In linear regression analysis with stepwise elimination, ARR was an independent explanatory factor for PWV . In conclusion, ARR was directly and independently associated with large arterial stiffness in individuals without clinical suspicion of PA. Therefore, ARR could serve as a clinical marker of cardiovascular risk.Aldosterone-to-renin ratio (ARR) is a screening tool for primary aldosteronism (PA), but the significance of ARR when the PA criteria are not met remains largely unknown. In this cross-sectional study we investigated the association of ARR with haemodynamic variables in 545 normotensive and never-medicated hypertensive subjects  without suspicion of PA. Supine haemodynamic data was recorded using whole-body impedance cardiography and radial tonometric pulse wave analysis. In sex-adjusted quartiles of ARR, determined as serum aldosterone to plasma renin activity ratio, the mean values were 282, 504, 744 and 1467 pmol/µg of angiotensin I/h, respectively. The only difference in haemodynamic variables between the ARR quartiles was higher pulse wave velocity (PWV) in the highest quartile versus other quartiles (Trial registration: ClinicalTrails.gov: NCT01742702. The estimated prevalence of PA has conventionally ranged from 5 to 15% among hypertensive patients6, but according to a recent study, the prevalence might be as high as 16% to 22%7. It is known that PA is associated with significantly higher risk of cardiovascular events and target organ damage than essential hypertension at comparable levels of blood pressure9. Aldosterone excess increases the accumulation of growth factors and collagen fibres in arterial wall11 and it has been shown that PA patients have an increased arterial wall stiffness in comparison with patients who have essential hypertension13.Primary aldosteronism (PA) is the most common form of secondary hypertension5.Screening of PA is based on the aldosterone-to-renin ratio (ARR). The Endocrine Society recommends the screening in the following cases with clinical suspicion pf PA: Blood pressure > 150/100 mmHg on three different days, drug resistant hypertension that is uncontrolled with ≥ three antihypertensive drugs, controlled hypertension with ≥ four antihypertensive drugs, hypertension with spontaneous or diuretic-induced hypokalaemia, hypertension with adrenal incidentaloma, hypertension with a family history of hypertension or cerebrovascular events at a young age (< 40 years), hypertension together with sleep apnoea, and all first-degree relatives of patients with PA18. A Japanese long-term observational analysis demonstrated that elevated ARR is associated with an increased incidence of cardiovascular disease in patients with essential hypertension19. In 60 healthy adults with a mean age 43 years, Shapiro et al. reported a direct correlation (rP = 0.298) between ARR and pulse wave velocity (PWV)20. In 2000 participants of the Framingham study, Lieb et al. found that ARR was a significant independent correlate of PWV (β = 0.20). However, the participants were not screened for the presence of PA, 33% were ingesting antihypertensive medications, and 12% had diabetes mellitus18.The role of ARR for screening of PA is robust, but there is a scarcity of data evaluating the significance of ARR in subjects who remain below the screening threshold for PA. Previously, ARR has been associated with the development and severity of hypertension, even in patients without excessive aldosterone levelsIn this cross-sectional study we analysed the association of ARR with several cardiovascular variables in normotensive subjects and previously undiagnosed never-medicated hypertensive patients. We tested the hypothesis whether ARR correlates with haemodynamic parameters in subjects who are not fulfilling the clinical criteria for the screening of PA.23. All subjects were examined by a physician and routine laboratory analyses for elevated blood pressure (BP) were taken24. The medical history, lifestyle behaviour and family history were documented. Alcohol use was evaluated as standard drinks  per week, and smoking amount was estimated in pack-years. The exclusion criteria were history of coronary artery disease, stroke, cardiac insufficiency, valvular heart disease, chronic kidney disease25, secondary hypertension, alcohol or substance abuse26, psychiatric illnesses other than mild to moderate depression or anxiety, heart rhythm other than sinus rhythm, use of antihypertensive or uric-acid-lowering medications, and ongoing pregnancy. Altogether 606 subjects, aged 19–72 years, were eligible for the study. Data of ARR was missing in 48 subjects while 13 subjects met the screening criteria of PA  and were therefore excluded. The Endocrine Society screening for PA is based on BP > 150/100 mmHg on three different days5. In the present study the BP criteria were applied on the 5-min laboratory BP measurements (see below), and the results were confirmed by applying the criteria for the office BP measurements on a single occasion. The final study population consisted of 545 subjects.The recruitment of the study subjects has previously been described in detailSigned informed consent was obtained from all participants. The study complies with the declaration of Helsinki and was approved by the Ethics Committee of the Pirkanmaa Hospital District (study code R06086M).27. Insulin sensitivity was evaluated by the quantitative insulin sensitivity check index (QUICKI)28, and homeostatic model assessment of insulin resistance (HOMA-IR)29. In addition, the subjects were invited to participate in a standard 75-g oral glucose tolerance test (OGTT) for the determination of the Matsuda index30.Blood and urine samples were taken after 12 h of fasting. Plasma renin activity  and aldosterone concentration  were determined using commercial kits. Plasma C-reactive protein (CRP), sodium, potassium, glucose, creatinine, cystatin C, uric acid, triglyceride, and total, HDL and LDL  cholesterol concentrations were determined using Cobas Integra 800 . Insulin and parathyroid hormone (PTH) were determined using electrochemiluminescence immunoassay . Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease – Epidemiology collaboration (CKD-EPI) cystatin C equation31. Products containing caffeine, smoking or heavy meal were not allowed for ≥ 4 h, and alcohol consumption was not allowed for ≥ 24 h before the investigation. The subjects rested supine on the examination table with impedance cardiography electrodes placed on body surface, tonometric sensor for pulse wave analysis on left radial pulsation, and oscillometric brachial cuff for BP calibration to the right upper arm. The left arm with the tonometric sensor was stabilized to 90° in a support, which held the measurement probe at the heart level.Haemodynamic recordings were performed in a noiseless, temperature-controlled laboratory by research nurses31.The measurement consisted of a 5-min period, during which haemodynamic data was captured continuously. For the statistical analyses, the mean values of each 1-min period of recording were calculated. The repeatability and reproducibility of the protocol have been demonstrated to be good22. The radial BP signal was calibrated approximately every 2.5 min by brachial BP measurements. Aortic BP was derived using the SphygmoCor pulse wave monitoring system 32. Aortic pulse pressure, augmentation index , and AIx adjusted to heart rate 75/min (AIx@75) were also determined. The central forward wave amplitude was defined as the difference between waveform foot and first systolic inflection point pressure in the aortic waveform34.Radial BP and pulse wave were recorded by a tonometric sensor  fixed on the radial pulse37. Systemic vascular resistance was calculated from radial BP and cardiac output measured by CircMon. Stroke volume, cardiac output and systemic vascular resistance were presented as indexes related to body surface area calculated using the DuBois equation38. The method and electrode configuration has been previously reported37.We used the CircMon device  to assess changes in body electrical impedance during cardiac cycles to record heart rate, stroke volume, cardiac output, and PWV31 and the thermodilution and direct oxygen Fick methods36, and the PWV values show very good correlation with values measured using ultrasound or the tonometric method39.With CircMon the recorded stroke volume and cardiac output are in good agreement with values obtained utilizing 3-dimensional echocardiographyTo illustrate the influence of ARR on the haemodynamic variables, the study participants were divided into quartiles of ARR. As serum aldosterone concentration was slightly higher in women than in men see ‘’, the ARP < 0.05 was considered significant.Analyses of normally distributed data were performed using analysis of variance (ANOVA) and ANOVA for repeated measurements, and non-normally distributed data using Kruskal–Wallis test with Mann–Whitney U-test in the post-hoc analyses. The Bonferroni correction was applied in all post-hoc analyses. The ANOVA for repeated measures analyses were adjusted for sex, age, BMI, and eGFR, as appropriate, by using these variables as covariates in the analyses. Normally distributed variables in the tables were presented as means and standard deviations and non-normally distributed variables as medians and 25th–75th percentiles. The figures were depicted as means and standard errors of the mean (SEM). Pearson’s correlations were calculated for normally distributed and Spearman's correlations for non-normally distributed variables. The values of the haemodynamic variables for the statistics in Table To investigate factors independently associated with PWV in the whole study population, linear regression analysis with stepwise elimination was