Sus scrofa domestica).We studied a novel approach for the evaluation and management of volemia: minimally invasive monitoring of respiratory blood flow variations in the superior vena cava (SVC). We performed an experiment with 10 crossbred (Landrace × large white) female pigs , located in a distal channel of a triple-lumen central venous catheter. The key parameters measured were venous return variation index (VRV)—a new index for fluid responsiveness, calculated from the maximal and minimal velocity time intervals during controlled ventilation—and systolic peak velocity . A Swan–Ganz catheter  was introduced into the pulmonary artery to measure pulmonary arterial pressure, pulmonary capillary wedge pressure, and continuous cardiac output measurements, using the Vigilance monitor .We analyzed 44 VRV index measurements during defined hemodynamic status events. The curves of VRV indexes for volume responders and volume non-responders intersected at a VRV value of 27, with 10% false negativity and 2% false positivity. We compared the accuracy of VRV and pulse pressure variations (PPV) for separation of fluid responders and fluid non-responders using receiver operating characteristic (ROC) curves. VRV was better (AUCROC 0.96) than PPV (AUCROC 0.85) for identification of fluid responders. The VRV index exhibited the highest relative change during both hypovolemia and hypervolemia, compared to standard hemodynamic measurement.The VRV index provides a real-time method for continuous assessment of fluid responsiveness. It combines the advantages of echocardiography-based methods with a direct and continuous assessment of right ventricular filling during mechanical ventilation. Accurate detection of early hypovolemia remains a challenging issue for both perioperative monitoring and critical care units. It is essential for optimal volume therapy. Both unrecognized hypovolemia and fluid overload worsen a patient’s prognosis . In routStatic markers—such as central venous pressure (CVP), pulmonary capillary wedge pressure (PCw), urine output, heart rate, and blood pressure—are not sufficient to indicate early phases of hypovolemia. Furthermore, they do not reliably predict the response of cardiac output to volume therapy . DynamicBased on the volume assessment limitations of the methods described, we propose a novel approach for the evaluation of intravascular volume status and fluid management. We hypothesize that minimally invasive monitoring of respiration-related blood flow variations—where they begin, in the SVC—might provide a superior fluid responsiveness index, especially when compared to measures derived from the left side of circulation. This would also be suitable for continuous measurement, unlike echocardiography-derived indices. To measure respiration-related variability in SVC flow, we used a wire with a miniaturized Doppler probe designed for intracoronary flow measurements  incorporated in a central venous catheter.Sus scrofa domestica), 4 to 5 months old, with a mean body weight of 51.6 ± 2.8 kg, were used in the study. The animals were obtained from a local certified farm, inspected on arrival by an institutional veterinarian, and were not subjected to any other interventions before or after the study protocol. Prior to the study, the animals were housed in a standard, accredited, university animal facility. They were kept in metal cages with minimum dimensions of 1.8 × 2.2 m, with natural daylight and free access to water, and were fed twice daily with a mixture recommended for young swine. Ambient conditions  were regulated according to relevant standards. Animals were kept in groups of up to four. Anesthesia was provided during the whole study.Ten crossbred (Landrace × large white) healthy female pigs  followed by ketamine hydrochloride (15 to 20 mg/kg IM). Anesthesia was continued with initial boluses of propofol and morphine , and animals were orotracheally intubated. A continuous IV infusion of propofol (8 to 10 mg/kg/h) combined with morphine (0.1 to 0.2 mg/kg/h) IV was used to maintain anesthesia, the depth of which was regularly assessed by photoreaction and corneal reflex.2O, FiO2 0.25, I:E 1:2, and MV adjusted to maintain pCO2 5.0–5.5 kPa (34–41 mmHg) and pO2 9.3–16 kPa (70–120 mmHg).Volume-controlled ventilation was delivered by the Hamilton G5 ventilator  set at Vt 8 ml/kg, PEEP 5 cm HA triple-lumen central venous oximetry catheter  was inserted via the left external jugular vein to allow for (i) insertion of the Doppler Flow wire (0.014″) via its distal lumen, (ii) central venous pressure measurement (CVP), and (iii) administration of i.v. medications.VO2) were measured using the Vigilance monitor . In addition, a high-fidelity pressure–volume catheter  was placed retrograde into the left ventricular apex via a 7F sheath inserted percutaneously into the left external carotid artery. The correct position was confirmed by fluoroscopy. This catheter provided simultaneous measurements of left ventricle (LV) pressure and volume. LV pressure–volume loops were obtained from PV data using Powerlab Pro 7.0. software .A Swan–Ganz continuous cardiac output (CCO) catheter  was inserted via the left femoral vein and advanced into the pulmonary artery to provide measurements of pulmonary arterial pressure (PAP) and pulmonary capillary wedge pressure (PCWP). CCO and mixed venous saturation (SAn introducer sheath (5F) was inserted into the femoral artery for invasive arterial blood pressure measurement. Another 6F introducer was placed in the contralateral femoral artery for blood removal during the hypovolemia protocol. A further 7F sheath was inserted into the right femoral vein for rapid blood and fluid replacement.All blood pressure measurements (excluding LV pressure) were obtained via a fluid-filled pressure transducer  connected to a patient monitor . Peripheral saturation, capnometry, and temperature recordings were also performed via the patient monitor.The technical details of Doppler-based blood flow velocity measurement has been fully described previously, in a paper done by Doucette et al. . A FlowiSVC flow velocity as a velocity time integral (VTI) of the Doppler envelope.Venous return variation index (VRV), an analogue to the SVV as a new index for fluid responsiveness. We used airway pressure for respiration gating and ECG R-R intervals for heart beat detection. We analyzed flow variations during each individual respiratory cycle at 20-s intervals. Beats with maximal and minimal VTI values were used in the formula. Minimal flow occurred during mechanical inspiration; maximal flow was recorded in expiration. The VRV index was calculated as VRV = (VTImax − VTImin)/(VTImax + VTImin)/2. Individual respiratory cycle VRV values were averaged over a 20-s period.Systolic peak velocity (S peak) was also recorded. It is defined as peak velocity on a systolic wave using the final end-expiratory beat.The following parameters were recorded:2, PCWP, PAP, CVP, AP—arterial pressure, temperature).Doppler envelope data were continuously recorded with a custom PC-based application specifically designed for the purposes of this trial. Other modalities recorded simultaneously by the same application were central venous pressure, arterial pressure, airway pressure, and ECG Fig. . The appInitial rapid IV infusion of 1000 ml of normal saline was given intravenously, followed by a continuous IV infusion to reach and maintain a central venous pressure of between 3 and 7 mmHg.Unfractionated heparin (100 UI/kg IV) was given as a bolus after sheath placement, followed by 40 to 50 U/kg/h continuous IV drip to maintain activated clotting time of 180 to 250 s .After sedation and ventilation set-up, the animals were kept in euvolemic status.An increase of stroke volume (SV) < 10% after saline bolus of 7 ml/kgA stroke volume respiratory variation < 15% (LV Volume with Powerlab Pro PV tools)Euvolemia was defined as:Euvolemia was then followed by bleeding periods.The bleeding was induced by opening the 6F sheath introduced to the femoral artery. Blood was collected in transfusion sets, which were stored at room temperature. Estimated blood volume (EBV) was calculated as 65 ml/kg .The first stage of bleeding removed 10% of EBV. This was followed by five subsequent stages, which each removed 5% of the initial EBV. A steady state of 10 min was kept after each bleeding period, after which measurements were performed.The last bleeding was followed by two stages of 500 ml blood return (each lasting 30 min) separated by 10-min steady states. Fluid challenge  administered after a non-responsive event was classified as fluid overload.We were searching for a new predictor of fluid responsiveness, defined as an increase in the stroke volume by more than 10% (in comparison with the previous stage of the experiment).The data presented is from 10 animals with a total of 44 events classifiable as responsive or non-responsive, in terms of changes in stroke volume variations. Fluid responsiveness was defined as a 10% change in stroke volume after all three study steps: bleeding, blood return, and fluid overload. During the trial, some events were not classifiable due to arrhythmias, PAC failure, or Doppler envelope detection failure. Five cases provided complete continuous trending data of all measured variables.The relationship between CO and VRV, during all phases of the experiment, is presented in Fig. We used a receiver operating characteristic curve (ROC), for comparison of the VRV and PPV indexes to predict fluid responsiveness Fig. .Fig. 5AUWe were searching for a cutoff level for the VRV index (for detection of fluid responsiveness) from a total of 44 measurements of VRV during defined hemodynamic status. The curves of VRV indexes for volume responders and volume non-responders intersected at a VRV value of 27, with 10% false negativity and 2% false positivity. The upper limit of the gray zone—with a 100% prediction of fluid responsiveness—is at the VRV value of 33. At this point, the false negative rate would be at 19.6% /(PPmax + PPmin)/2]. We compared the accuracy of VRV and PPV for separation