taken equal to 0.017. Multiple linear regression analysis with stepwise selection was applied to evaluate significance correlation of CAVI with continuous parameters in groups with and without CMD. Binary logistic regression with forward selection (Likelihood Ratio) was used to assess the significant relationship between the presence of pathological CAVI and quantitative or qualitative features in groups with and without CMD. The level of critical significance (p) during the regression analysis was taken equal to 0.05.Statistical processing was using STATISTICA 8.0 and SPSS 17.0 software packages. The Shapiro–Wilk test was used to check the distribution. The data were presented as medians and quartiles ), if variables were not normally distributed. The Kruskal–Wallis test was used to assess the differences between the three groups . For pairwise comparison of groups, The Mann–Whitney test and χ2 (chi-square) test were used to compare two independent groups. With a small number of observations, Fisher’s exact test was used with Yates’ correction. The Bonferroni correction was used to solve the problem of multiple comparisons. Thus, taking the number of degrees of freedom into account, the critical level of significance n = 272), pre-diabetes (n = 44), and normoglycemia (n = 1301) are summarized in The main clinical and anamnestic characteristics in the groups of subjects with diabetes (p < 0.001), in the diabetes group there were fewer men (33.1%) compared to the groups with pre-diabetes and with normoglycemia . The following trend can be noted: patients with diabetes and prediabetes were comparable in most parameters, but differed from patients without CMD. Among patients of both groups with diabetes and prediabetes, there was a greater prevalence of arterial hypertension, kidney disease compared with the normoglycemia group (p < 0.001) but were comparable to the group of prediabetes (p > 0.05). Patients in the diabetic and prediabetes groups had a greater smoking duration (p < 0.05) compared with the group without CMD, without differing from each other. At the same time, the number of smokers was smaller in both groups with CMD in comparison with the group without CMD (p = 0.005). The group without CMD had the highest percentage of employed . Waist and hip circumference was significantly greater in the groups with CMD (p < 0.001 compared with the group without CMD). Signs of obesity (BMI ≥30 kg/m2) were detected in 60.3% of diabetes patients (p = 0.003 versus group without CMD), 50% of prediabetes patients (p < 0.001 versus group without CMD), and 29.1% of patients without CMD.In the diabetes and pre-diabetes groups, patients were older (55.0 and 52.5 y) than in the group without CMD , 79.6% in prediabetes group (p = 0.020 versus group without CMD), and 62.2% in the group without CMD.Visceral obesity (waist circumference > 80 cm in women and > 94 cm in men) was extremely common among patients with CMD—84.1% in diabetes group (p < 0.001 in both cases compared with the group without CMD). The median CAVI was higher in diabetes and pre-diabetes groups . CAVI ≥8 occurred in 40.3% of diabetic patients (p < 0.001 versus group without CMD), 38.6% of patients with prediabetes (p = 0.009 versus group without CMD) and in 23.3% of those examined without CMD. CAVI ≥9.0 was defined as pathologic. Pathologic CAVI (≥ 9.0) was detected in 16.8% of diabetes patients, in 15.9% of those with prediabetes, and in 9.0% of those without CMD  in comparison with individuals without CMD, while not differing among themselves . The preThe glomerular filtration rate (GFR) calculated using the CKD-EPI formula was the highest in group without CMD, compared to both groups with CMD. In the groups with diabetes and prediabetes, GFR was comparable, and significantly lower in comparison with the group without CMD . The desAccording to the result of the correlation analysis conducted in the general sample, CAVI positively correlated with age, male sex, type 2 diabetes, waist circumference, visceral obesity, but not with BMI . CAVI alp < 0.0001, R2 = 0.263. All five variables added statistically significantly to the prediction, p < 0.05. In CMD group only age, SBP, and BMI statistically significantly predicted CAVI, F  = 30.90, p < 0.0001, R2 = 0.252. All three variables added statistically significantly to the prediction, p < 0.05.A multiple regression was run to predict CAVI from age, systolic blood pressure (SBP), diastolic blood pressure (DBP), Heart Rate, WC, GFR_CKD-EPI, BMI, TG, Glucose, Cholesterol, and LDL . In norm2(3) = 111.5, p < 0.0001. The model explained 19.9% (Nagelkerke R2) of the variance in pathological CAVI and correctly classified 90.9% of cases. Increasing age and DBP was associated with an increased likelihood of exhibiting pathological CAVI, but cholesterol increasing was associated with a reduction in the likelihood of exhibiting pathological CAVI in these subjects. In CMD patients the logistic regression model was statistically significant, χ2(4) = 35.32, p < 0.0005. The model