applied. The covariates in the analysis were age, sex, BMI, categorised smoking status , categorised alcohol consumption ; plasma aldosterone, renin, aldosterone-to-renin ratio, HDL cholesterol, LDL cholesterol, triglycerides, CRP, uric acid, calcitriol, PTH, QUICKI, eGFR, ejection duration, heart rate, and mean aortic pressure. Coefficients (B) and standard coefficients (Beta) of regression were calculated, and assumptions of linearity were confirmed by the analysis of residuals. IBM SPSS Statistics Version 26  was used for statistics.p < 0.001). Therefore, the ARR results were examined in sex-adjusted quartiles (Q)  vs. 0.97 (0.95) ng of angiotensin I/ml/h; 779 (527) vs. 719 (531) pmol/µg of angiotensin I/h, respectively; mean (SD)]. However, serum aldosterone concentration was higher in women than in men (561 (481) vs. 449 (208) pmol/l, respectively, 2 with no differences between the quartiles. Average alcohol use was moderate 4.3 standard drinks/week, and the prevalence of present and previous smokers was 12% and 31%, respectively. Alcohol intake and the prevalence of smokers were corresponding in all quartiles . Office systolic BP was higher in Q4 than in Q1, and office diastolic BP in Q4 than in Q1 and Q2. The proportion of hypertensive subjects in the office measurements was higher in Q4 than in Q1.When applying the office cut-off values of hypertension (systolic BP ≥ 140 or diastolic BP ≥ 90)During the haemodynamic measurements, systolic and diastolic BP values were 13–16 and 16–17 mmHg lower, respectively, and heart rate 3–5 beats/min lower, than in the office measurements, with no significant differences between the quartiles. With the office cut-off values of hypertension, no significant differences were found in the proportion of hypertensive subjects between the quartiles during the haemodynamics measurements , while age and ARR were directly correlated .In sex adjusted quartiles of ARR, the mean values were 282, 504, 744 and 1467 pmol/µg of angiotensin I/h, respectively  .04) Fig. . Among tAldosterone and haemodynamics. When examined in sex-adjusted quartiles of serum aldosterone concentration, the quartiles presented with differences in age and BMI (not shown). In the sex-, age- and BMI-adjusted quartiles of serum aldosterone concentration, no differences in the haemodynamic variables were detected between the quartiles except for PWV, the value of which was lower in Q1 versus Q4 .Renin activity and haemodynamics. In sex-adjusted quartiles of plasma renin activity, no additional adjustments were needed (not shown). Corresponding to the results in quartiles of aldosterone concentration, all haemodynamic variables in quartiles of renin activity were similar except for PWV. However, the difference in PWV was observed between Q1 and Q2 , while PWV in Q1, Q3 and Q4 was corresponding .2 = 0.634). The variables in the model included both aldosterone concentration and renin activity, yet neither of them turned out as independent predictors for PWV. QUICKI was used as an insulin sensitivity variable in the model, as the Matsuda index was not available from all participants (Table p < 0.001) and between QUICKI and HOMA-IR-0.720 (p < 0.001).The results of the linear regression analyses with stepwise elimination are presented in Table 24, ARR was an independent explanatory factor for PWV in both the normotensive  and hypertensive  subgroups. The result did not change when applying the home BP measurement cut-off (BP ≥ 135/85 mmHg).When the office cut-off for hypertension (BP ≥ 140/90 mmHg) was applied for the laboratory measurementsp < 0.001), while the other explanatory factors were age, mean aortic pressure, heart rate, and plasma concentrations of HDL cholesterol, uric acid, and triglycerides (R2 = 0.572 of the model).If the office BP measurements were applied for the exclusion of participants with potential PA, 499 subjects were eligible for the statistical analyses. Also, in this analysis ARR was an independent explanatory factor for PWV . A small study in 24 patients with essential hypertension by Mahmud and Feely found no correlation between ARR and PWV, but showed that aldosterone antagonist-induced decrease in systolic BP correlated with pre-treatment ARR50. However, in 102 patients with confirmed PA, no correlation was found between ARR and baseline PWV, or between ARR and the reduction in PWV following adrenalectomy51. Yet, the subsequent increase in plasma renin activity after adrenalectomy was an explanatory factor for the reduction in PWV during 6 months of follow-up51. Altogether, the effects of aldosterone excess on large arterial stiffness may be manifested early in the course of the disease, and the beneficial changes in the vasculature following surgical treatment do directly correlate with the plasma concentrations of aldosterone or ARR.Some former studies have suggested a direct association between ARR and arterial stiffness. Shapiro et al. reported a significant association of ARR with PWV in 60 normotensive subjects, but in contrast to our study, their approach did not provide evidence of ARR as an independent explanatory factor of PWV52 and treated hypertensive patients53. Out-of-office BP monitoring provides better assessment of overall BP and response to treatment in patients with white-coat hypertension54. The average difference between the office and laboratory BP in our study was rather large, whereby haemodynamic measurements under standard conditions can also result in clearly lower BP when compared with the office measurements. The correlations between office and laboratory measurements were 0.70 and 0.65 for systolic and diastolic BP, respectively. We used the algorithm recommended by The Endocrine Society for the screening of PA patients5, in order to exclude potential PA patients from the study population. Regardless of whether office BP > 150/100 mmHg measured on a single occasion, or average BP > 150/100 mmHg during haemodynamic measurements, was applied for the exclusion of participants, ARR was an independent explanatory factor for PWV. Of note, the results were corresponding when studied in normotensive and hypertensive subjects with two different cut-off values for hypertension (140/90 or 135/85 mmHg).Noteworthy, in the present study the systolic and diastolic BP values were 13–16 and 16–17 mmHg lower, respectively, during the haemodynamic laboratory measurements than in the office measurements. This resembles the white-coat effect in hypertension, which has been related to large arterial stiffness in both untreated57. Even in the absence of PA, plasma aldosterone concentration was related to insulin resistance in 251 male African American subjects58. Higher ARR was also associated with insulin resistance in 483 young adult African Americans without cardiovascular or renal disease59. In our study, no differences in insulin sensitivity between the ARR quartiles were observed as the indices QUICKI, HOMA-IR and Matsuda did not deviate. Therefore, the differences in PWV between the ARR quartiles could not be explained by variations in insulin sensitivity. Also the plasma concentrations of uric acid, the levels of which are usually elevated in insulin resistance and metabolic syndrome23, were similar in quartiles of ARR.Seven of the present participants had fasting plasma glucose in the diabetic range, 53 participants had impaired fasting plasma glucose, while 89% of the participants presented with glucose values within the normal range. PA has been linked to abnormalities in glucose metabolism, especially to insulin resistance and impaired glucose tolerance60, and induce alterations in the components of the renin-angiotensin system in the vasculature61. Moreover, vitamin D receptor activation downregulates the synthesis of renin in the juxtaglomerular cells and influences the expression of other components of the renin-angiotensin system in the kidney63. In the present study, the plasma concentrations of calcium and vitamin D metabolites were similar in the ARR quartiles. Therefore, putative changes in the metabolism of calcium and vitamin D were not the explanations for the differences in arterial stiffness between the ARR quartiles.Changes in calcium metabolism may influence BP36, and central aortic BP waveform from the applanation tonometry signal32. Therefore, the results must be interpreted with caution, albeit the methods have been validated against direct or invasive measurements37. However, the approach to examine central haemodynamics instead of plainly focusing on brachial artery pressure, may be better related with the level of cardiovascular risk65.Our study has limitations. The cross-sectional design cannot substantiate causality. A potential selection bias caused by the recruitment of voluntary subjects and the exclusion protocol must be acknowledged. The haemodynamic recordings lasted for five minutes and the values of the last three minutes were used for the analyses, which gives a rather short window of observation. Still, the analyses were based on average on 190 cardiac cycles in each subject (mean HR in the study population was 63.3 beats/min). In addition, we applied indirect non-invasive methods requiring mathematical processing to derive PWV, stroke volume and cardiac output from the bioimpedance signalIn conclusion, a direct association between ARR and PWV was observed in 545 normotensive and never-treated hypertensive subjects when the screening criteria of PA were not met. Therefore, our results indicate that ARR is related to arterial stiffness in individuals without clinical suspicion of PA according to the prevailing guidelines. Altogether, increased ARR in the absence of stage II and more severe hypertension should be recognized as an indicator of increased cardiovascular risk.