of fluid responders and fluid non-responders using receiver operating characteristic (ROC) curves. VRV was better  than PPV  for identification of fluid responders, as described in Fig. The correlation of the dynamic markers of volume status (VRV index and PPV index) to static markers of hypovolemia—with normalized values to 100 points at the baseline—is presented in Fig. This experimental study was performed to validate a new marker for hemodynamic status—the Venous return variation index (VRV). This index is a venous analogy of the arterial SVV index. It is generated by monitoring the respiratory blood flow variations where they occur in the SVC. Performing measurements in the SVC allows for evaluation of changes in right ventricle filling caused by lung–heart interactions, thereby eliminating many factors leading to false measurements (both positive and negative) associated with indexes acquired on the arterial side. The VRV can be easily calculated from changes in blood flow velocity in the superior vena cava (using VTI of flow) during mechanical ventilation. The VRV index closely reflects changes in right ventricular preload. Its measurement is easy, using a Doppler wire introduced to the superior vena cava via a central venous catheter. A Doppler sensor, on a regularly sized guidewire, can easily be inserted through a catheter’s distal lumen. The Doppler signal of the SVC blood flow appears when the sensor exits the catheter’s distal opening. Successful monitoring depends on the catheter tip being positioned within the laminar flow zone in the SVC. During central venous catheter placement, a Doppler sensor can also help to avoid a dangerous wall or near-wall catheter tip placement position. Unintended right atrial placement can also be easily detected from its unique waveform. We have found the Doppler signal to be very stable over the course of many hours in individual cases. The catheter tip had to be placed within a solid column of the laminar flow zone (at least 1 cm long).min during inspiration and VTImax during expiration. VTImin steeply decreases during the early bleeding stage, while VTImax does not change as much. Further bleeding leads to a more significant decrease of VTImax than VTImin resulting in a decrease of the VRV index during more significant bleeding. However, the VRV index remains above the threshold for hypovolemia. It is important to mention that the absolute value of VTImin continues to decrease during bleeding and can help distinguish normalization of the VRV index during volume therapy from a decrease of the VRV index during prolonged bleeding.We observed interesting changes in both the VRV and the PPV indexes during the bleeding phase of the study. The steepest changes were seen during the first four bleeding stages. Further bleeding did not result in any increase for these indexes. Rather, a decrease was observed in both indexes. This reaction seems paradoxical at first. However, the situation is quite complex. The VRV index is defined as the ratio of VTIThis type of behavior was also seen with PPV. Previously published trials found a continuous decrease of PPV during bleeding , 20. UnlThe VRV index can be used for continuous measurement to detect changes of hemodynamic status and for the guidance of volume therapy. Currently recommended dynamic indices for hemodynamic monitoring  still have many limitations.2O [Types of ventilation and cardiac arrhythmias can cause misinterpretations of the respiratory variations in arterial blood pressure . Other c2O , high fr2O , increas2O , and ope2O . Further2O , 27.The VRV index has not yet been tested during these conditions. This is the work of future studies. We tested the VRV index only during mechanical ventilation without spontaneous breathing, and none of the experimental animals had any significant arrhythmias. Anecdotally, we observed the behavior of the VRV index and PPV during ventilation with low tidal volume (5 ml/kg) in both experimental animals and in several clinical cases in patients with hypovolemia. The VRV index stayed in the responsive zone (above 33), while PPV frequently dropped into the non-responsive or gray area (below 15).The VRV index can be a fully automated, fast, real-time method, developed for continuous usage with the most pronounced changes evident during early stages of hypovolemia or fluid overload. This method combines the advantages of echocardiography-based methods with a direct and continuous assessment of right ventricle filling during intrathoracic pressure fluctuations caused by mechanical ventilation. Current European guidelines, published in 2017, emphasize the U-shaped curve relationship between hypovolemia and volume replacement. Infusing too much can be as deleterious as infusing too little. Artificial hypervolaemia predisposes patients to interstitial edema, which appears to be associated with perioperative mortality. They also prioritize dynamic parameters, such as SVV or PPV, over static ones and mention Doppler-based devices for assessment of cardiac preload. Our approach follows all these recommendations. We aimed to improve detection of the early phase of hypo- and hypervolemia .The main limitations of this study were the small number of animals and the use of only mechanical ventilation in fully sedated animals. However, we analyzed 44 hemodynamic situations to test the VRV index as a predictor of fluid responsiveness. Mechanical ventilation was chosen to analyze the VRV index during precisely defined conditions that can be repeated at any time. We used blood at room temperature for blood transfusions. This could influence the cardiac output measurement due to thermodilution. We were able to minimize this influence to a negligible level.All measurements were understood and analyzed as independent values. Multi-level analysis was not possible due to the low number of experimental animals. Additionally, we only measured flow in the SVC, as this approach most accurately reflects routine clinical practice.


We analyzed differences in structural lung changes over time between patients with COPD and those with COPD with asthma-like features using these CT parameters.Some patients with chronic obstructive pulmonary disease (COPD) have asthma-like features. However, there have been few reports on the structural lung abnormalities found in this patient population. Multi-detector computed tomography (MDCT) can detect emphysematous low-attenuation areas (LAA) within the lung, airway thickness , and the loss of pulmonary vasculature as the percentage of small pulmonary vessels with cross-sectional area (CSA) less than 5 mmWe performed pulmonary function tests (PFTs), MDCT, and a COPD assessment test (CAT) in 50 patients with COPD and 29 patients with COPD with asthma-like features at the time of enrollment and two years later. We analyzed changes in clinical parameters and CT indices over time and evaluated differences in structural changes between groups.1 did not significantly change during the follow-up period in either group. Emphysematous LAA regions significantly increased in both groups. The %CSA<5 showed a small but significant increase in COPD patients, but a significant decrease in patients with COPD with asthma-like features. The WA% at the distal bronchi was significantly decreased in COPD, but did not significantly change in COPD with asthma -like features.The CAT score and FEVEmphysematous LAA increased in patients with COPD with and without asthma-like features. The %CSA<5 and WA% at the distal bronchi did not change in parallel with LAA. Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Patients with COPD with asthma-like features may have different longitudinal structural changes than those seen in COPD patients. Chronic obstructive pulmonary disease (COPD), a common disease that is increasing in prevalence, is characterized by persistent respiratory symptoms and chronic airflow limitation . Worldwi1 in patients with COPD . Our data indicates that emphysematous destruction progresses in both patients with COPD and those with COPD with asthma-like features due to persistent airway inflammation even after smoking cessation.” or “We speculate that appropriate treatment, including ICS, decreases bronchial inflammation, which reduces vascular alterations near the small airways.”Please correct this because these speculations could not be based or associated with you research results.Please add the difference in management and other patient characteristics (smoking cessation rate) to the Limitations section of the manuscript.Please change the last sentence in the Conclusions because it represents a too farfetched assumption.[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: I believe this is an important clue in the puzzle of COPD. This study should prompt more bigger studies to clarify the asthma COPD difference. I personally do not support the ACO but believe that patient can have both diseases in different ratios. Regards.