explained 21.0% (Nagelkerke R2) of the variance in pathological CAVI and correctly classified 87.1% of cases. Patients with visceral obesity were 4.42 times more likely to exhibit pathological CAVI than patients without visceral obesity, but for general obesity, an inverse relationship was noted. Increasing SBP and decreasing GFR were associated with an increased likelihood of exhibiting pathological CAVI in CMD patients.A logistic regression was performed to ascertain the effects of variable on the likelihood that participants have pathological CAVI (≥ 9.0) in groups with CMD and with normoglycemia . In normIn the present study, it was shown that in patients with prediabetes, CAVI values were increased to the same extent as in patients with type 2 diabetes and significantly differed from the CAVI values in individuals without CMD. The groups with diabetes and prediabetes also did not differ in factors affecting the level of arterial wall stiffness . In the groups with normoglycemia and CMD various associations of indicators with CAVI were noted. Pathological CAVI in normoglycemia was determined by age, blood pressure and dyslipidemia; in patients with CMD by blood pressure, visceral obesity, and decreased GFR.Our results were somewhat unexpected and differ from those obtained earlier ,27. So, Other data on the association of arterial stiffness with different variants of carbohydrate metabolism disorders were revealed in the work of Namekata T. et al., . The CAVp < 0.01) and diabetic (p < 0.0001) groups, but there were no differences between the prediabetes and diabetes groups. The results of multiple regression analysis showed that fasting glucose was closely associated with baPWV, as well as with age and SBP. Similar results were obtained by us in the intergroup comparison; however, the differences in the regression analysis are explained by the differences in the surveyed sample . In the study by Chirinos JA, et al. [Other studies on the prediabetes association with arterial stiffness examined other indicators of the arterial wall state based on the assessment of the pulse wave velocity ,30. It s, et al. , when asYou can note, the discrepancy between the results obtained in different studies evaluating arterial stiffness in prediabetes can be due to a number of reasons. Firstly, these are the characteristics of the subjects, which were analyzed; secondly, applying various methods of measuring arterial stiffness; and, thirdly, using various adjusted variables. All of these factors make it difficult to compare results between studies. Prospective studies that adjust the underlying variables affecting arterial stiffness are needed to understand the role of different blood glucose measurements on arterial stiffness in subjects with prediabetes.Nevertheless, the results of prospective studies can serve as indirect evidence in favor of the adverse effect of prediabetes on the state of both the arterial wall as a whole and the severity of atherosclerotic changes in it ,32,33. SIt is clear that these studies did not assess arterial stiffness, but the study of CAVI may be useful in another aspect. Since the presence of prediabetes is an unfavorable prognostic factor, targeted measures are needed both to normalize carbohydrate metabolism and to influence other associated risk factors in the complex. In our study, it was shown that pathological CAVI in patients with CMD is associated primarily with the level of blood pressure and the presence of visceral obesity, which may be the primary targets for impact in secondary prevention programs. At the same time, the assessment of CAVI in dynamics is quite capable of being the tool that will allow to monitor the success of measures to prevent cardiovascular complications. This assumption is consistent with the data Otsuka K. et al.  that theThere are several limitations to allow when considering the results of this study. First, there is a cross-sectional study design. Thus, the link between arterial stiffness and prediabetes cannot be considered a causal link. Second, in our study prediabetes was determined by as impaired fasting glucose or impaired glucose tolerance, or a combination of both, and oral glucose tolerance test and the assessment of HbA1c were not carried out. So, somewhat underestimate the real prevalence of prediabetes and type 2 diabetes, but in our opinion, this could not affect the association between prediabetes and the CAVI index that we identified, since in previously published studies it was the HbA1c index that was most associated with arterial stiffness , includip < 0.001 and p < 0.009). Pathological values of CAVI (≥ 9.0) were more often detected in the groups of diabetes (16.8%) and pre-diabetes (15.9%) than in persons without CMD (9.0%). In the groups with normoglycemia and CMD various associations of indicators with CAVI were noted. Pathological CAVI in normoglycemia was determined by age, blood pressure, and dyslipidemia; in patients with CMD by blood pressure, visceral obesity, and decreased GFR. Since the identified disorders of arterial stiffness in prediabetes are similar to those in diabetes, their identification is important to prevent further cardiovascular complications. The possibility of using the CAVI index to monitor such preventive effects requires further research.In this study it was shown that in the population sample of the Russian Federation, the values of the CAVI index in patients with prediabetes and diabetes were higher than in the group of persons with normoglycemia (