Patients with chronic kidney disease (CKD) reportedly have a high prevalence of aortic valve calcification (AVC). In population-based studies, AVC is considered a manifestation of systemic atherosclerosis. The association of AVC with atherosclerotic lesions has not been fully investigated in predialysis patients. The present study was performed to determine whether carotid artery lesions and peripheral artery disease (PAD) are associated with AVC in patients with CKD not on dialysis.In total, 749 patients were included in this cross-sectional study. AVC was evaluated using echocardiography. Carotid artery lesions including carotid artery plaque (CAP) and PAD were simultaneously examined in each patient. A logistic regression analysis was applied to determine the factors associated with AVC.AVC, CAP, and PAD were found in 201, 583, and 123 patients, respectively. In the multivariable analyses adjusted for covariates including the estimated glomerular filtration rate and makers of mineral metabolism , AVC was significantly associated with the presence of CAP , the presence of PAD , the CAP score (per 1.0-point increase) , and the ankle-brachial blood pressure index (per 0.1-point increase) .AVC was associated with atherosclerotic lesions independent of kidney function and mineral metabolism. We consider that this association between AVC and atherosclerosis might reflect the burden of shared atherosclerotic risk factors. A previ/1.73 m2 . Researc/1.73 m2 . Further/1.73 m2  patients. In contrast, patients with CKD have been shown to have a high prevalence of AVC. In dialysis patients, the prevalence of AVC ranges from 14.1 to 75.0% [The reported prevalence of AVC ranges from 6.6 to 18.4% in population-based studies –15. In cto 75.0% , 16–19, to 75.0% , 20–22. to 75.0% . In patito 75.0%  and Wangto 75.0%  demonstrto 75.0% , 26. Theto 75.0% –31. Howen = 7) or had no available data regarding echocardiography (n = 7), blood samples (n = 33), ankle-brachial blood pressure index (ABPI) (n = 5), or carotid artery lesions (n = 20). The remaining 749 patients were enrolled in this cross-sectional study, and no patients had bicuspid aortic valves or rheumatic heart disease.In total, 821 patients were admitted to our hospital for evaluation and education of CKD from May 2010 to July 2019. We excluded 72 patients who underwent aortic valve replacement . The eGFR (mL/min/1.73 m2) was calculated using the new Japanese equation: eGFR = 194 × SCr− 1.094 × age− 0.287 × 0.739  [2 or by kidney damage regardless of a decrease in eGFR, in accordance with the Kidney Disease: Improving Global Outcomes clinical practice guidelines [Blood samples were obtained from each patient in the early morning after an overnight fast. Daily proteinuria was also measured. The intact FGF23 level was measured using an FGF23 enzyme-linked immunosorbent assay kit . The intact PTH level was measured by electrochemiluminescence immunoassay . A radioimmunoassay was used to measure the 1,25-dihydroxyvitamin D [1,25(OH) female) , where Sidelines .2. Blood pressure was measured on the second day of hospitalization at three separate times, with the patient in a sitting position; the average of the three readings was recorded.All enrolled patients were interviewed and clinically examined at presentation. Their medical histories and outpatient records were evaluated in detail. Demographic information (age and sex), medication history, and atherosclerotic risk factors  at presentation were recorded for each patient. Hypertension was defined as systolic blood pressure of ≥140 mmHg, diastolic blood pressure of ≥90 mmHg, or the current use of antihypertensive drugs. Diabetes mellitus was defined as a previous or current plasma fasting glucose level of ≥6.99 mmol/L or the use of hypoglycemic agents. Dyslipidemia was defined as plasma triglycerides ≥1.69 mmol/L, plasma low-density lipoprotein cholesterol ≥3.62 mmol/L, plasma high-density lipoprotein cholesterol < 1.03 mmol/L, or the use of lipid-lowering drugs based on a history of dyslipidemia. Ischemic heart disease was defined as a history of angina, myocardial infarction, coronary angioplasty, or coronary artery bypass surgery. Cigarette smoking was evaluated as current or past. The body mass index was calculated as weight in kg divided by height in mThe method of ABPI measurement is described in our previous report . PAD was2D levels were log-transformed to achieve an approximately normal distribution prior to statistical analysis. A logistic regression model was also applied to elucidate the factors associated with AVC. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each variable. In addition, we examined linear regression analyses to evaluate the association between AVC score and CAP score, ABPI, and eGFR. All statistical analyses were performed using STATA ver. 14 . A P-value of < 0.05 was considered to indicate statistical significance.Continuous data are expressed as either mean ± SD or median (interquartile range), depending on their distribution. Categorical data are expressed as n (%). The non-normally distributed C-reactive protein, FGF23, PTH, and 1,25(OH)P for trend < 0.01). Table 2D level and a higher FGF23 level were related to AVC. AVC was significantly associated with the presence of CAP and PAD, a higher CAP score, and a lower ABPI. In addition, linear regression analyses showed that AVC score was related to CAP score  in this study was 70 years . The primary causes of renal disease were chronic glomerulonephritis , hypertensive nephrosclerosis , diabetic nephropathy , other defined causes , and unknown causes . Of the total 749 patients, 127 (17.0%), 221 (29.5%), 237 (31.6%), and 164 (21.9%) patients were categorized as having stage 1–2, 3, 4, and 5 CKD, respectively. The prevalence of AVC was 26.8% (201 patients). CAP and PAD were found in 583 and 123 patients, respectively. The prevalence of AVC in patients with stage 1–2, 3, 4, and 5 CKD was 11.0, 25.3, 30.8, and 35.4%, respectively 2D, and higher log FGF23 were related to AVC, whereas serum phosphorus and log PTH were not. Left ventricular hypertrophy was also associated with AVC. In addition, patients with CAP, PAD, higher CAP score, lower ABPI, and higher carotid IMT had a significantly higher risk of having AVC. We performed multivariable analyses to determine whether the presence of CAP, CAP score, the presence of PAD, ABPI, and carotid IMT were independently associated with AVC  in the univariable analyses, but not in the multivariable analyses (model 4) (data not shown). Based on these findings, the substantial effects of derangement of mineral metabolism on the development of AVC have remained controversial, and further investigations are warranted to elucidate the association between AVC and deranged mineral metabolism.The association between AVC and derangement of mineral metabolism has been documented in several studies. Deranged mineral metabolism occurs with advancing CKD stages. One study showed that AVC was associated with higher FGF23 and PTH levels in patients with mild to moderate CKD , whereasIn the present study, univariable logistic analysis revealed no significant association between AVC and male sex Table . Further2D, and log FGF23, which were measured simultaneously. Accordingly, despite the limitations, our results may indicate a robust relationship between AVC and atherosclerotic parameters.The present study has some limitations. First, all patients were recruited at a single regional hospital; thus, the selection of patients was limited and the sample size was relatively small. Second, our cohort had an imbalanced sex ratio and was relatively old, probably because of the recruitment of consecutive patients who were admitted to our hospital. Third, this cross-sectional study did not allow us to draw causal relationships. Fourth, the clinical data including the echocardiographic findings were recorded at one study time. Fifth, we did not evaluate fetuin-A, matrix-Gla-protein, reactive oxygen species, asymmetric dimethylarginine, or receptor activator of nuclear factor-κB ligand, all of which can play roles in aortic valve calcific degeneration associated with CKD . FinallyThe present study showed that AVC was associated with the presence of CAP and PAD, and the CAP score and ABPI, independent of traditional and nontraditional CV risk factors. We consider that the association between AVC and these subclinical atherosclerotic lesions might reflect the burden of shared atherosclerotic risk factors.Additional file 1: Supplementary materials 1. Correlation between AVC score and CAP score. The dashed lines indicate 95% confidence intervals. R2 = 0.097, coefficient of correlation = 1.868, P < 0.01. AVC, aortic valve calcification; CAP, carotid artery plaqueAdditional file 2: Supplementary materials 2. Correlation between AVC score and ABPI. The dashed lines indicate 95% confidence intervals. R2 = 0.048, coefficient of correlation = − 0.036, P < 0.01. AVC, aortic valve calcification; ABPI, ankle-brachial blood pressure indexAdditional file 3: Supplementary materials 3. Correlation between AVC score and eGFR. The dashed lines indicate 95% confidence intervals. R2 = 0.027, coefficient of correlation = − 5.064, P < 0.01. AVC, aortic valve calcification; eGFR, estimated glomerular filtration rate


Hyperventilation is a commonly used therapy to treat intracranial hypertension (ICTH) in traumatic brain injury patients (TBI). Hyperventilation promotes hypocapnia, which causes vasoconstriction in the cerebral arterioles and thus reduces cerebral blood flow and, to a lesser extent, cerebral blood volume effectively, decreasing temporarily intracranial pressure. However, hyperventilation can have serious systemic and cerebral deleterious effects, such as ventilator-induced lung injury or cerebral ischemia. The routine use of this therapy is therefore not recommended. Conversely, in specific conditions, such as refractory ICHT and imminent brain herniation, it can be an effective life-saving rescue therapy. The aim of this review is to describe the impact of hyperventilation on extra-cerebral organs and cerebral hemodynamics or metabolism, as well as to discuss the side effects and how to implement it to manage TBI patients. Intracranial hypertension (ICHT) is the most critical and potentially devastating complication in traumatic brain injury (TBI) patients . Since t2) has been used since decades in neuro-anesthesia and in neuro-intensive care, because lowering PaCO2  through increased minute volume ventilation  can rapidly contribute to reduce the volume of the swollen brain and help control ICP  have been evaluated, while pre-hospital hyperventilation or spontaneous hyperventilation will not be discussed.2 <38 mmHg) in order to manipulate cerebral hemodynamics and compliance , forced (PaCO2 26–30 mmHg), or intensified forced (PaCO2 <26 mmHg), according to PaCO2 levels  or dilating  , and is proportionally more relevant with hypercapnia than with hypocapnia  could improve indices of cerebral autoregulation function in TBI patients with disturbed pressure-reactivity at baseline, whereas those with intact pressure-reactivity at baseline would have no effect of such intervention , although these results were not consistent in all studies  is a regional technique, is well-correlated with local CBF and can directly monitor the areas at higher-risk of secondary ischemia    , 74. Rec30 mmHg) , 40.n = 9) showed that moderate and intense hyperventilation resulted in reduced CBF and increased oxygen extraction, but a constant oxygen metabolism  (2 <30 mmHg) increased the volume of hypoperfused cerebral areas within the injured brain, which, in the absence of increased oxygen extraction, would result in tissue hypoxia.Cerebral metabolic function can be assessed at bedside using the microdialysis technique, or performing PET and