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  15 Nov 2019RESPONSE TO EDITOR:EVALUATION: This is an interesting topic, especially because morphological features of the chronic progressive disease was followed. But there are some things that need to be improved prior to the decision about publication.RESPONSE: We greatly appreciate the editor’s constructive comments, which have helped us to considerably improve the quality of our manuscript. We have revised our manuscript according to the editor’s comments. For easy reference, we have provided the revised text in red font.COMMENT 1: In the Methods section (MDCT) there is a need to clarify in more details how this was done:“All data were analyzed independently by two pulmonologists (RA and YM) who were blinded to all patient clinical information.” How the blinding was provided? Were they blinded also for the sequence (baseline and follow up)? How was the result calculated?RESPONSE: We appreciate your helpful comment. The MDCT measurements were evaluated by two pulmonologists (RA and YM) independently. All information including the MDCT data were anonymized and the observers were blinded to other characteristics of the subjects when imaging analysis were performed.We have revised the manuscript and added the following sentences in the Materials and methods section regarding MDCT measurements (Page 5).Page 5, lines 133-135, in Materials and methodsBefore:“All data were analyzed independently by two pulmonologists (RA and YM) who were blinded to all patient clinical information.”After:“The MDCT measurements were evaluated independently by two pulmonologists (RA and YM). All data were anonymized and the observers were blinded to other characteristics of the subjects when the imaging analyses were performed.”COMMENT 2: There is no data on sample size calculation and why this size of sample was used for this research. Please provide this! Also provide the Flowchart of the patients according to the STROBE! Please also provide the STROBE checklist!RESPONSE: We thank the editor for these important comments. We have rechecked the STROBE checklist 1 and have added a flow chart of the study participants as Figure1 below. We have also calculated the required sample size by JMP 13.0. The number of subjects needed for comparison of the two groups is 118 when the level of significance is 0.05, power (1-β) is 0.8, the difference is 0.1, and standard deviation is 0.2 2. However, the present study is an observational, preliminary, and exploratory study. A few previous studies on longitudinal structural changes have used these three CT parameters  mentioned in the present study in patients with COPD 2, 3. Tanabe et al. reported the impact of exacerbations on emphysema progression in COPD 4. They compared the change over two years in CT parameters related to emphysematous progression between the exacerbation group (n=34) vs a non-exacerbation group (n=26). In our previous study, we evaluated the change in three CT parameters in COPD (n=58) for two years 2 and described the morphological changes in the following groups: exacerbation (n=14) and non-exacerbation (n=44), and ex-smokers (n=46) and current smokers (n=12).  There are also a few studies on longitudinal structural changes using CT parameters in patients with ACO or those with COPD with asthma-like features. We have reported previously radiological findings between baseline and following budesonide/formoterol treatment in 20 patients with ACOS 3. Another report described CT parameters for emphysema and airway wall thickening between three groups: COPD group (n=118), ACOS group (n=32), and asthma with airflow limitation (n=27) 5. The present study had a small number of subjects with COPD with asthma-like features similar to these previous studies, and is therefore a preliminary and exploratory study. Accordingly, based on the sample size calculation and the advice of the statistician of our institution we consider it is better that the study is defined as a preliminary investigation. However, we would like to elucidate our findings in a further multi-center cohort study on a large number of subjects according to the editor’s very helpful insights.We have revised the manuscript in the Limitation section.Page 13, lines 299-300, in LimitationBefore:“First, our sample size was small because this study was conducted at a single institute.”After:“First, the study only enrolled a small number of patients and was a preliminary and exploratory investigation conducted at a single institute”We have also revised the manuscript and added the following text in the Materials and methods section regarding subjects (Page 3). We also added a flowchart of the patients as new Figure1 in the manuscript (Page 4).Page 3, lines 74-81, in Materials and methods“This prospective observational study enrolled 137 patients who presented to Chiba University Hospital from June 2010 to August 2016 for the management of COPD. Patients were excluded if they had abnormal lung parenchymal lesions other than emphysematous change. At enrollment, 10 patients were excluded for the following reasons: 4 interstitial pneumonia, 1 infectious pneumonia, 1 old pulmonary tuberculosis, and 4 lung cancer or nodules. At the follow up period, 15 patients were excluded: 6 interstitial pneumonia, 2 infectious pneumonia, 3 lung cancer or nodules, 2 cardiac failure, and 2 pleural effusion. Finally, 50 patients with COPD and 29 patients with COPD with asthma-like features were enrolled in the study .”Fig 1. Flow chart of the study participantsCOMMENT 3: In the Statistical analysis for the comparison of the follow up data an appropriate method of the analysis should be used – analysis of variance for repeated measurements. Please repeat your analyses using this method and report the results.RESPONSE: We thank the editor for this comment. In accordance with the comment, we performed a repeated measure two factorial ANOVA. There was a significant relationship between the change in %CSA<5, and the interaction between COPD/ACO and elapsed time (P=0.003) The present study consisted of two groups and we measured each parameter two times. In previous reports using MDCT parameters 2, 4, the longitudinal changes within each two groups measured two times were evaluated by the Wilcoxon signed-rank test. For the longitudinal changes between the two groups, the difference between baseline and follow-up in each group was compared using the Mann-Whitney U test. We consulted regarding this point with the statistician at our institution. Finally, we decided to compare the longitudinal changes within each group in this preliminary study using the Wilcoxon signed-rank test. For longitudinal changes between the two groups, we compared differences in the changes using the Mann-Whitney U test. The results of the annual change in lung function and computed tomography parameters are shown in the new Table 3 as below.Page 8-9, in ResultsTable 3. Annual changes in CAT score, PFTs, and CT measurements: Intra- and inter-group comparisons between patients with COPD with and without asthma-like features COPD COPD with asthma-like features P value(between groups) Value P value(within group) Value P value(within group) CAT score -0.1 ± 3.0 NS 0.3 ± 1.8 NS NSFEV1 (L) -0.01 ± 0.11 NS -0.02 ± 0.08 NS NSFEV1% predicted (%) 0.010 ± 0.086 NS -0.001 ± 0.054 NS NSLAA% (%) 0.83 ± 1.72 < 0.0001 0.40 ± 0.53 < 0.0001 NS%CSA<5 (%) 0.051 ± 0.104 0.0074 -0.035 ± 0.094 0.0148 0.0007Mean　WA% (%) Third -0.007 ± 0.037 NS 0.002 ± 0.027 NS NSFifth -0.011 ± 0.025 0.0043 -0.004 ± 0.021 NS NSCAT score, COPD assessment test score; PFTs, pulmonary function tests; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; LAA, low-attenuation area; CSA<5, cross-sectional area of pulmonary vessels <5 mm2; WA%, wall area percentage; NS, not significant.The data are expressed as mean ± standard deviation.The difference in CAT score was calculated by subtracting the value measured after 2 years from that measured at enrollment.The difference in FEV1 (L) was calculated by subtracting the value measured after 2 years from that measured at enrollment.The difference in FEV1% predicted (%) and the CT parameters (%) were calculated as follows: subtraction of the value measured after 2 years from that measured at enrollment, divided by the value at enrollment.We have revised and added the following sentences to the Results section regarding CT parameters (Page 10).Page 10, lines 210-217, CT parameters in Results“The annual changes in %CSA<5 were significantly different between the two groups . On the other hand, the mean WA% at the distal bronchi significantly decreased in the COPD group , while the WA% in the COPD with asthma-like features group did not significantly change during the follow-up period . The annual changes in mean fifth WA% were not significantly different between the two groups .”We have revised the manuscript and added the following text in the Materials and methods section regarding the statistical analysis (Page 5-6). Page 5, lines 138-141, the statistical analysis in the Materials and methods“JMP 13.0 software was used for all statistical analyses , with the results expressed as mean (± standard deviation) unless otherwise indicated. Comparison of longitudinal changes in CT parameters, PFTs, and CAT scores between enrollment and follow-up in each group was performed using the Wilcoxon signed-rank test. Comparisons were performed with a chi-square test for categorical variables. Differences in the data between the patients with COPD or COPD with asthma-like features were analyzed using the Mann-Whitney U test.”COMMENT 4: In Table 1 please express the rate of exacerbations per 1 year as this is the usual way to do it.RESPONSE: We have revised this in accordance with the editor's comment .Page 7, in Table 1 COPD COPD with asthma-like features P valueExacerbations per 1 year 0.8 ± 0.5 1.6 ± 1.9 NSCOMMENT 5: In Table 2 there is variable that is not explained anywhere – V50/V25. Please explain or remove if this is a mistake.RESPONSE: We appreciate your helpful comment. We have revised the table in accordance with the comment (Page 8).Page 8, lines 178-179, in abbreviations of Table 2“V50/V25, forced expiratory flow at 50% vital capacity and forced expiratory flow at 25% vital capacity”COMMENT 6: For Figure 1 there is no explanation on which data is represented on the box and whiskers plots! Please add this to your legend. Also it would be more appropriate if you would present the data for each variable for the comparing groups beside each other and not separately for each group. Please correct this. Also it would be better if you would present line graphs instead of box-plots.RESPONSE: We appreciate the reviewer’s helpful comment. We have revised the figure as a new Figure 2 in accordance with the comment). We have shown comparisons of the data for each variable in the groups beside each other, instead of separately using line graphs. We have also added an explanation of the CT parameters in the Figure legend in the Results section.Fig 2. Changes in radiological parameters over two years of follow-upBefore:After:Page 9, line 219-223, in Results section Notes: Radiological parameters were compared between enrollment