Nonsteroidal anti‐inflammatory drug (NSAID) exacerbated respiratory disease (N‐ERD) is a triad with asthma, chronic rhinosinusitis with nasal polyps, and NSAID intolerance. Uncontrolled N‐ERD forms a major public health problem due to frequent and difficult‐to‐treat exacerbations and/or requiring putatively frequent endoscopic sinus surgeries (ESS). Our aim was to study factors affecting control of N‐ERD.Retrospective patient record data  from 167 N‐ERD patients undergoing consultation at three tertiary hospitals from 2001 to 2017 was used. Outcome measurements reflecting uncontrolled N‐ERD were revision ESS, corticosteroids/biological therapy, and antibiotic courses during 2016–2020. Associations were analyzed by using nonparametric tests, Cox's proportional hazard, and binary logistic regression models.Nasal polyp eosinophilia increased the risk of revision surgery during the follow‐up . Also baseline oral corticosteroids  and baseline surgery without total ethmoidectomy increased the risk of revision ESS  in unadjusted models. In addition, both baseline OCS  and a history of ≥4 previous ESS  were associated with the use of OCS/biological therapy during the follow‐up, but not with high number of antibiotics.Nasal polyp eosinophilia, baseline OCS, and a history of recurrent ESS predict uncontrolled N‐ERD. These factors might be clinically useful in risk‐estimation of uncontrolled disease and for organizing follow‐ups. Prospective cohort studies with larger sample size are needed to further study the factors affecting the upper airway control of N‐ERD. The patient record data of 167 patients with NSAID‐exacerbated respiratory disease was analyzed to study factors affecting the disease control. Nasal polyp eosinophilia increased the risk of revision surgery, and baseline oral corticosteroids and a history of four or more endoscopic sinus surgeries were associated with poor disease control during the follow‐up. ADaspirin desensitizationARallergic rhinitisATADaspirin treatment after desensitizationCRSchronic rhinosinusitisCRSwNPchronic rhinosinusitis with nasal polypsCTcomputed tomographyENTear nose and throatESSendoscopic sinus surgery(ies)LMLund‐MackayN‐ERDNSAID‐exacerbated respiratory diseaseOCSoral corticosteroid(s)1Nonsteroidal anti‐inflammatory drug (NSAID) exacerbated respiratory disease (N‐ERD) is an inflammatory disease of the airways usually including a triad of chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and hypersensitivity to acetylsalicylic acid (ASA) and other NSAIDs.Chronic rhinosinusitis (CRS) is one of the most common chronic adult health problems and causes severe impact on the quality of life.p < .001) and were significantly younger at the time of their first surgery than were CRSwNP patients without N‐ERD.CRSwNP treatment includes saline irrigations, nasal steroids, oral steroids, oral antimicrobials, and surgery if conservative treatment is not sufficient.Moderate‐to‐severe asthma is common in N‐ERD patients. Severe asthma, with the need for high dose inhaled corticosteroid treatment, steroid bursts and/or continuous OCS, and increased risk for healthcare visits, hospitalizations, and intubations due to asthma exacerbations are more common in N‐ERD patients than other asthmatics.Aspirin treatment after desensitization (ATAD) can be considered if an N‐ERD patient has insufficient response to other CRS treatments, has insufficient control of asthma symptoms despite the use of asthma medications, or needs ASA or NSAID treatment for other medical reasons.In the past few years, biologic therapy modulating the type 2 inflammation present in eosinophilic asthma, but also in CRSwNP, has become intriguing for rhinologists also. At the moment, anti‐IL4/IL13 and anti‐IL5 have been shown to be effective and are the recommended treatment options in otherwise suitable CRSwNP patients.We and other study groups have previously shown that revision ESS is associated with gender, young adults, smoking, allergic rhinitis, previous ESS, occupational exposure, presence of nasal polyps, need for systemic medication, asthma, and N‐ERD.N‐ERD forms a long‐lasting health problem due to frequent and difficult‐to‐treat exacerbations and frequent surgeries.22.1This retrospective follow‐up study was carried out in the Skin and Allergy Hospital and Department of Otorhinolaryngology at Helsinki University Hospital, as well as Departments of Otorhinolaryngology at Tampere and Kuopio University Hospitals, between 2001 and 2020. The study (No. 31/13/03/00/2015) was approved by