magnetic resonance imaging (MRI) spectroscopy studies. In one study, early hyperventilation  was associated with a significant increase in tissue lactate and lactate/pyruvate ratio, suggesting anaerobic metabolism and tissue hypoxia ; these mfailure) . In two failure) , 75, hypn = 251), Gordon et al. (2 between 25 and 30 mmHg for 6 to 41 days); however, more severe neurological sequelae were observed among survivors in the hyperventilation group when compared to the other. Only one prospective randomized clinical trial has investigated the effects of hyperventilation in this setting; Muizelaar et al. , there was a higher proportion of patients with long-term favorable neurological outcome when compared to the others.With all these potential side effects, which is the effect of controlled hyperventilation on the outcome of TBI patients? In one large retrospective study  monitoring, is necessary in this phase, as hyperventilation in the absence of elevated ICP is frequently observed in adult TBI patients   and therefore be less accurately predicted, using PaCO2 levels and quantifying changes in cerebral hemodynamics and physiology to PaCO2 changes at bedside is more feasible for physicians. If ICP remains within acceptable values after 48 h from the injury , lower PaCO2 values  could result in improved cerebral autoregulation  could be tolerated, although a more comprehensive neuromonitoring would be the only effective solution to detect the potential occurrence of tissue hypoxia.The initial PaCOagement [, internaagement [, 50. Proagement [ as it wopatients . Importa output) . Whethergulation , howevergulation ; as such2 values of 30 mmHg because: (a) the most important effects of PaCO2 on ICP are observed between 30 and 50 mmHg and (b) most of the relevant cerebral side effects were reported for forced hyperventilation. If possible, the use of hyperventilation should be minimized for these patients during the first 24 h after injury, when CBF often is the most reduced  are present  and coul reduced , unless 2 around 33–36 mmHg and avoid values <30 mmHg , international guidelines recommended the use of controlled hyperventilation only as “tiers 2” therapy, after the failure of increased sedation and osmotics infusion ; indeed,<30 mmHg . In the 2 values on cerebral oxygenation and metabolism. As such, PaCO2 values and hyperventilation could be adjusted to the brain tolerance and therapeutic targets individualized on the patients' need. In case of the need for low PaCO2 values and concomitant lung injury, other interventions aiming at reducing CO2 production, such as increasing sedation or hypothermia, could be considered to induce hypocapnia and avoid lung stress and VILI. However, this strategy should be further evaluated in clinical studies.In our opinion, invasive neuromonitoring should be also considered in severe TBI patients and ICHT to optimize overall management and, in particular, to assess the effects of low PaCO2 values are mandatory in severe TBI patients because of the significant effects on brain hemodynamics and compliance, high doses of sedatives, often in association with neuromuscular blocking agents (NMBAs), are required to adjust ventilatory parameters to obtain desired PaCO2 targets. As such, in the absence of aggressive therapies for ICHT, it remains unknown when it would be safe to discontinue sedatives and eventually tolerate spontaneous hyperventilation in these patients. If this occurs after several  days from injury, the risk of oligemia would be probably limited. Also, spontaneous hyperventilation after acute brain injury is often triggered by local acidosis , which result in vascular dilation and would probably compensate from vasoconstriction induced by hyperventilation. In these cases, non-invasive  and invasive  monitoring would again be helpful to individualize therapeutic decisions.If controlled PaCO2 values should be maintained in the early phase after TBI if ICP remains within acceptable values. Controlled hyperventilation  should be used as a temporary life-saving intervention in case of severe intracranial hypertension; PaCO2 levels should be also adjusted and individualized in each patient using CTP and cerebral ultrasound of, whenever possible, advanced multimodal neuromonitoring.In conclusions, controlled hyperventilation is effective in reducing ICP but it also reduces CBF and might have both cerebral and systemic serious side effects. As such, normal PaCOEG, LP, JC, and FT contribute equally to the elaboration of this manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Anti-T2 biological therapies have proven to effectively reduce acute exacerbations and daily doses of oral steroids in severe eosinophilic asthma. Despite the remarkable clinical efficacy, there are usually only moderate improvements in airflow limitation, suggesting that other measures of lung function like small airway dysfunction (SAD) might better reflect the clinical response. We aimed to investigate if measures of small airway function would predict and correlate with the clinical response to anti-T2 therapy.25-75). We also studied air trapping (RV and RV/TLC), blood eosinophils and FeNO. Patients were classified into responders and partial or non-responders. Clinical response was defined as at least 50% reduction in annualized severe exacerbations and daily oral steroid doses accompanied with a minimum increase of 3 points in the ACT score. We used a Receiver Operator Characteristic (ROC) to study the capacity of FDR in predicting clinical response compared to other clinical variable like blood eosinophils. We studied the correlation between FDR measures and clinical response, represented by the ACT score and number of exacerbations, using linear regressions.We studied data of patients who were previously included in the German prospective longitudinal All Age Asthma Cohort (ALLIANCE) that recruits asthma patients of all severity grades and inflammatory phenotypes. The selection criteria for this analysis were adult patients with severe eosinophilic asthma under treatment with anti-T2 biological agents. Asthma control was assessed by asthma control test (ACT) and number of severe exacerbations. Small airway function was assessed by the frequency dependence of resistance ) derived from impulse oscillometry (IOS) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity . Responders had significantly higher baseline FDR compared to partial or non-responders but similar FEV1, FEF25–75, RV and RV/TLC. ROC analysis showed that the combination of FDR and blood eosinophils had the best predictive capacity of the clinical response among all tested clinical markers  with an AUC of 85% [67–100%], . Linear regressions indicated better associations between improvements in FDR and ACT score  than with FEV1 and ACT score . Likewise, we observed better associations between improvements in FDR and reduction of exacerbations  than with FEV1 .20 patients were included , 27.6 ± 5.4 kg/mOur data suggest that severe SAD may represent a distinct phenotype of eosinophilic asthma that substantially improves under anti-T2 biological therapy. Measures of small airway function might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count. To the Editor,Anti-T2 biological therapy is recommended as an add-on treatment for severe eosinophilic asthma . SeveralIn this study, we analyzed data of patients who were previously recruited in the prospective longitudinal All Age Asthma Cohort (ALLIANCE), a national cohort of pediatric and adult patients with asthma in Germany, initiated by the German Centre for Lung Research (DZL). The study was approved by the local ethics committee at the medical school Luebeck (Az.21–215) and is registered at clinicaltrials.gov (adult arm: NCT02419274) . Study vThe selection criteria for this study were adult patients with severe eosinophilic asthma in whom a treatment with anti-T2 biological agent has been initiated while already being recruited into the observational ALLIANCE study and in whom at least one complete follow-up visit was available. Indication, prescription and administration of the biological therapy were not part of the study but rather were done by their respiratory physicians.25–75) and IOS measures ). Percent predicted FDR values (FDR %pred.) were calculated according to recently provided prediction equations by the German KORA cohort [On each study visit, we assessed asthma control by asthma control test (ACT) as well as number of severe exacerbations 12 months prior to the study visit, defined as a burst of systemic corticosteroids for ≥ 3 days . We perfA cohort . We alsoA cohort , 17. BasA cohort  and addiA cohort . Partial2). All patients were on inhaled corticosteroids  and long-acting β2 adrenoceptor agonists (LABA). 55% were treated with long-acting muscarinic receptor antagonists (LAMAs) and 80% were on maintenance oral corticosteroids  prior to starting with biological therapies. Mean predicted FEV1 at baseline was 76 ± 21%, mean FEF25-75 1.1 ± 0.73 (l/s), mean predicted RV 148 ± 25%, mean RV/TLC 47 ± 8%, mean FDR 0.21 ± 0.18 kPa/L/s, mean FDR%pred. 224% ± 140%, mean absolute blood eosinophils 570 ± 389/µl, mean FeNO 60 ± 33 ppb. Mean ACT score was 15.5 ± 5.4 points and patients experienced 5 ± 3 severe exacerbations 12 months prior to initiating the biological therapy. Between responders and partial-/non-responder, there were no significant differences in the baseline values of all clinical variables except for FDR%pred, which was significantly higher in responders  were included, , 27.6 ± 5.4 kg/mWithin response groups, responders to anti-T2 biological therapies experienced significant improvements in all clinical markers  in contrast to partial/non-responders that did not demonstrate any statistically significant changes; details are given in Table .25–75, RV and RV/TLC) were not superior to FEV1 when correlated to improvements in exacerbations or ACT with R2 values around 0.20.Linear regressions indicated better associations between improvements in FDR and ACT score than with FEV1 and ACT score as well as better associations between improvements in FDR and reduction of exacerbations than with FEV1 Fig. . The oth25-75, lung clearance index, regional ventilation inhomogeneity in acinar and conducting airways improve significantly under biological therapy [The main finding of our study is that SAD improves substantially under anti-T2 biological therapy in patients with severe eosinophilic asthma. Furthermore, pre-treatment IOS measures of SAD demonstrated to be meaningful predictors of clinical response, thereby indicating that severe SAD might describe a distinct phenotype with therapeutic implications among patients with severe eosinophilic asthma. Our results are consistent with the findings of previous studies which indicated that measures of SAD like FEF therapy , 21. Osc therapy , diurnal therapy  and atop therapy . Our obs therapy . In our  therapy .The main limitations of this study are its observational nature and the small number of the included subjects. Further, additional measures of small airway function like inert gas distribution could have supported our findings. Therefore, clinical trials involving larger cohorts and multimodular assessment of small airway function are needed to confirm our observation. Finally, two patients had a treatment with either dupilumab or benralizumab which do not share the exact same pharmacological mechanism compared with mepolizumab.Our data support that SAD is potentially linked to asthma control as SAD improves substantially under anti-T2 biological therapy in therapy responders. Measures of small airway function like the FDR might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count and might also serve as markers to assess clinical treatment response in patients with newly initiated biological therapy.