and two-year follow-up using the Wilcoxon signed-rank test. WA% shows the mean wall area percentage at the 5th generation of bronchi.Abbreviations: ALF, asthma-like features; LAA, low-attenuation area; CSA<5, the cross-sectional area of pulmonary vessels < 5 mm2; WA%, wall area percentage; NS, not significantCOMMENT 7: In Discussion section there are too many speculations about possible mechanism like: “Indeed, interleukin (IL)-6 known as inflammatory biomarker was associated with emphysema progression (LAA) as assessed by CT scans in COPD [35]. Our data indicates that emphysematous destruction progresses in both patients with COPD and those with COPD with asthma-like features due to persistent airway inflammation even after smoking cessation.” or “We speculate that appropriate treatment, including ICS, decreases bronchial inflammation, which reduces vascular alterations near the small airways.”Please correct this because these speculations could not be based or associated with you research results.Please add the difference in management and other patient characteristics (smoking cessation rate) to the Limitations section of the manuscript.Please change the last sentence in the Conclusions because it represents a too farfetched assumption.RESPONSE: We appreciate this important comment. We have revised and added the following text in the Abstract, Discussion, and Conclusion section.Page 1, lines 21-22, Conclusion in AbstractBefore:“Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Appropriate medical management may have a different effect on structural changes in COPD with and without asthma-like features.”After:“Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Patients with COPD with asthma-like features may have different longitudinal structural changes than those seen in COPD patients.”We revised the Discussion.Page 11, lines 241-246, in DiscussionBefore:“Exposure to tobacco smoke leads to chronic airway inflammation through the activation of inflammatory cells [33]. Regardless of smoking cessation, chronic inflammation persists [34] and causes emphysema progression [21]. In our study, most patients were past smokers, and all had a significant smoking history. Indeed, interleukin (IL)-6 known as inflammatory biomarker was associated with emphysema progression (LAA) as assessed by CT scans in COPD [35]. Our data indicates that emphysematous destruction progresses in both patients with COPD and those with COPD with asthma-like features due to persistent airway inflammation even after smoking cessation.”After:“In COPD, exposure to tobacco smoke leads to chronic airway inflammation through the activation of inflammatory cells [33]. Regardless of smoking cessation, chronic inflammation persists [34] and causes emphysema progression [21]. Therefore, our data indicates that emphysematous destruction may progress in both patients with COPD and those with COPD with asthma-like features due to the fact that airway inflammation persist even after smoking cessation.”Page 11-12, lines 261-268, in DiscussionBefore:“Moreover, appropriate treatment might reduce the %CSA<5 in the COPD patients with asthma-like features. Although previous studies reported that patients with ACO have a worse clinical course than patients with COPD alone , recent studies have found that patients with ACO have a better prognosis . Suzuki et al. demonstrated that appropriate treatment improved the clinical course of patients with COPD with asthma-like features due to a better response to treatment [9]. Furthermore, Cosio et al. found that patients with ACO had a better 1-year prognosis than patients with COPD alone [8].”After:“Regarding the response to treatment, although previous studies reported that patients with ACO have a worse clinical course than patients with COPD alone , recent studies have found that patients with ACO have a better prognosis . Suzuki et al. demonstrated that appropriate treatment improved the clinical course of patients with COPD with asthma-like features due to a better response to treatment [9]. Furthermore, Cosio et al. found that patients with ACO had a better 1-year prognosis than patients with COPD alone [8]. Therefore, these various patient factors may affect the changes in %CSA<5 observed in both groups.”Page 12-13, lines 294-296, in DiscussionBefore:“Optimal management including ICS reduces the airway inflammation and may provide a greater effect on patients with COPD with asthma-like features.”After:“These findings support the strategy of considering treatment with ICS in patients with COPD with asthma-like features, even if they have not been already diagnosed with ACO .”We have also revised and added differences in management and other patient characteristics (smoking cessation rate) to the Limitations section of the manuscript.Page 13, lines 301-304, in Limitation“Third, because of the small number of subjects we could not evaluate each CT parameter for differences in treatment, with or without ICS, rate of smoking cessation, and frequency of exacerbations. Further prospective studies with larger study populations and longer observational period are required to confirm these results.”The Conclusion has been revised as follows.Page 13, lines 310-312, in ConclusionBefore:“Management strategies may have different effects on pulmonary vascularity between COPD with and without asthma-like features.”After:“Patients with COPD with asthma-like features may have different longitudinal structural changes compared to those observed in COPD patients. RESPONSE TO REVIEWER:EVALUATION: I believe this is an important clue in the puzzle of COPD. This study should prompt more bigger studies to clarify the asthma COPD difference. I personally do not support the ACO but believe that patient can have both diseases in different ratios. Regards.RESPONSE: We greatly appreciate your helpful and important insights on the subjects with asthma-COPD overlap (ACO). As the reviewer has commented, the pathogenesis and physiological findings are distinct between COPD and asthma 6. Recently, ACO has been recognized in clinical practice. Although GINA/GOLD published a consensus on ACO 7, the diagnosis of ACO has not been defined definitively, and previous studies have used multiple different diagnostic criteria 8. On the other hand, some patients with COPD have asthma-like features 9, even if they have not been diagnosed with ACO. Several previous reports have described the characteristics of ACO and COPD with asthma-like features 3, 9, 10. COPD with asthma-like features might be a clinical phenotype of COPD, and identifying this phenotype is used for designing individualized treatments 9, 11, 12. We consider that larger studies on COPD, asthma, and ACO are required in the near future in order to elucidate the characteristics of each phenotype 13, 14. References1. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014; 12: 1495-9.2. Takayanagi S, Kawata N, Tada Y, et al. Longitudinal changes in structural abnormalities using MDCT in COPD: do the CT measurements of airway wall thickness and small pulmonary vessels change in parallel with emphysematous progression? Int J Chron Obstruct Pulmon Dis. 2017; 12: 551-60.3. Suzuki T, Tada Y, Kawata N, et al. Clinical, physiological, and radiological features of asthma-chronic obstructive pulmonary disease overlap syndrome. Int J Chron Obstruct Pulmon Dis. 2015; 10: 947-54.4. Tanabe N, Muro S, Hirai T, et al. Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011; 183: 1653-9.5. Kitaguchi Y, Yasuo M and Hanaoka M. Comparison of pulmonary function in patients with COPD, asthma-COPD overlap syndrome, and asthma with airflow limitation. Int J Chron Obstruct Pulmon Dis. 2016; 11: 991-7.6. Barnes PJ. Against the Dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases. Am J Respir Crit Care Med. 2006; 174: 240-3; discussion 3-4.https://goldcopd.org/asthma-copd-asthma-copd-overlap-syndrome/.7. Asthma COPD and Ashtma-COPD Overlap Syndrome (ACOS). Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease 2015. Available from: 8. Tho NV, Park HY and Nakano Y. Asthma-COPD overlap syndrome (ACOS): A diagnostic challenge. Respirology. 2016; 21: 410-8.9. Suzuki M, Makita H, Konno S, et al. Asthma-like Features and Clinical Course of Chronic Obstructive Pulmonary Disease. An Analysis from the Hokkaido COPD Cohort Study. Am J Respir Crit Care Med. 2016; 194: 1358-65.10. Hardin M, Cho M, McDonald ML, et al. The clinical and genetic features of COPD-asthma overlap syndrome. Eur Respir J. 2014; 44: 341-50.11. Leigh R, Pizzichini MM, Morris MM, Maltais F, Hargreave FE and Pizzichini E. Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur Respir J. 2006; 27: 964-71.12. Fattahi F, ten Hacken NH, Lofdahl CG, et al. Atopy is a risk factor for respiratory symptoms in COPD patients: results from the EUROSCOP study. Respir Res. 2013; 14: 10.13. Hizawa N. LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes. Int J Chron Obstruct Pulmon Dis. 2015; 10: 1093-102.14. Agusti A, Gea J and Faner R. Biomarkers, the control panel and personalized COPD medicine. Respirology. 2016; 21: 24-33.AttachmentResponse to reviewers.docxSubmitted filename: Click here for additional data file. 25 Nov 2019PONE-D-19-20122R1Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like featuresPLOS ONEDear Dr Naoko Kawata,Thank you for submitting your manuscript to PLOS ONE. 