the ethical committee of Hospital Districts.This study involved 167 N‐ERD patients undergoing ENT consultation between 2001 and 2017. Inclusion criteria were N‐ERD , follow‐up data available, and patient record data of nasal endoscopic signs of NPs at the baseline visit or baseline surgery. CRSwNP was diagnosed according to the European Position Paper on CRS and NPs.Asthma was diagnosed according to Global Initiative for Asthma, for example, patient record documentation was based on typical history and asthma symptoms, and findings of lung function test of at least 15% improvement with bronchodilator test in spirometry  and/or recurrent 20% diurnal variation in PEF monitoring or recurrent 15% bronchodilator response in PEF monitoring or positive methacholine challenge test . N‐ERD diagnosis was based on a positive history of wheeze/cough or naso‐ocular symptoms after intake of NSAID.The background data  were collected from the patient records. We also collected data of baseline ESS ; and previous surgery .The follow‐up data were collected in 2018–2020; mean (min–max) 7.5 (0.9–16.2) years after the consultation visit. The collected follow‐up data included revision ESS during the follow‐up; information regarding start with biological therapy during the follow‐up, continuous OCS during the follow‐up, and purchased, doctor‐prescribed OCS and antibiotic courses (due to exacerbation of CRSwNP and/or asthma) during 2016–2020, was obtained from the national electronic prescription system. Uncontrolled N‐ERD during the follow‐up was in interest. The signs of uncontrolled N‐ERD during the follow‐up were determined by using three outcome measurements: (1) revision ESS; (2) more than one purchased OCS courses/year and/or continuous OCS and/or biological therapy; (3) more than two purchased oral antibiotic courses/year.2.2U tests (continuous). Cox's proportional hazards models were used to evaluate the hazard ratio (HR) of the revision surgery rate between different background variables. Each predisposing factor was modeled separately. The background variables that were associated with purchased of corticosteroids/biological therapy or antibiotics during follow‐up were separately modeled by binary logistic regression. The background variables that were associated significantly with revision surgery or use of corticosteroid/biological therapy/antibiotics, were entered into the multivariable model. p values of <.05 were considered statistically significant.Statistical analysis was carried out by the SPSS Base 15.0 Statistical Software Package (SPSS Inc.). Associations between follow‐up surgery rate and background/follow‐up factors were assessed with Fisher's exact test (dichotomous), Kruskal–Wallis, and Mann–Whitney 3The N‐ERD patients who underwent ESS during the follow‐up were statistically significantly younger and purchased more OCS and/or antibiotics during the follow‐up Table . Other bThe proportion of the N‐ERD patients who underwent baseline ESS was 138 of 167 82.6%). This patient group data were analyzed in univariate and multivariable Cox's proportional hazard models to analyze the background variables fitted for the need for revision ESS during the follow‐up. Nasal polyp eosinophilia  increased the risk of revision ESS during the follow‐up  in univariate models .The proportion of the N‐ERD patients of whom we had data of medication during follow‐up was 140 of 168 (86.4%). This patient group data were analyzed in univariate and multivariable logistic regression models to analyze the background variables that were associated with OCS/biological therapy during follow‐up. Both baseline OCS  and a history of ≥4 previous ESS  were associated with the use of OCS/biological therapy during the follow‐up in univariate models  and there was no difference between the groups. Concerning the time of the data collection, the indication for initiating biological treatment was most likely asthma, as CRSwNP got the official indication for the first biological only in late 2019. In the future, patients with N‐ERD are likely to be among the first when considering the initiation of biologicals for CRSwNP patients.When assessing the factors affecting the need for OCS courses during the follow‐up, we found that the amount of baseline OCS as low as one per year predicted corticosteroid use also for the future. This might be linked to higher eosinophilic inflammation with those who have benefitted from OCS—it suppresses the inflammation very effectively and the patients get relief quickly, making the medicine an attractive choice. On the contrary, the amount of previous surgeries predicting OCS use was quite high, four, or more. This also indicates for an active inflammatory disease—if the patient has already been operated several times and the symptoms persist or return quickly after operations, the use of OCS courses is needed to keep the symptoms bearable. This, together with the finding of high eosinophilia in the tissue as a predicting marker for poor disease control, speaks for the need