Arteriole and venule diameter ratio (A/V-ratio) can be measured using fundus photography. In this pilot study, we correlated changes in the intracranial pressure with the diameter of vessels of the retina. We investigated whether increased intracranial pressure (ICP) was reflected in a measurable and quantifiable distention of the venule diameter, leading to a decreased A/V-ratio. This was demonstrated by assessment of the A/V-ratio in patients already undergoing conventional ICP monitoring with a cerebral intraparenchymal pressure monitor. Our method shows a correlation between A/V ratio and ICP and suggests an easily obtainable and usable point-of-care (POC), non-invasive method to estimate the intracranial pressure without the necessity of mydriatic drugs. Furthermore, the sensitivity/specificity analysis with a cut-off of < 0.8015 A/V-ratio, showed a sensitivity of 94% [85–98%] and a specificity of 50% [34–66%] with a positive likelihood ratio of 9.0. This means that in a clinical setting there is a 94% chance of correctly identifying individuals with ICP ≥ 20 mmHg. The threshold value for intracranial hypertension varies not only throughout the literature but also in clinical practice. In general, ICP > 20 mmHg is considered pathological and often requires treatment6. ICP monitoring is considered paramount in diseases like intracranial hemorrhages, traumatic brain injury, subarachnoid hemorrhages, malignant infarction, cerebral edema and infections of the central nervous system to optimize treatment of secondary brain injuries and thereby improve outcome7.It is well-known that intracranial pressure (ICP) ranges from 5–15 mmHg at rest in a healthy adult8. Invasive procedures, however, carry the risk of bleeding10, infection11 and brain damage. Furthermore, invasive intracranial pressure tools are prone to device failure due to baseline drift of the probe in the tissue and breakage of equipment13, and the invasive nature of reliable ICP-monitoring equipment makes them unsuitable for usage in settings outside neurosurgical intensive care units.Neuromonitoring still heavily relies on invasive methods such as parenchymal or ventricular neuromonitoring , both placed through a cranial burr hole14 and optic nerve sheath diameter15. However, they have not been validated for daily clinical use and are prone to a high degree of inter-observer variations16. There is therefore a need for further research in other non-invasive intracranial pressure modalities.To date, the most promising non-invasive ICP measuring methods studied are pupillometry 18. A quick, non-invasive and easy-to-use screening tool for intracranial pressure would be of great benefit in such and other cases, where elevated intracranial pressure can be a potential hazard.In the United States and Europe, the incidence of traumatic brain injury (TBI) is 500/100,000 and more than 200/100,000 patients are admitted due to TBI related incidence in Europe20. ICP affects intracranial arteries and venules and thereby influences the draining and feeding vessels to the eye, which in turn under higher ICP can cause papilledema by retrobulbar compression. Guidoboni et al.21 has published a theoretical work, which describes mathematically the association between vessel diameter, intraocular pressure and optic nerve tissue pressure and by that ICPs involvement. Furthermore, the intracranial hypertension treatment trial (2015) reported a decreasing retinal A/V-ratio in correlation with the severity of papilledema, which suggests an association between prolonged increased ICP and A/V-ratio22.A relationship between acute elevation in ICP and retinal venule dilation was shown in animal models in the 70′sWe here propose a novel, cheap, fast and easy measurement using non-invasive fundoscopy on non-dilated pupils to assess ICP by using retinal A/V-ratio. .The study was an observational, prospective and single-blinded proof-of-concept study of patients from a neurosurgical department investigated for suspected normal pressure hydrocephalus (NPH) or ventriculoperitoneal (VP) shunt dysfunction. Inclusion criteria were: 18 years or older and competent, informed consent and indication for intraparenchymal, intraventricular or lumbar intracranial pressure (ICP) monitoring. All experiment protocols were approved by The Regional Committees on Health Research Ethics for Southern Denmark, which is a part of the ethics committee system in Denmark (S-20170038). The Regional Committees on Health Research Ethics for Southern Denmark is based on the second Declaration of Helsinki and we confirm all methods were carried out in accordance with those guidelines and regulations.All demographic and clinical data were either collected from the patient’s medical records or bedside. Data collected included: age, gender, blood pressure at time of data collection, past medical history, medication, smoking and indication for ICP monitoring.An EpiCam M , a handheld retinal fundus camera with a monochromatic image sensor, was used. The EpiCam is a CE marked Class I medical device and complies with ISO 10,940:2009, the international standard for retinal fundus cameras. The camera can correct focus in excess of ± 15 diopters. Mydriasis is not necessary. EpiCam viewer software version 2.1.1  was used to capture the videos. Figure All videos were recorded with patients in a horizontal, left side position Fig. A. Patien. Videos were captured with a frame width of 1,280 pixels (px) and height of 1,024 px with 16 frames per second. Image processing software  was used to split the videos into individual images. The fundus was correctly identified using the software (The “Is Fundus” function) ) was used to measure the diameter of the vessel. This process was automatized through a CNTK deep learning algorithm based on 1.043.000 images of vessels to ensure correct identification of venules and arterioles on the basis of 64 × 64 px images . A mixed-effect linear regression model with random intercepts was used to assess association between mean ICP and median A/V-ratio for patients with ICP values < 15 mmHg and ≥ 15 mmHg, accounting for the repeated measurements of patients. Also, mixed-effect linear regression was performed to compare median A/V values between the groups with ICP ≤ 19 and ≥ 20 ICP. In addition, a Receiver operating characteristic (ROC) curve analysis and sensitivity/specificity analysis were performed on all A/V-ratio values ≤ 19 mmHg versus ≥ 20 mmHg to assess how well A/V-ratio predicts a potentially dangerous ICP ≥ 20 mmHg.The study was conducted between August 2017 and December 2017 and approved by The Regional Ethics Committee (ID S-20170038) and the The Danish Data Protection Agency . After signed informed consent, a total of 24 patients were included in the study. Of the 24 patients, 20 patients were suspected of normal pressure hydrocephalus (NPH) and four were suspected of ventriculoperitoneal (VP) shunt dysfunction. Two patients with suspected NPH withdrew their consent. Out of the remaining 18, six were excluded due to insufficient video imaging quality, leaving a total of twelve included patients with presumed NPH. Two of the patients with suspected VP shunt dysfunction were excluded due to insufficient video quality.Data from all patients were plotted with ICP on the y-axis and A/V-ratio on the X-axis. ICP and corresponding A/V ratios were grouped into Low mean ICP 0–14 mmHg and Medium–High mean ICP ≥ 15 mmHg for analyses. The analyses were performed on all 14 patients with a mean of 6.1 observations per patient in total 86 total observations.p = 0.212, with a regression slope estimate of 0.0017 and 95%-CI [− 0.0010 to 0.00445] ]. The correlation between A/V-ratio and mean ICP above 15 was negative, and a positive change in ICP resulted in a fall in A/V-ratio . Moreover, we performed a linear regression based on the A/V-ratio inter-variability between patients. The patients show a significant different A/V-ratio.For mean ICP values below 15 mmHg (Low ICP) the data showed an insignificant correlation between ICP and Median A/V ratio, 45] Fig. A. For mep = 0.01), with mean [95%-CI] = 0.8551 [0.8184–0.8918] for ICP values ≥ 20 mmHg and 0.8757 [0.8406–0.9107] for ICP values ≤ 19 mmHg (p = 0.01).In the Medium–High ICP group, the means of the median A/V-ratios were significantly different for ICP values ≥ 20 mmHg and ICP values ≤ 19 mmHg  value AUC = 0.74 (0.63–0.85), The present study correlated measurements of A/V-ratio in patients subjected to direct intracranial pressure monitoring. The study shows that A/V-ratio varies within the patient population. We found a correlation between a rise in ICP and a drop in A/V-ratio at mean ICP values above 15 mmHg. However, there was no correlation between ICP and A/V-ratio in low/normal ICP values (below 15 mmHg). Furthermore, potentially dangerous ICP ≥ 20 mmHg is distinguishable from not elevated ICP ≤ 19 mmHg.26. Moss et al. used a similar image analysis but acquired the images with scanning laser ophthalmoscopy. In the present study we used a white light fundoscopy. This results in less sharp images, but it is easier to handle for other medical personal than ophthalmologists. Despite differences in study designs the two studies come to similar conclusions. Moss et al. found no association between A/V-ratio and normal ICP. Similarly, we found no correlation at ICP lower than 15 mmHg. However, our data suggest that a significant correlation exits with ICP ≥ 15 mmHg, but with a high inter-patient variation. As shown in Fig. 28.Our hypothesis regarding a change in A/V-ratio and a change in ICP is supported by the recently published work by Moss et al.29. The vessels of the retina run within the optic nerve dural sheath30 and therefore are surrounded by CSF and connected to the subarachnoid space. Thus, changes in the intracranial pressure might potentially reflect the optic nerve vessel diameter32 and is affected by both changes in ICP as well as IOP34. The intraocular and intracranial spaces are both pressure compartments with variable pressures. The passing vessels are therefore regulated according to the Starling resistor mechanism,a fluid dynamic that governs the flow in collapsible tubes exposed to variable external pressure35. Therefore, increased pressure in one compartment will cause vessels to partially collapse, which in turn increases resistance to flow. It has long been known that IOP responds to a rise in ICP36, which changes the transmural equilibrium