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If eligible, we will contact you to opt in or out.We look forward to receiving your revised manuscript.Kind regards,Davor PlavecAcademic EditorPLOS ONEAdditional Editor Comments (if provided):Dear Authors,your manuscript is acceptable for publication after small revisions that should be done on Figures. On Figure 1 please change the words "abnormal chest shadows" into something more appropriate, like "abnormal lung parenchymal lesions other than emphysematous change". On Figure 2, and also the markings for the median and interquartile range for each time point and group.https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  11 Dec 2019RESPONSE TO EDITOR:EVALUATION:Your manuscript is acceptable for publication after small revisions that should be done on Figures. On Figure 1 please change the words "abnormal chest shadows" into something more appropriate, like "abnormal lung parenchymal lesions other than emphysematous change". On Figure 2, and also the markings for the median and interquartile range for each time point and group.RESPONSE:We greatly appreciate the editor’s constructive comments which have helped us to considerably improve the quality of our manuscript. We have revised our manuscript according to the editor’s comments.1) We revised Figure 1 according to the editor’s comment.Fig 1. Flow chart of the study participants2) We also revised Figure 2 according to the editor’s comment. We have added bars at which represent the median and interquartile range (Page 11).Fig 2. Changes in radiological parameters over two years of follow-upPage 11, lines 220-223, in ResultsBefore:“Notes: Radiological parameters were compared between enrollment and two-year follow-up with the Wilcoxon signed-rank test. WA% shows the mean wall area percentage at the 5th generation of bronchi.”After:“Notes: Radiological parameters were compared between enrollment and two-year follow-up with the Wilcoxon signed-rank test. WA% shows the mean wall area percentage at the 5th generation of bronchi. The thick horizontal bars at the sides of each graph show the median, while the thin horizontal bars at the sides of each graph show the interquartile range.”AttachmentResponse submission(1205).docxSubmitted filename: Click here for additional data file. 13 Dec 2019Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like featuresPONE-D-19-20122R2Dear Dr. Naoko Kawata,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. 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Every third patient in the clinic is misdiagnosed due to white-coat phenomenon, necessitating needless and costly treatment. We aimed to study the hemodynamic response of the physician’s visit on hypertensive and normotensive patients by investigating the trend of blood pressure (BP) before, during and 15 min after the physician-patient encounter.A descriptive, cross-sectional study was conducted over a period of 8 months in the cardiology clinics at the Aga Khan University Hospital, Karachi. Both hypertensive and normotensive patients, aged ≥18 years, were recruited. Pregnant females or those with a history of volume loss were excluded. BP readings were taken using an automated, validated device (Omron-HEM7221-E) at three points: pre-clinic BP by the assessment nurse, in-clinic BP by the attending physician and post-clinic BP 15-min after the physician-patient encounter by a research assistant. Independent samples t-test was used to calculate the statistical difference between hypertensive and normotensive BP values.n = 128) were hypertensive and 57% (n = 103) of all were males. The mean age of the participants was 57 ± 15 years. The mean and standard deviation(±SD) systolic BP (SBP) taken pre-clinic, in-clinic and 15-min post-clinic for hypertensive population was 128.7 ± 20 mmHg, 137.1 ± 21 mmHg and 127.9 ± 19 mmHg. The mean and standard deviation(±SD) SBP taken pre-clinic, in-clinic and 15 min post-clinic for normotensive population was 112 ± 16 mmHg, 115.8 ± 20 mmHg and 111.8 ± 15 mmHg. The hypertensive SBP values showed statistically significant difference from the normotensive values .Of 180 participants, 71% (Hypertensive and normotensive patients display congruent hemodynamics upon visiting the physician, the alert response being accentuated amongst the hypertensive group. In-clinic BP readings are higher for both hypertensive and normotensive patients making them unreliable for screening and management of hypertension amongst both the groups. Hypertension is a coronary risk factor which poses significant health challenge around the globe, most of the disease burden caused by high blood pressure (BP) being borne by lower and middle-income countries . The preOffice blood pressure (BP) is unable to overcome the white-coat effect , which aThe methodology of this study is already published and available in our previous paper on post clinic BP . In brieA sample size of 101 participants was needed to calculate a mean difference among clinic readings of 7.5 mmHg systolic BP (SBP) and 2.9 mm diastolic BP (DBP) at an alpha of 5% and a beta of 80%. After accounting for a 10% dropout rate, the minimum sample size needed to show the differences in readings taken at various points within the clinic was 110. A total of 180 participants were enrolled in the study.Blood pressure and pulse readings were taken at three different points in the clinic. The first set of pre-clinic readings were taken by the assessment nurse 16 ± 1.7 min after the patient had entered the hospital. The next set of in-clinic readings were taken by the physician 15 ± 2.1 min after the pre-clinic readings. Then the participants were asked to wait for another 15 min in the regular waiting area where they were asked to refrain from smoking and/ or exertion. Our rationale for waiting 15 min before taking the post-clinic readings was based on van der Wel et al’s study which showed that BP readings reach a plateau over 15 min . This waAt the start of the study, all three observers taking the readings in the pre-clinic, in-clinic and post-clinic periods were given a small training course on the proper method of measuring blood pressure to ensure standardization. The method used was as follows: each participant sat on a chair with the back supported and feet placed flat on level ground; arm was supported at heart’s level; an adequate size cuff was used, the bladder of which covered 80% of the arm ; with anWe used the Statistical Package for Social Sciences (SPSS), version 23 for re-analyzing our data. For quantitative variables were used mean and standard deviation (SD) whereas for qualitative variables were used frequency and percentages. A mean was calculated on the basis of all the readings measured during different points in the clinic. Independent samples t- test was used to determine the statistical difference between hypertensive and normotensive SBP, DBP and pulse values. We also determined the trend of BP among those using anti-hypertensive and compared them with those not using anti-hypertensive medications at each point in the clinic by employing t-test for independent sample.n = 102) were males. Of all participants, 71% (n = 128) were hypertensive of which 92% patients were on antihypertensive medications. Baseline characteristics of our study population is shown in Table A total of 200 patients were contacted to participate in the study. Of the total, due to lack of time on part of the participants, 12 (6%) refused to enroll themselves in the study whereas 8 (4%) left before the 15 min waiting period was over. Therefore, the total number of participants was 180. The mean age of the participants was 57 ± 15 years. Of the 180 participants, 57% (The mean and standard deviation (±SD) systolic blood pressure (SBP in mmHg) taken pre-clinic, in-clinic and 15 min post-clinic amongst hypertensive and normotensive participants is shown in Figure-1A. The mean and standard deviation (±SD) diastolic blood pressure (DBP in mmHg) taken pre-clinic, in-clinic and 15 min post-clinic amongst hypertensive and normotensive participants is shown in Figure-1B. The mean and standard deviation (±SD) pulse (in beats per minute) taken pre-clinic, in-clinic and 15 min post-clinic amongst hypertensive and normotensive participants is shown in Figure-1C. The difference between BP values in hypertensive and normotensive groups during the pre-clinic, in-clinic and post-clinic phase are shown on the respective Fig. n = 128) on antihypertensive medications versus those who were not on antihypertensive medications is shown in Table The difference between BP values in hypertensive patients n = 18 on antiIn the post-clinic BP study, we showed that the BP in the post-clinic period is about 10 mmHg lower than the BP readings taken in the presence of the physician . The PC-As we did not study the anxiety scores of the patients participating in our study, our results may not be able to determine the correlation of anxiety level with the BP readings taken at each point in the clinic. However, we believe that the accentuated rise in BP in the physician’s presence amongst the hypertensive patients is due to the greater effect of alert response of the clinic visit amongst these patients and this is similar to Spruill et al’s study where they showed that the patients’ perception of being hypertensive confers a greater state anxiety score and therefore white-coat effect . SimilarThere are two theories to explain the white-coat phenomenon. The generalized anxiety theory states that the patients with a general tendency of getting anxious display white-coat hypertension . The secBoth hypertensive and normotensive patients show congruent hemodynamic trends during a physician-patient encounter, the alert response being accentuated in the diagnosed hypertensive. In-clinic BP readings are higher for both hypertensive and normotensive patients, therefore, they are not reliable to screen or manage hypertension in both the groups.It is possible that different antihypertensive medications may modify the BP response shown by the participants which was not studied due to a limited sample size.The level of anxiety among our study participants were not studied therefore we were not able to correlate BP readings with anxiety scores.The readings were taken by three different observers as is the norm in a routine clinic setting, therefore, it is possible that this may have an implication on the white-coat phenomenon, however standardization was ensured by using an automated, validated BP device and same method of BP measurements.Our results were not stratified according to age and gender, it is possible that different age groups and different gender groups may show a difference in BP trends.The study was conducted in cardiology clinics at a single center, therefore, generalization may be limited.