of systematic evaluation of overall type 2 inflammation activity of the patients initially and keeping those patients with high grade of inflammation in closer control.There are some limitations worth discussing in our study. Due to its retrospective nature, the diagnostics or treatments of N‐ERD were not standardized, making the comparison with other studies more challenging. Ninety percent of the population had a history of using baseline intranasal corticosteroids, 4% were not using, and 6% were lacking the data in patient records. We acknowledge that data were lacking concerning treatment adherence and/or reason for not using intranasal corticosteroids. There might have been limitations in the variables collected from the patient records and the lack of quality‐of‐life measurements limits the analyses. Some patients with exacerbations may also have been treated elsewhere. However, public medical care covers over 90% of operations in Finland.5Nasal polyp eosinophilia, baseline corticosteroid course(s), and a history of recurrent ESS predict uncontrolled N‐ERD. Prospective cohort studies with larger populations are needed to evaluate the risk factors of uncontrolled N‐ERD.Sanna Toppila‐Salmi reports a grant of GSK and consultancies for ERT, Novartis, Sanofi Pharma, and Roche Products outside the submitted work. Anu Laulajainen‐Hongisto reports a grant from the Orion Research Foundation, outside of the submitted work. The other authors declare that there are no conflict of interests.Annina Lyly, Anu Laulajainen‐Hongisto, and Sanna Toppila‐Salmi wrote the article. Sanna Toppila‐Salmi planned the study and collected and analyzed the data. Anu Laulajainen‐Hongisto, Heikki Turpeinen, Seija I. Vento, Jura Numminen, Saara Sillanpää, Jyri Myller, Johanna Sahlman participated in data collection. All the authors critically reviewed the final article text.


A 24-year-old female presented to our clinic with symptomatic tachycardia. In the clinic, she was able to replicate her symptoms, which were due to tachycardia in a standing position that resolved upon sitting. The patient was then offered eight ounces (236.6 mL) of water and, after consumption of such, the standing tachycardia was no longer observed. A diagnosis of postural orthostatic tachycardia syndrome (POTS) was made. This case report discusses a novel approach to acute treatment for POTS. Postural orthostatic tachycardia syndrome (POTS) is an orthostatic intolerance syndrome often seen in young females in which symptoms and tachycardia occur with standing. Although no treatment has yet been proven to be ideal, supine exercise and hydration may provide some benefit. We describe a case of a 24-year-old female with POTS whose standing tachycardia was eliminated after drinking eight ounces (236.6 mL) of water. The effects of water ingestion as a treatment for POTS have rarely been described.. This was reproduced multiple times during this clinic visit. She was symptomatic at this heart rate. Upon sitting, her heart rate returned promptly to 75 bpm and her symptoms resolved. This was deemed consistent with a diagnosis of POTS.A 24-year-old nurse with syncope and palpitations had undergone an evaluation that included loop recorder implantation and tilt-table test two years prior, with negative results. She presented to our clinic after her symptoms worsened and was noted to have multiple episodes of tachycardia recorded on her loop recorder the month before. While sitting in the clinic, she was found to be in sinus rhythm, with a heart rate of 75 beats per minute (bpm). Additionally, her resting blood pressure was 112/72 mmHg while sitting. However, during continuous monitoring via her loop recorder, within seconds of standing, sinus tachycardia (rate: 150 bpm) ensued without an appreciable drop in blood pressure As water ingestion can help some patients with orthostatic hypotension, we thought that such might be effective in her case as well. We had her sit and drink eight ounces (236.6 mL) of water. Ten minutes later, upon standing, her heart rate remained identical to her resting heart rate. This effect was reproducible.1 blood pressure acutely in patients with orthostatic hypotension, but its use as an acute treatment for POTS has not yet been widely reported, to our knowledge. Along with initial conservative measures , we prescribed atenolol. The patient subsequently demonstrated resolution of her symptoms. She was followed using a Reveal LINQ™  implantable loop recorder. With more frequent and regular hydration, the tachycardia and symptoms abated.Acute water ingestion can elevate3 Associated symptoms include lightheadedness, weakness, palpitations, fatigue visual changes, “brain fog,” presyncope, and exercise intolerance.4 POTS occurs most commonly in women aged between 15 years and 45 years, with an incidence rate of 0.2%.5POTS is a chronic, systemic orthostatic intolerance disorder characterized by a heart rate increase of at least 30 bpm  without a corresponding drop in blood pressure.6 These authors suggested