in the retinal vessels. The cerebral pressure–volume curve shows that autoregulation ensures transmural equilibrium until an ICP > 20 mmHg causes a change in the equilibrium37. Due to physiological differences between veins and arteries, veins are more compliant than arteries, which causes veins to distend when a rise in ICP occurs38.Based on our data and the literature, we suggest that intraocular pressure (IOP) influences A/V-ratio. IOP ranges from 5–20 mmHg39, where they measured both IOP and venous outflow pressure (vOP) of the central retinal vein. They describe that the pressure within the central retinal vein is greater or equal to ICP because the vein follows the optic nerve prior to draining into the venous sinus, which is independent from IOP because the vein collapses when IOP > vOP.The above corresponds with our data , where a rise in ICP causes a drop in A/V-ratio. However, it does not explain the data from 0–15 mmHg (low). We hypothesize the data resembles some form of inverted U with the IOP as top point of A/V-ratio . However, this needs to be explored in future studies, where IOP will be included. We hypothesize that the retinal vein collapses when ICP < IOP due to forces mentioned above and by perceived distention in the 2D images. This is further supported by the works of Firsching et al.Limitations: In the present study we did not measure IOP. Further studies are needed to confirm the relationship between IOP and ICP. Second, we recorded mean ICP, and we can therefore not account for changes in vein pulsation or beta-waves.p = 0.0001) and there was a significant difference between ICP that is considered to be elevated and potentially dangerous (≥ 20 mmHg) and not elevated ICP. The technique shows promise for non-invasive detection of changes in ICP and possibly detection of absolute ICP values. However, further studies are needed to validate this.In this pilot investigation, a novel methodology using a standard CE marked fundus camera for a quick, easy and inexpensive way to visualize the arterioles and venules of the eye is described. We used a semi-automatized software to measure the diameter of the vessels, and the arteriole/venule ratio was calculated. Despite limitations, a significant change in A/V-ratio could be correlated to ICP. A/V-ratio decreased with ICP above 15 mmHg (


Background: Orthostatic hypotension (OH) is a major sign of cardiovascular autonomic failure leading to orthostatic intolerance and syncope. Orthostatic hypotension is traditionally divided into classical OH (cOH) and delayed OH (dOH), but the differences between the two variants are not well-studied. We performed a systematic clinical and neuroendocrine characterization of OH patients in a tertiary syncope unit.Methods: Among 2,167 consecutive patients  evaluated for unexplained syncope and severe orthostatic intolerance with standardized cardiovascular autonomic tests including head-up tilt (HUT), we identified those with a definitive diagnosis of cOH and dOH. We analyzed patients' history, clinical characteristics, hemodynamic variables, and plasma levels of epinephrine, norepinephrine, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal-endothelin-1, mid-regional-fragment of pro-atrial-natriuretic-peptide and pro-adrenomedullin in the supine position and at 3-min HUT.Results: We identified 248 cOH and 336 dOH patients (27% of the entire cohort); 111 cOH and 152 dOH had blood samples collected in the supine position and at 3-min HUT. Compared with dOH, cOH patients were older , more often male , had higher systolic blood pressure , had lower estimated glomerular filtration rate , more often pathologic Valsalva maneuver , pacemaker-treated arrhythmia , Parkinson's disease  and reported less palpitations before syncope . Supine and standing levels of CT-proAVP were higher in cOH , whereas standing norepinephrine was higher in dOH (p = 0.001). After 3-min HUT, increases in epinephrine (p < 0.001) and CT-proAVP (p = 0.001) were greater in cOH, whereas norepinephrine increased more in dOH (p = 0.045).Conclusions: One-quarter of patients with unexplained syncope and severe orthostatic intolerance present orthostatic hypotension. Classical OH patients are older, more often have supine hypertension, pathologic Valsalva maneuver, Parkinson's disease, pacemaker-treated arrhythmia, and lower glomerular filtration rate. Classical OH is associated with increased vasopressin and epinephrine during HUT, but blunted increase in norepinephrine. Orthostatic hypotension (OH) is the most common manifestation of cardiovascular autonomic dysfunction leading to orthostatic intolerance and syncope. Orthostatic hypotension has multiple etiologies and is traditionally divided into neurogenic or non-neurogenic types. Neurogenic OH is caused by primary neurodegenerative disorders or is secondary to endocrine and autoimmune diseases or renal failure. Non-neurogenic causes include drugs, volume depletion, venous pooling, and heart failure .The prevalence of OH increases with advancing age and comorbidities, such as diabetes, Parkinson's disease or kidney failure, ranging from around 3% in younger individuals, to 35% and more in individuals above 75 years . In the Studies have shown that OH is independently associated with increased mortality, cardiovascular events, incident heart failure, atrial fibrillation, and renal failure , 3.Orthostatic hypotension is clinically classified into classical OH (cOH) and delayed OH (dOH). Classical OH is defined as a sustained decrease in systolic blood pressure (SBP) ≥20 mmHg and/or diastolic blood pressure (DBP) ≥10 mmHg, within 30 s−3 min of active standing or head-up tilt (HUT). In dOH, the progressive fall in systolic blood pressure occurs after 3 min  but therGiven the scarcity of data, we aimed to perform a systematic clinical, hemodynamic, and neuroendocrine characterization of patients presenting with OH in a tertiary syncope unit.We asked the following questions: what are the differences in clinical characteristics between cOH and dOH? Do patients with cOH and dOH have detectable neuroendocrine and hemodynamic differences during supine rest and HUT?The present study is a part of the previously described SYSTEMA project , 6 and wThe definition of unexplained syncope was a transient loss of consciousness without an established diagnosis after the initial evaluation according to the current syncope guidelines , 8. DuriPatients were requested to take their regular medications and fast for 2 h before the test but were allowed to drink water. A self-administered questionnaire was used to collect data about past medical history and the characteristics of syncope-related symptoms.The examination included basic cardiovascular autonomic testing  and a standard HUT according to the Italian protocol  i.e., a All disputable or difficult to interpret cases were resolved by adjudication involving one syncope and autonomic expert, and the examining physician.Beat-to-beat blood pressure and electrocardiogram were monitored continuously by a validated non-invasive method  , 12.Blood samples were collected from an intravenous line, both in supine position and at 3 min of HUT. The decision to collect blood at 3 min of HUT was based on previous studies  indicatiMeasurement of plasma neuroendocrine concentrations has previously been described . In brieThe regional ethical review board in Lund, Sweden approved the study protocol (reference no 82/2008). All study participants gave written informed consent.The main characteristics of the study population are presented as mean and standard deviation for normally distributed continuous variables, as median and interquartile range for non-normally distributed variables and percentages for categorical variables. Intergroup differences were analyzed using ANOVA test for non-categorical variables and Pearson's chi-square test for categorical variables. Neuroendocrine concentrations were log-transformed and standardized (expressed per 1 standard deviation). Logistic regression model adjusted for age and gender was applied to test inter-group differences in neuroendocrine concentrations.p < 0.05 was considered significant.Statistical analyses were carried out using IBM SPSS Statistics version 25 . All tests were two-sided and The main characteristics of the study population are presented in p < 0.001), taller , more likely men , had higher supine blood pressure , lower estimated glomerular filtration rate , reported less palpitations before syncope , more often had a pathologic Valsalva maneuver , a pacemaker , and Parkinson's disease . Patients with cOH had a more pronounced fall in systolic  and diastolic  blood pressure during HUT than those with dOH. Compared with dOH, patients with cOH were older , coronary artery disease, and medications .p = 0.022 and p < 0.001). In contrast, at 3 min of HUT, norepinephrine was higher in dOH (p = 0.001). Further, Δepinephrine (p < 0.001) and ΔCT-proAVP (p = 0.001)  were higher in cOH, whereas Δnorepinephrine was higher in dOH (p = 0.045) compared with cOH.The plasma levels of neuroendocrine markers are shown in The plasma levels of CT-proET-1, MR-proANP, and MR-proADM were not different between the cOH and dOH groups.This study examined the differences in clinical characteristics, hemodynamic variables, and plasma concentrations of neuroendocrine hormones in patients with classical and delayed orthostatic hypotension. We found that patients with classical OH were older, more likely men, more often hypertensive, treated with pacemaker, had lower kidney function and more often pathologic Valsalva test, Parkinson's disease, and reported less palpitations before syncope. Compared with delayed OH, classical OH was associated with increased levels of vasopressin and epinephrine during HUT, whereas norepinephrine increased more during HUT in delayed OH.Moving from supine to standing position causes an immediate redistribution of up to 1 l of blood to the capacitance vessels of the legs and splanchnic/pelvic circulation. This prompts a decrease in venous return and cardiac output, which, in the healthy individual, is counteracted by the baroreflex, causing increased sympathetic outflow and vagal inhibition. Heart rate, cardiac contractility, and peripheral vascular resistance increase to maintain blood pressure. During prolonged standing, transcapillary fluid filtration into the interstitial space can reduce plasma volume up to 20% . NeuroenIn patients with