The new guidelines on hypertension of the European Society of Cardiology (ESC) 2018 have refined the treatment cut-offs and therapy decisions in adults. This review highlights important recommendations of the guidelines and also on the situation of hypertension in Austria. The general treatment targets of blood pressure have been lowered to at least 130/80 mmHg for most patients. The definition of hypertension is specified as a repeated systolic blood pressure in the office of ≥140 and or diastolic BP ≥90 mmHg. For home blood pressure monitoring, an average value of ≥135/85 mmHg is now defined as hypertension. Ambulatory 24h-blood pressure measurement is recommended for diagnosis of hypertension and to demask lack of nocturnal blood pressure dipping. Whether drug treatment should be initiated immediately or after a delay with lifestyle intervention is focused on the individual high or low cardiovascular risk of the patients and the degree of hypertension. For most patients a combination therapy with single pill is now recommended as initial therapy for hypertension from the start. The salt consumption should be reduced in the majority of patients. The new guidelines have clarified the treatment of hypertension in different comorbidities. The new 2018 guidelines on hypertension of the European Society of Cardiology (ESC) have refined the treatment cut-offs and therapy decision-making in adults [The definition of hypertension is now specified as a constant, repeated systolic blood pressure (SBP) in the office of ≥140 mm Hg and or diastolic BP (DBP) ≥90 mm Hg. Before office determination patients should be seated quietly for 5 min.A 24 h ambulatory BP (ABPM) is strongly encouraged in all patients for screening and diagnosis of hypertension. It is important to note that in ABPM a lower value with an average of ≥130/80 mm Hg is already defined as hypertension. For home BP monitoring, an average value of ≥135/85 mm Hg is now defined. These values enable patients and physicians to choose from the available diagnostic tools; however, the different cut-offs for the definitions should be considered. It also empowers patients and their own responsibility by home measurements to detect and monitor hypertension.The general treatment targets of BP have been lowered to at least 130/80 mm Hg for almost all patients. This is in line with the recommendations of the American ACC/AHA guidelines for hypertension . In all The degree of hypertension grades 1–3) determines the initiation of treatment and the individual cardiovascular risk of the patient. Fig. –3 determWhether pharmaceutical treatment should be initiated immediately or after a delay with life style interventions is focused on high or low cardiovascular risk of the patients Fig. .Fig. 2ThIn lower risk patients with grade 1 hypertension  in the general population and in all hypertensive patients is now recommended. Adding salt and processed foods with hidden salt should be avoided, as they involve 80% of salt consumption. The BP lowering effect of sodium restriction is endorsed as greater in black patients and in older patients and concomitant diabetes or chronic kidney disease. Importantly, sodium restriction may reduce the necessary number or dose of antihypertensive drugs. For cardiovascular event reduction, a controversial J‑shaped curve for sodium intake has been suggested in meta-analyses . OverallThe new guidelines emphasize that medical treatment should in general be started straight away with a combination pill of two drugs as usual care. In most patients the currently recommended lower BP targets will not be reached without modern dual therapy. Furthermore, a single pill approach with optimal retardation drug formulation for a long plasma half-life will increase the medical adherence of the patients. If BP targets are not reached, augmenting to a single pill with 3 drugs is preferred.For most patients, a combination of a renin-angiotensin system (RAS) blocker, either an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), with a calcium channel blocker (CCB) or thiazide/thiazide-like diuretic (TH) such as chlorthalidone and indapamide is preferred as initial therapy. If three drugs are required to lower BP to targets, a combination of an ACEI or ARB with a CCB and a TH-diuretic are the right choice, again in a single pill combination. Beta-blockers are only recommended in specific indications such as angina, after myocardial infarction, heart failure with reduced ejection fraction or heart rate control in arrhythmias. Beta-blockers should be combined with any of the other major antihypertensive drug classes . A combination of two RAS blockers (ACEI and ARB) is not recommended. In resistant hypertension, especially the addition of spironolactone (25–50 mg o.d.) is recommended. Also, another diuretic, an alpha-blocker or beta-blocker can be added. Hypertension is defined as resistant when the recommended treatment fails to lower office SBP and DBP to <140 mm Hg and/or <90 mm Hg, respectively and is confirmed by 24 h ABPM or home BP measurements despite confirmed drug adherence. Optimal doses of tolerated drugs and three or more drugs are recommended along with life style changes. Secondary causes of hypertension should be excluded. BP resistance can be mimicked by severe brachial artery calcification, white coat hypertension, wrong measurements, e. g. with too small cuffs, and of course a lack of patient therapy compliance.Treatment thresholds of office BP are defined as ≥140/≥90 mm Hg and are the same in hypertensive patients with additional diabetes, coronary artery disease (CAD), chronic kidney disease (CKD), stroke or transient ischemic attack (TIA); however, in very high-risk patients with CAD, previous stroke or TIA, treatment may be considered already in high–normal SBP of 130–<140 mm Hg. In patients older than 80 years, a threshold of ≥160/≥90 mm Hg is advised for all groups, equally in diabetes, CAD, CKD or stroke.In CAD, diastolic BP should not be lowered <70 mm Hg as myocardial perfusion may be impaired in lower values . In CAD,For patients with diabetes, the same treatment targets are recommended for an office SBP target of 130 mm Hg or lower. SBP should not be lowered to <120 mm Hg. DBP target should be <80 mm Hg. In older patients ≥65 years the SBP target range is 130–140 mm Hg if tolerated. A variable visit to visit BP should be noted due to associated increased cardiovascular and renal risk. Caution is emphasized in autonomic polyneuropathy concerning postural or orthostatic hypotension. Nocturnal BP should be assessed by 24 h ABPM or in order to detect hypertension in apparently normotensive diabetic patients.2, as thiazide/thiazide-like diuretics are less effective or ineffective at this level. There is risk of hyperkalemia with spironolactone, especially when eGFR is <45 ml/min/1.72 m2 or baseline K+ ≥4.5 mmol/l.The RAS blockers (ACEI or ARB) are endorsed as more effective in reducing albuminuria than other antihypertensive drugs. The guidelines recommend a RAS blocker and CCB as the initial regimen drugs. In both diabetic or non-diabetic CKD, the SBP target is 130–139 mm Hg. Individualized treatment is advocated according to electrolytes. The use of loop diuretics is recommended when the estimated glomerular filtration rate (eGFR) is <30 ml/min/1.72 mIn hypertensive patients with preserved or reduced ejection fraction (EF), antihypertensive treatment should be considered if BP ≥140/≥90 mm Hg. If antihypertensive treatment is not needed, the treatment of heart failure (HF) should follow the current ESC HF guidelines . In HF wFor pregnant women the special considerations are outlined in the new pregnancy guidelines in cardiovascular disease . It is iStatins should in general be prescribed in hypertensive patients with established coronary disease or in moderate to high cardiovascular risk by SCORE evaluation Fig.  but are The use of device-based interventions such as carotid baroreceptor stimulation with pulse generator or baroreflex amplification stent device implantation, as well as catheter-based renal denervation for reduction of sympathetic tone is not recommended for the routine treatment of hypertension. Currently, not enough evidence for efficacy and safety is considered to be available.The new ESC guidelines have lowered the treatment target to a BP of 130/80 mm Hg. The definition of hypertension is set at systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg. This has caused some discussion, although the guidelines clearly aim at especially lowering the high-risk profiles of patients with concomitant cardiovascular diseases, e. g. coronary disease or diabetes [Importantly, the new guidelines have also introduced lower BP thresholds, below which treatment should not be continued, in general SBP 120 mm Hg as lower systolic threshold. Therefore, the current ESC guidelines have defined clear BP target ranges: SBP of 120–130 mm Hg in patients younger than 65 years old and 130–139 mm Hg in those older than 65 years and even over age 80 years if tolerated. Diastolic BP should not be lowered below 70 mm Hg. Therefore, the diastolic target range is now 70–79 mm Hg in all patients. It has been realized that excessive BP lowering causes more adverse events and higher discontinuation rates by patients [A single pill prescription with two or more drug ingredients is now confirmed as usual care when initiating antihypertensive treatment right from the start. This regimen will increase patient compliance and reduce side effects, as a relatively lower dosage of individual drugs may be applied with better galenics. Beta-blockers are now only recommended in special situations, e. g. after myocardial infarction, reduced ejection fraction heart failure and arrhythmias.A wider use of out of office measurements is now recommended. Ambulatory 24 h BP measurement is useful to demask nocturnal hypertension and lack of adequate dipping. In Austria, ABPM is not reimbursed by all public healthcare systems so far and will need to be established further. The salt consumption should be reduced in the majority of patients. The usual consumption of sodium is 3.5–5.5 g per day , depending on country or region. In Austria, half of the adults consume more than 2 teaspoons of salt per day . There iHigh altitudes above 3000 m and possibly 2000 m may contribute to aggravation of hypertension, which must be considered especially in the alpine regions of Austria , 12. FreThe new ESC guidelines have clearly defined therapeutic targets with lower thresholds. In most patients a BP goal of at least 130/80 mm Hg is recommended, but not below 120/70 mm Hg. Life style interventions are enforced in all stages of hypertension.