that such patients with smaller hearts who have POTS should be considered to have “Grinch syndrome,” referring to the Dr. Seuss character whose heart was “two sizes too small.”6The pathophysiology of POTS is not fully understood, but several mechanisms have been considered. Patients with POTS have orthostatic intolerance due to the inability to adequately vasocontrict veins in the legs and/or splanchnic circulation. In one study, POTS patients were compared with healthy controls to investigate autonomic function and heart size in response to exercise. Results indicated that patients with POTS had, on average, 16% smaller hearts versus the controls. Exercise training increased ventricular cavity size and symptoms.5 aiming to evaluate the prevalence and pathogenetic mechanisms of POTS found that, in a population of 152 patients, at least half of the cases had a neuropathic basis and that a substantial percentage of cases could be of autoimmune origin . Potential risk factors for POTS in children and adolescents include a faster supine heart rate, less water intake, and shorter sleeping hours.7A separate study by the Mayo Clinic8 another suggested a multidisciplinary approach that includes both conservative and nonpharmacologic measures may be best.9 Examples5 include withdrawing offending medications, applying waist-high compression stockings, and increasing water intake (2–3 L/day) and salt intake (10–12 g/day). Symptoms and quality of life may improve with a supervised exercise program consisting of lower-extremity supine exercises.3Currently, there are no clinical trial– or guidelines-established treatments for POTS or class I recommendations for its therapy. Although one study has indicated that one treatment may yield better outcomes over another,11 pyridostigmine,12 low-dose propranolol,13 midodrine,14 droxidopa15 and β-blockers including bisoprolol11 may provide some benefit. Clonidine and methyldopa can be considered in neuropathic POTS.3 Recent trials have indicated a slight heart rate improvement with modest symptom improvement and minimal side effects following ivabradine administration.17 Acetylcholinesterase inhibitors represent another option.18 Additionally, administration of intravenous saline in hypovolemic patients has had some reported benefit and has been proposed to possibly prevent hospitalizations.3 Regular intravenous saline infusions, sinus node modification, and drugs blocking norepinephrine reuptake transporters are not recommended in POTS patients.3 Intravenous immunoglobulin is being explored19 for select patients with an immune form of POTS.Although no drugs are currently approved by the United States Food and Drug Administration to treat POTS, fludrocortisone,1 reported on patients with orthostatic hypotension and autonomic failure who drank 480 mL of tap water and subsequently acutely experienced an increase in blood pressure greater than 30 mmHg within five minutes of ingestion. This pressor response persisted for one hour. Healthy individuals were compared with these individuals without any appreciable response. This oral ingestion proved to elicit a greater response as compared with intravenous infusion. The proposed mechanism revolves around decreased systemic vascular resistance in patients with autonomic dysfunction. Interestingly, an increase in sympathetic activity and norepinephrine levels was noted with the ingestion of water; however, this effect was blunted by β-blockade. May et al.1 described this effect in nine patients with POTS syndrome who showed an appreciable drop in heart rate, although not one as exaggerated as that seen in our patient. Similar findings were described by Shannon et al. in a study of nine orthostatic-intolerant patients. After ingestion of room-temperature water, the previously seen tachycardic response was blunted slightly, with no appreciable change in seated blood pressure or heart rate. However, this change was also not as abrupt as that seen in the case we describe.20 Elsewhere, water and clear soup have been shown to improve orthostatic tolerance in POTS.21May et al.In conclusion, we describe the use of water ingestion as an acute treatment of POTS in a 24-year-old female. In our clinic, she demonstrated a dramatic increase in her sinus rate as it nearly doubled upon standing. Her heart rate went back to her identical resting rate upon sitting. After ingestion of eight ounces (236.6 mL) of water and five minutes of rest, standing did not affect her heart rate. This phenomenon has rarely been described for POTS, and the actual mechanism remains poorly understood. Nevertheless, it should be considered a safe adjunct to treat patients with POTS. Given the difficulties inherent in treating POTS, acute water ingestion is a safe, quick, and easy intervention that can be performed in the outpatient setting. This phenomenon needs to be investigated further.We present this case to spur discussion on the subject of water ingestion for the acute management of POTS. We additionally welcome further thoughts.