autonomic dysfunction, norepinephrine release from postganglionic sympathetic nerves is reduced or insufficient, causing inadequate peripheral arteriolar vasoconstriction and subsequent hypotension during orthostasis . This prVasopressin is released in response to hyperosmolarity and reduced arterial pressure, leading to renal water reabsorption and vasoconstriction . VasopreVasopressin levels increased 3-fold in healthy subjects during HUT , 22 and Our findings are consistent with previous studies. Patients with cOH had more pronounced falls in systolic and diastolic blood pressure than those with dOH. The supine and standing levels of CT-proAVP were significantly higher in cOH compared to dOH. The fall in blood pressure and right atrium filling stimulates vasopressin secretion. Vasopressin was measured after 3 min of HUT, when the hemodynamic impairment is fully developed in cOH but not in dOH. Consequently, vasopressin response after 3 min of standing was greater in cOH.In healthy volunteers, epinephrine initially increased 3-fold during standing, and normalized after prolonged orthostasis . In a stWe found that the change in epinephrine concentration at 3 min of HUT was more pronounced in cOH compared with dOH. A variety of stressors induce higher plasma epinephrine increases than those in norepinephrine, indicating a greater adrenomedullary than noradrenergic system response . Since bIn healthy subjects, plasma norepinephrine concentration doubles within 5 min of standing . OrthostConsistent with previous studies, we found that orthostatic norepinephrine concentration was higher in dOH and that it increased more on HUT compared with cOH. These data would indicate dOH as a milder form of sympathetic autonomic dysfunction compared with cOH.Consistent with previous reports, we found that patients with dOH were younger than those with cOH, supporting the idea that dOH might be an early presentation of autonomic dysfunction, preceding cOH . AnotherOrthostatic hypotension is frequently associated with supine hypertension , 36. GolStudies have shown that cOH is associated with increased risk of cardiovascular disease , 37, whiDelayed OH was first described by Streeten and Anderson  and has Better characterization of classical and delayed orthostatic hypotension can have implications for diagnosis, prevention, and treatment of these conditions. In clinical practice, delayed orthostatic hypotension is often overlooked although there are similar clinical consequences in both variants such as syncope as indicated by this study. Whether delayed and classical orthostatic hypotension represent a sequential worsening of the same disease, or constitute two different entities of cardiovascular autonomic dysfunction with different therapeutic approaches, warrants further research.There are several important limitations that should be acknowledged. One is that this a single-center study and another is that there is no healthy control group. Vasoactive medications were not withdrawn before HUT as the tests were performed to detect syncope etiology in the real-life scenario, meaning without discontinuing the regular medication. The amount of water ingested prior to HUT, which may have potentially introduced a bias in the measured neurohormone levels, was not recorded. Neuroendocrine hormones were only measured in supine position and at 3 min of HUT. Other changes in the levels of these hormones might have occurred after prolonged orthostasis. Other neuroendocrine hormones that were not included in this study may have a significant role in OH pathophysiology. Finally, plasma norepinephrine concentration represents the spillover from synapses. The concentration is dependent on both the release into plasma and removal by reuptake into nerve terminals and might not accurately reflect the rate of sympathetic nerve traffic.Compared with delayed orthostatic hypotension, patients with the classical form are older, more often have supine hypertension, autonomic dysfunction, Parkinson's disease, pacemaker-treated arrhythmia, and lower glomerular filtration rate. Classical orthostatic hypotension is associated with increased levels of vasopressin and epinephrine during head-up tilt, but blunted increase in circulating norepinephrine. These findings suggest that classical orthostatic hypotension, compared with the delayed form, is associated with more severe abnormalities of both autonomic and neuroendocrine control mechanisms and can be regarded as a more advanced and severe condition.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Regional Ethical Review Board in Lund (82/2008). The patients/participants provided their written informed consent to participate in this study.All the coauthors conceived and designed the study. PT, AF, FR, and VH reviewed the literature. RS gave a critical input for the analyses. PT, AF, and VH collected the data for the study. PT, AF, and FR performed the statistical analyses. PT and AF drafted the manuscript. FR, VH, and RS performed the critical review of the manuscript. All coauthors accepted the final version. AF provided the founding for the study.AF reports personal fees from Medtronic Inc. and Biotronik outside the submitted work; RS reports personal fees and other from Medtronic Inc., St. Jude Medical Inc. (Abbott Laboratories) outside the submitted work; RS is a member of the speaker's Bureau St. Jude Medical/Abbott Inc.; RS is shareholder in Boston Scientific Inc., Edwards Lifesciences Inc. and AstraZeneca PLC. 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.


Little is known about the systemic and pulmonary macrohemodynamics in early COVID‐19 infection. Echocardiography may provide useful insights into COVID‐19 physiopathology.Twenty‐three COVID‐19 patients were enrolled in a medical ward. Gas exchange, transthoracic echocardiographic, and hemodynamic variables were collected.2/FiO2 = 273.0 ± 102.6 mmHg) and mildly hypocapnic . Mean arterial pressure was decreased (86.7 [80.0–88.3] mmHg). Cardiac index was elevated (4.32 ± 0.90 L∙min‐1∙m‐2) and the resulting systemic vascular resistance index low . The right heart was morphologically and functionally normal, with pulmonary artery pressure  and Total Pulmonary Resistances  within normal limits. When stratifying for SVRI, patients with an SVRI value below the cohort median had also more severe oxygenation impairment and lower TPR, despite a similar degree of CXR infiltrates. Oxygen delivery index in this group resulted supranormal.Mean age was 57 ± 17 years. The patients were hypoxemic (PaOIn the early stages of COVID‐19 infection the hemodynamic profile is characterized by a hyperdynamic circulatory state with high CI and low SVRI, while the right heart is functionally unaffected. Our findings suggest that hypoxemia, viral sepsis or peripheral shunting are possible mechanisms for the vasodilation that dominates at this stage of the disease and may itself worsen the gas exchange. Early COVID‐19 infection is characterized by a hyperdynamic circulatory state, with low systemic resistances. Moreover, pulmonary pressures and pulmonary resistances are low. This suggests two main findings: at least in the initial stage, pulmonary vasodilation prevails over vasoconstriction and the hyperdynamic state may worsen the severe ventilation‐perfusion mismatch.  It is by now clear that COVID‐19 infection is whole‐body disease: together with severe pneumonia, hypercoagulability  was estimated accordingly. Continuous Positive Airway Pressure (CPAP) or Non‐Invasive Ventilation (NIV) were, at this stage, not applied. The Alveolar‐arterial O2 gradient (A‐aO2) was calculated as:The study was approved by the ethical committee of the institution. Consecutive, non‐critical, non‐intubated COVID‐19 positive patients undergoing TTE from 22nd March to 30th of April were screened for enrollment in a medical ward. Patients with a history of ischemic, myocardial, valvular heart diseases, or suspicion of present acute cardiac illness were excluded. The arterial blood gas analysis was acquired either in room air or during the oxygen administration through low‐flow nasal cannulas or Venturi mask. The Inspired oxygen fraction  were measured non‐invasively.TTE measurements and cardiac function analysis were performed in accordance with the American Society of Echocardiography recommendations. Stroke volume (SV) was calculated from the velocity‐time integral profile of PW Doppler on the left ventricular outflow tract (LVOT) and multiplied by the heart rate to calculate the cardiac output (CO). Systolic pulmonary artery pressure (PAPs) was assessed measuring the tricuspid regurgitation velocity and the right atrial pressure (RAP) was estimated through the collapsibility of the inferior vena cava  to calculate the Stroke Index (SVI) and Cardiac Index (CI). The systemic vascular resistance index was calculated as:2) and the oxygen delivery index (DO2i) were calculated as the arterial oxygen content (CaO2) multiplied by CO and CI, respectively. The chest x‐ray scans (CXR) were were graded into five levels of severity according to Taylor et al  were calculated as PAPm/CO. The oxygen delivery  and stage 2 (n = 1). Seventeen percent of patients suffered from diabetes. The anthropometric characteristics and comorbidities of the population are presented in Table Twenty‐three patients were enrolled Figure , aged 57ge 2 n = . Sevente3.22/FiO2 = 273.0 ± 102.6 mmHg) and mildly hypocapnic  with of a moderately increased respiratory rate (20 [18–23] breaths per minute). Moreover, the A‐aO2 was markedly increased (115.0 [37.5–164.3] mmHg). In contrast, the CXR resulted only mildly altered (Taylor score = 2 [2–3.5] out of 5).The patients were hypoxemic (PaO3.3‐2. Cardiac Index (CI) was on average elevated (4.32 ± 0.90 L∙min‐1∙m‐2) and 26% of the patients exhibited a CI greater than 5 L∙min‐1∙m‐2.The patients had no sign of altered mental status. Body temperature was 36.5 ± 0.6°C. Only two patients had a temperature >37.5°C. They were all hemodynamically stable, with a mean systemic arterial pressure of 86.7 [80.0–88.3] mmHg . Blood lactate levels were 1.0 [0.9–1.3] mmol/l. Heart rate was 77 ± 12 bpm and stroke index 56.5 ± 10.8 ml∙m‐5∙m‐2). In Panel B we show the distribution of the Oxygen Delivery index (DO2i) which was elevated above the physiological value (600 ml∙min‐1∙m‐2) in 78% of the population.The distribution of the SVRI is reported in Figure 2 despite an equal PaO2 and a remarkably higher