To assess whether the simultaneous performance of exercise stress echocardiography and cardio-pulmonary testing (ESE-CPET) may facilitate the timely diagnosis of subclinical left ventricular diastolic dysfunction (LVDD) in patients with non-severe chronic obstructive pulmonary disease (COPD), preserved left ventricular systolic function, and exertional dyspnea or exercise intolerance.2), ventilatory efficiency, heart rate reserve, and blood pressure.This cross-sectional study, conducted between May 2017 and April 2018, involved 104 non-severe COPD patients with exertional dyspnea and preserved ejection fraction who underwent echocardiography before CPET and 1-2 minutes after peak exercise. Based on the peak E/e’ ratio, patients were divided into the group with stress-induced LVDD – E/e’>15 and the group without stress-induced LVDD. We assessed the association between LVDD and the following CPET variables: minute ventilation, peak oxygen uptake , and higher VE/VCO2 slope than patients without stress-induced LVDD . None of the CPET variables correlated with E/e’.During ESE-CPET, stress-induced LVDD occurred in 67/104 patients (64%). These patients had lower work load, peak VOCombined ESE-CPET may distinguish masked LVDD in patients with non-severe COPD with exertional dyspnea and preserved left ventricular systolic function. None of the CPET variables was a predictor for subclinical LVDD. During the last decade, chronic obstructive pulmonary disease (COPD) has caused significant morbidity and mortality . COPD paStudies using magnetic resonance imaging established that patients with mild COPD without diseases, hypertension, or diabetes have arterial stiffness and myocardial fibrosis -8. Both Dyspnea and exercise intolerance are common symptoms of both COPD and heart failure with preserved ejection fraction ,13. ThisThere are no studies dealing with the problem of masked heart failure in COPD population. We hypothesized that the simultaneous performance of exercise stress echocardiography and cardio-pulmonary testing (ESE-CPX) may facilitate the timely diagnosis of subclinical LVDD in patients with non-severe COPD, preserved left ventricular systolic function (LVSF), and exertional dyspnea or exercise intolerance. The aims of the current study are to detect the frequency of exercise-induced LVDD in non-severe, non-symptomatic at rest COPD patients and to establish CPET parameters that can be applied as surrogate markers for masked LVDD.This cross-sectional study involved 224 clinically stable outpatients diagnosed with COPD at the University Hospital for Respiratory Diseases “St. Sophia” in Sofia, Bulgaria. Only 163 of them met the inclusion criteria – FEO1 > 50% and lack of overt cardiovascular diseases. All patients had exertional dyspnea and preserved left ventricular systolic function. The following exclusion criteria were used: 1) LVEF<50%; 2) LVDD at rest more than first grade; 3) echocardiographic signs of systolic pulmonary arterial hypertension; 4) valvular heart disease; 5) documented cardiomyopathy; 6) severe uncontrolled hypertension (systolic blood pressure >180 mm Hg and diastolic blood pressure >90 mm Hg); 7) atrial fibrillation or malignant ventricular arrhythmia; 8) anemia; 9) cancer; 10) chronic kidney disease; 11) recent chest or abdominal surgery; 12) recent exacerbation (during the last three months); 13) recent change (during the last three months) in medical therapy. Based on these criteria, 59 patients were excluded, and 104 patients  were considered eligible . The recPatients’ data included general demographic information, self-reported medical history, and concomitant medication. Demographic and clinical data are presented in All participants underwent preliminary clinical examination that included chest x-ray, spirometry, electrocardiogram, and echocardiography. The patients eligible for the study performed spirometry and exercise stress test. Both tests were performed on Vyntus  following the manufacturer’s instructions. Spirometry was performed after bronchodilation test with the application of 400 mg salbutamol. Following the ERS guidelines, a post-bronchodilation ratio of FEV1/FVC<70% was used as a diagnostic criterion of COPD . Only pa2, heart rate, and arterial blood pressure were obtained before and during the recovery period, 1 minute after the end of the test.Six-minute walk test was performed in accordance with the ATS guidelines . It was After the clinical examination and spirometry, all the patients underwent symptom-limited incremental exercise stress test on a supine bicycle in accordance with the guidelines . Gas andA continuous RAMP protocol was applied – two minutes of unloaded pedaling (rest phase – 0W), a three-minute warm-up phase (20W), and the test phase including 20 W/2-min load increments. Patients were instructed to pedal with 60 rotations per minute.2) are presented as the highest 30-second average value obtained during the last stage of the exercise test. These values were used to estimate peak respiratory exchange ratio (RER). RER>1.00 was considered as a maximum effort. The modified Borg scale was applied for peak dyspnea evaluation. Heart rate recovery was defined as the difference between peak heart rate and heart rate during the first minute of recovery.Expiratory gases were analyzed by breath-by-breath analysis. Peak values of oxygen consumption, carbon dioxide production, and ventilatory efficiency .Descriptive statistics was used to summarize demographic and clinical data. Normality of distribution was tested with the Kolmogorov-Smirnov test. Continuous variables are expressed as mean values ± standard deviation, while categorical variables are expressed as proportions. Normally distributed variables were compared between the patients with and without LVDD with the 2. According to the stress echocardiography results, they were divided into the group with stress-induced LVDD and the group without stress-induced LVDD. The groups did not differ in anthropometric, respiratory (P < 0.0001)  . Non-sev 0.0001) , achieviThis study found 1) a high frequency (64%) of stress-induced LVDD in non-severe COPD patients with exertional dyspnea and preserved LV ejection fraction; 2) stress-induced elevation of systolic pulmonary arterial pressure (>35 mm Hg) and a reduced functional capacity, as measured by both CPET and 6-min walk, in participants with stress-induced LVDD; 3) difference in CPET variables between patients with and without stress-induced LVDD, but no correlation of these variable to stress E/e’. These results only partially confirm our hypothesis, as we expected that in addition to the high prevalence of stress-induced LVDD, some CPET parameters would predict LVDD. The reasons for the discrepancy may be the complex lung-heart interaction during exercise and multifactorial nature of LVDD.COPD is a multi-systemic disease that remains a worldwide leading cause of disability ,25. Comp2 ratio as the best predictor of stress E/e’ was also confirmed in a diastolic heart failure group . These results differ from data obtained in the general population, which had a significantly lower prevalence of exercise-induced LVDD. Nedeljkovic et al  performere group .Since LVDD is associated with an increased risk of exacerbations and mortality, its timely diagnosis in non-severe COPD is important for disease management. As none of the clinical, ventilatory, cardio-pulmonary, and echocardiographic characteristics can predict stress-induced LVDD in non-severe COPD, the combined ESE can facilitate its early diagnosis.Our study has the following limitations: 1) the relatively small sample size; 2) the lack of body plethysmography for the measurement of hyperinflation and the lack of diffusion capacity measurements, which are informative for the proper assessment of dyspnea; 3) measurements were performed at the end of expiration due to the huge pressure gradients accompanying the respiratory cycle in COPD patients; 4) measurements were performed in the early recovery period (approximately 2 min) after symptom-limited exercise. The timeline of pulmonary and intrathoracic pressures changes during the brief time interval from peak exercise to their measurement in early recovery is not well known, leading to possible underestimation.In non-severe COPD patients with preserved LV systolic function, the combined ESE-CPX test can reliably identify stress-induced LVDD, the early diagnosis and proper management of which may facilitate the prevention of cardiovascular complications. Although none of the routine clinical and CPET parameters predicted increased E/e’, the high prevalence of exercise-induced LVDD in these patients indicates the need for performing stress echocardiography.


Most guidelines all over the world recommended metformin as the first-line treatment for in type 2 diabetic patients. Therefore, the present study was suggested to assess the outcome of metformin administration and glycemic status on alterations in red blood cell (RBCs) indices as well as the oxidative stress in type 2 diabetic patients.Between December 2016 and October of 2017, a total of 158 eligible individuals were classified as 50 healthy subjects and 108 diabetic patients who were subdivided into six groups according to the type of anti-diabetic treatments.P < 0.001) elevated in all diabetic groups as compared to control. Moreover, in all diabetic groups, malondialdehyde (MDA) concentration was elevated noticeably (P < 0.001), while reduced glutathione (GSH) revealed a lower concentration (P < 0.001) than that of control.Overall, the results elucidated that hemoglobin concentration was markedly diminished, while red cell distribution width (RDW) value was significantly (The present study exhibited the amelioration effect of metformin administration on oxidative stress and glycemic status which reflected on some RBCs indices. However, hemoglobin concentration showed a noticeable diminution in all metformin-treated groups in spite of the improvement in glycemic and oxidative stress status which indicated that the metformin-induced anemia is independently from diabetic complications. Diabetes is a worldwide health problem with a close link exists between diabetes and cardiovascular disease (CVD), whereas CVD is the most prevalent cause of mortality and morbidity among the diabetic populations . The preCurrently, the orally employed antidiabetic agents: biguanides , sulfonylureas , α-glycosidase inhibitors  and thiazolidinediones , act to regulate a specific pathological pathway . MetformOxidative stress and inflammation contribute to the development of diabetic complications. Intracellular hyperglycemia promotes the production of mitochondrial reactive oxygen species (ROS). ROS is directly increase the expression of inflammatory and adhesion factors, the formation of oxidised-low density lipoprotein, and insulin resistance . DepletiRecently, a great attention re-given to the hematological indices as predictors of endothelial dysfunction and inflammation status . Anemia Among RBCs indices, the red blood cell distribution width (RDW) is a simple and non-expensive parameter, which can reflect the level of erythrocyte volume heterogeneity (anisocytosis) and is commonly used in the laboratory for differential analysis of anemia . FurtherThe study was conducted on 158 individuals of both sexes , aged between 30 and 75 years. These individuals enrolled in this study were classified into 50 normal healthy subjects and 108 T2DM patients who were followed up at the Diabetic Section of General Institution of Healthy Insurance, Egypt, between December 2016 to October 2017. Written agreements were obtained from all patients before participation