A‐aO2. Despite that, DO2i, was particularly elevated especially in this group. Interestingly, the CXR score was similar between patients with lower or higher SVRI.In Table ‐1∙min‐1). In Figure p < .001, R2 = 0.55). In contrast, TPR and CI were inversely related .No intracardiac shunts, moderate‐to‐severe TR or additional echocardiographic signs suggesting pulmonary hypertension (PH) were detected. Right heart function, dimensions, and pressures were within physiological limits: Tricuspidal Annular Plane Systolic Excursion was 21 [20–22] mm, PAPs 26.2 ± 4.7 mmHg, PAPm 18.0 ± 2.9 mmHg, estimated RAP 3.0 [3.0–4.5] mmHg. Interestingly, the TPR was normal , the absence of fever, normal white blood cell count, and lactates within normal ranges make the hypothesis of a septic status unlikely.In this study, we found that in the early stages of the disease, COVID‐19 infection leads to a hyperdynamic circulatory state characterized by an elevated CI and low SVRI. Moreover, patients with particularly low SVRI, despite a supranormal DO4.12 and, consequently, SaO2 decrease to such extent that the arterial oxygen content (CaO2) is extensively reduced  on oxygenation may act, at least in part, by reducing the disproportionate CO. Lung recruitability in COVID‐19 is moderately low (Pan et al., In this context, it is possible that the overall reduction of vasomotor tone further worsens the hypoxemia. Notably, patients with lower SVRI were more hypoxic, despite similar severity of the chest x‐ray infiltrates. The hyperdynamic state may itself lead to further V4.2Reportedly, pulmonary embolism and microthrombosis are distinguishing features of COVID‐19 (Wichmann et al., 5These preliminary data have several limitations, primarily the low number of patients enrolled and the indirect estimation of the echo‐acquired pulmonary pressures. Even if we excluded subjects with probable pathological elevation of wedge pressure, these values must be confirmed by pulmonary artery catheterization. It is worth noting, however, that positive pressure ventilation and/or development of overt pulmonary embolism may change dramatically the overall picture.6In the early stages of COVID‐19 infection, we detected a hyperdynamic state characterized by high CI and low SVRI. This was in turn associated with the severity of the hypoxemia, in absence of macrohemodynamic signs of pulmonary embolism. Rather, pulmonary pressures were normal despite the high CI, favoring the hypothesis of a reduction of the pulmonary vasomotor tone or an increased vascular bed.The authors report no conflicts of interest to disclose.MS, AL, GBF, EC, CBC, and AG collected the data. MB analyzed the data. MB, MS, and AG wrote the first draft of the manuscript. All authors critically revised and approved the manuscript.The study was approved by the ethical committee of the institution.


Arterial hypertension is a major risk factor for cardiovascular disease worldwide. Office blood pressure measurements (OBPMs) are still recommended for diagnosis and follow-up by all major guidelines; however, the recommended procedures differ significantly. In analogy, major outcome studies usually apply OBPMs, again, with a variety of procedures. This variety of OBPM procedures complicates the comparability between studies and challenges daily clinical practice. In this narrative review, we compile the most recent recommendations for office blood pressure measurement together with the major limitations and strategies and how these could be overcome. Four thousand years ago, the Chinese Emperor Huang-Ti was aware of the changing characteristics of the pulse and realized that if people ate too much salt, they had hard pulses and tended to suffer strokes ,2. It toThe risk of death from strokes, ischemic heart disease and other vascular causes correlates linearly with the BP measured, starting from as little as 115/75 mmHg, as mentioned above, though there is a lack of data for even lower values . For exaAll major guidelines (the American College of Cardiology/American Heart Association (ACC/AHA), the Eighth Joint National Committee (JNC8), Hypertension Canada, the European Society of Cardiology/European Society of Hypertension (ESC/ESH), the International Society of Hypertension (ISH), and the National Institute of Health and Care Excellence (NICE)) allow using office blood pressure measurements (OBPMs) to diagnose AHT and to base treatment adaptions on ,12,13,14Despite these differences in recommended procedures, most guidelines agree on a threshold of 140/90 mmHg for the definition of AHT, but not all. Distinctly, the ACC/AHA chose a lower threshold, in comparison to the other guidelines, of 130/80 mmHg to define AHT , whereasThe assumed basis for the recommendation of the application of OBPMs is that most major outcome studies use OBPMs in their protocols, though none of the guidelines state which exact studies they base their specific recommendations on. One would assume that at least one protocol has been specifically linked to the prediction of an outcome such as cardiovascular events or target organ damage. However, the variety of OBPM protocols used in those outcome studies is equally large as that of the ones recommended by the guidelines. The procedures applied by a selection of major hypertension trials are depicted in Whereas some studies applied a procedure that was later recommended by a set of guidelines, such as AASK or PATHWAY 2 ,26,27,28Disregarding all recommendations for OBPMs, many colleagues report usually performing single OBPMs . Though Repeated measurements, in general, but especially in the context of BPMs, follow a regression to the mean pattern . This coThere is a difference not only between single and repeated measurements, but also between the different procedures recommended by guidelines stipulating repeated measurements, as our group has extensively studied.First, we compared the Canadian to the ACC/AHA guidelines: For this comparison, we used the OBPMs of 802 participants and calculated the BPs from the same measurement set (four consecutive BP measurements under standardized conditions) once according to the ACC/AHA and once according to the Hypertension Canada guidelines . ApplyinLater, we compared the ACC/AHA to the ESC/ESH guidelines for the same cohort of participants: Again, all the BP values were classified according to ACC/AHA but calculated once according to the ACC/AHA and once according to the ESC/ESH procedure. This time, there was a statistically non-significant increase in AHT prevalence of 6% upon applying the ACC/AHA procedure instead of the ESC/ESH procedure . When alExtrapolating the data from our published papers ,45, we cThough on a population basis, these differences may not all be statistically significant and seem minor, they may play an important role for our individual patients. Clearly, underestimating BP puts the patient in jeopardy regarding cardiovascular events . On the Keeping the regression to the mean phenomenon in mind, it appears quite logical that the more measurements we take, the closer they should get not only to a population mean but also to the individual’s true baseline BP . TherefoTo our knowledge, the effect of the rest period as such has not been examined. However, talking, for example, leads to a BP surge of 9.1 mmHg for the systolic and 4.5 mmHg for the diastolic values . The timTo the best of our knowledge, there are no studies to date comparing the validity of different OBPM procedures as predictors for outcomes such as myocardial infarction, stroke or cardiovascular death. Only indirect comparisons are possible when looking at the risk reduction per mmHg lower BP in different individual trials—with the bias of different patient groups. It seems likely that in patients potentially eligible for an AHT diagnosis, the BP values would become lower the more often we repeated the measurements, theoretically, until we reached the population mean or, more likely, the true resting baseline BP of the patient, which we expect to reflect the risk of the patient. In reality, we would also expect a certain time factor—either the person measuring, the patient or both would become fed up with the measurements, which might lead to another increase in BP values. Therefore, a trade-off is needed to approach the “true OBPM” as much as possible without overly straining the time budget.An important way to overcome the OBPM dilemma in clinical practice is to apply possible alternatives to OBPMs, such as automated OBPMs, ABPMs and HBPMs frequently, as there is evidence that they are better predictors of target organ damage and outcomes than OBPMs ,53,54,55Some oscillometric devices allow multiple automated readings performed with the patient sitting alone in the office . For unaSeveral studies have compared the BP results obtained through AOBPMs to other OBPM methods, to ABPMs and to HBPMs, and the results have been summarized in meta-analyses . Two metUnattended AOBPM has the advantage of overcoming several aspects of human error during OBPMs such as single readings, conversation with patients, and digit preference and may reduce the “white coat effect” ,60,61.Unattended AOBPM is criticized due to a lack of data regarding outcomes, though, for example, the SPRINT trial, a large and well-known outcome study, applied AOBPM in at least some patients . In addiFor ABPM, patients are fitted with an ABPM device to wear during their regular activities . The devFor HBPM, patients measure BP themselves at home, ideally over several days, e.g., morning and evening values over 5–7 days according to defined protocols . SimilarEven in 2021 and the near future, there will likely be situations where OBPMs for either clinical or research purposes are inevitable. In such cases, it is recommendable to use an OBPM procedure that is likely to produce stable values close to the patient’s true BP but that is not too time consuming. In addition, it has to be easily reproducible. In our opinion, stable BP values can best be achieved by applying a rest period of five minutes and then taking OBPMs repetitively. We recommend then discarding the first OBPM, as this is usually significantly different from the subsequent measurements . By usinIn conclusion, if using OBPMs is inevitable, we recommend using the mean of second and third OBPMs after a 5 min rest period and discarding the first measurement, as the best compromise between the stability of the measurements, feasibility and reproducibility.