in the study. The present study was performed in accordance with the declaration of Helsinki and good clinical practice guidelines and also approved by the committee of General Institutions of Health Insurance.Enrolled patients were allocated to normal healthy subjects (control) who had no previous history of chronic diseases and free of type I or 2 diabetes, and 108 patients diagnosed as T2DM according to WHO 1999 criteria. Pregnant and lactating women, patients receiving immuno-modulatory drugs and patients with medical conditions such as infections, cerebrovascular diseases, ischemic heart disease, malignancies, autoimmune disorders, eczema, respiratory disorder, thyroid dysfunction, kidney failure, liver dysfunction and alcohol abuse were excluded from the study. In addition, diabetic patients who underwent medication changes during the 2 months preceding participation were also excluded.The diabetic patients were subdivided into six groups according to the treatment administration.The demographic data regarding anthropometric variables such as height, weight, body mass index (BMI), gender, duration of disease and blood pressure (BP) were collected. Blood samples were taken from participants after overnight fasting in EDTA and plain tubes (4 mL each). Following an incubation period of 30 min at room temperature, blood in plain tubes was centrifuged at 4,000× g for serum isolation. Sera were rapidly separated, aliquoted and stored at −40 °C until the biochemical measurements. The second tube blood sample was taken on potassium fluoride for immediate glucose estimation. The third part of the blood sample was taken on EDTA for determination of HbA1c levels and complete blood picture at the same time, then, the blood was centrifuged, the plasma and leucocytes layer were then removed and the packed erythrocyte sediments were washed three times with normal saline and hemolyzed by adding approximately 1.5 volumes of ice-cold distilled water. The stock hemolysate stored at −40 °C for estimation of MDA and GSH levels. Fresh morning urine samples were obtained for the measurement of microalbuminuria concentration.The concentrations of glucose, creatinine, total cholesterol, triglyceride and HDL-c were estimated using commercially available assay kits obtained from Reactivos Spinrect, Spain. low density lipoprotein (LDL)-cholesterol level was calculated according to Friendewald formula . The antP < 0.05 were considered statistically significant.The data were analysed by one-way analysis of variance (ANOVA). To compare the difference between the groups, post hoc testing was performed by the Duncan test with least significant difference (LSD). Pearson’s correlation coefficient analysis was used to determine the correlations between different studied parameters. Statistical analysis was performed using the Statistical Package for the Social Science (SPSS) for Windows . Data are expressed as mean (SD). Values with P < 0.001) in all diabetic groups as compared to the healthy control  and dual therapy groups, however, HB observed a positive significant correlation with GSH in all metformin therapy groups . MoreoveMoreover, HCT value observed a negative correlation between HbA1c, microalbuminuria and MDA with metformin monotherapy and combined therapies of metformin. On the other hand, HCT value had a positive significant correlation between GSH with mono-and dual metformin therapies with a sulphonylurea and insulin  . RDW levOverall, our results confirmed that Hb concentration was lowered in all diabetic groups, while RDW was elevated significantly in diabetic patients. Also, the erythrocytes (RBCs) count revealed a significant decrease in patients treated with metformin plus insulin. The decrease in RBCs counts in diabetic patients may be due to RBC membrane protein alterations, a decrease in hemoglobin levels and erythropoietin deficiency . HemogloAnemia is a highly prevalent condition in people with T2DM. The causes of diabetic anemia are multifactorial including inflammation, concomitant autoimmune diseases, antidiabetic medication, hormonal changes and kidney diseases . The manThe main pathophysiological consequences of free radical-induced lipid peroxidation are disturbing the assembly of cell membranes, which inevitably will impact membrane fluidity, and lipid-protein interaction dynamics, membrane permeability, and physicochemical properties . MoreoveIn addition, in accordance with the current study, several findings showed that patients with T2DM had lower GSH content in erythrocytes than that in the control group. Also, a decrease in intracellular glutathione level in patients with T2DM was reported especially in the presence of microvascular complications , which wIn accordance with our results, the RDW values were significantly higher in diabetic patients than that of healthy subjects . FurtherMicroalbuminuria, the best sign for diabetic nephropathy development in T2DM, was also, accepted as an indicator of diabetic microangiopathy . UrinaryWhen fructose-fed rats were treated with metformin, the imbalance between peroxidation and antioxidants defense system was mitigated . HoweverThe data indicated that metformin administration can induce amelioration in hyperglycemia and oxidative stress as well as inflammation status regarded to MDA, GSH and RDW levels. However, Hb concentration showed a reduction in metformin-treated groups in spite of improvements in glycemic and oxidative status. This mean that the metformin-induced anemia is independent of diabetes.


Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD.2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex.This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort  age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/mA greater GLP-1 response was associated with lower central systolic and diastolic BP of − 1.17 mmHg  − 2.07 to − 0.27 mmHg, P = 0.011) and − 0.74 mmHg , respectively, as well as lower brachial systolic and diastolic BP of − 1.27 mmHg  and − 1.00 , respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response  mmHg, central diastolic BP: − 3.05 (95% CI − 5.29 to − 0.80) mmHg, brachial systolic BP: − 5.18 (95% CI − 8.94 to − 1.42) mmHg, and brachial diastolic BP: − 2.96 (95% CI − 5.26 to − 0.67) mmHg).Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality.Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005 Globally, cardiovascular diseases (CVDs) were the leading cause of death in 2017 . In rece−/−) [−/− mice exhibited both structural and functional cardiac abnormalities compared to wild type mice. Another study in humans, found that acute GLP-1 infusion in physiological concentrations  did not change systolic blood pressure but did increase heart rate, brachial artery diameter and brachial artery flow velocity [Chronic low-grade inflammation has been proposed to contribute to development of cardiovascular disease and atherosclerosis  and seve−/−) , it has −/−) . This stvelocity , indicatTreatment studies with supra-physiological pharmacological doses of GLP-1 RAs have shown decreased risk of CVD , 5 and aThis cross-sectional study is part of a large observational cohort study: the ADDITION-PRO study, a longitudinal cohort study of individuals at high risk for diabetes, recruited from Danish primary care. A thorough description of the design can be found in the ADDITION-PRO protocol .In the ADDITION-PRO study, a detailed examination programme was executed during 2009–2011, and 2082 individuals participated. Blood sampling for GLP-1 measurement was performed at three out of four study centres, comprising 1853 individuals. Of those, 252 had known type 2 diabetes and 15 did not fast and did not have an OGTT. Of the remaining 1586 participants, 657 were taking antihypertensive medication and 92 additional participants had missing information on central haemodynamics or GLP-1, leaving 837 individuals available for the present analysis. No individuals were using incretin-based drugs. Of the 837 individuals, 116 were using lipid-lowering drugs, which we allowed in the present analysis.Brachial blood pressure was measured three times with the participant in a sitting position after 10 min of rest  and reported as an average. Aortic pulse wave velocity (PWV) and central blood pressure were assessed with the participant in a supine position after 10 min of rest using a SphygmoCor apparatus  and a tonometer, which captured wave forms at the carotid, femoral and radial artery. Using simultaneous ECG monitoring, the time from the R wave to the arrival of the pulse wave at the carotid and femoral artery, respectively, was captured. An anthropometer  was used to measure the distance from the suprasternal point to the carotid artery recording site and from the suprasternal point to the femoral artery recording site to avoid overestimation of the distance. The ratio between the distance and the time defined the PWV. The PWV was measured twice between the right carotid and right femoral artery and in case of a difference of more than 0.5 m/s, a third measure was taken. It was reported as an average of the two closest measures. Peripheral pressure waveforms assessed at the radial artery were used to estimate central blood pressure . The aveA 3-point standard 75 g oral glucose tolerance test (OGTT) was performed, with blood sampling before (0 min) and 30 and 120 min after glucose intake. Plasma glucose was measured using one of two different methods; Hitachi 912 system  or Vitros 5600 system . Subsequently, Vitros values were converted to Hitachi values . HbA1c wGLP-1) was log2-transformed to fulfil the requirement of a normal distribution of the model residuals. All analyses were adjusted for age and sex. Analyses of PWV were additionally adjusted for mean blood pressure and heart rate at time of PWV measurement. Additional analyses adjusting for age, sex and either iAUC insulin, fasting plasma glucose, BMI or HOMA-IR were performed for association between iAUC GLP-1 and central and brachial blood pressures. The study population was categorized into quartiles according to the iAUC GLP-1 response and the lowest and highest quartiles were compared with regards to blood pressure measures (adjusting for age and sex). Sub-analysis of the study population was made dividing the population into a normo glucose (fasting glucose < 5.6 mmol/l) group and a pre-diabetes risk (fasting glucose ≥ 5.6 mmol/l) group and association to blood pressures were investigated (adjusting for age and sex). Analyses were performed using SAS version 9.4  and figures were created in R version 3.2.2 . A P-value of < 0.05 was considered significant.GLP-1 response was defined as the incremental area under the curve (iAUC), from start of the OGTT to 120 min after glucose intake, using the GLP-1 measurements before glucose intake and after 30 and 120 min. Using the trapezoid rule, iAUC was calculated as total area under the curve subtracted the fasting GLP-1 value × 120 min . Associations between GLP-1 release and central haemodynamics were analysed in separate models using linear regression analysis. Prior to analysis, iAUC for GLP-1 mmol/l, HbA1c level of 5.6 (5.4 to 5.8) % and a median blood pressure within the normal range  mmHg and diastolic blood pressure of 80 (73.3 to 87.0) mmHg), Table The 837 individuals included for analysis had a median (interquartile range) age of 65.5 (59.8 to 70.7) years and 47.7% were women, BMI of 26.1 (23.4 to 28.5) kg/mGLP-1) was associated with a lower central systolic  and diastolic  blood pressure as well as a lower brachial systolic  and diastolic  blood pressure. Central pulse pressure and brachial pulse pressure were not significantly associated with GLP-1 secretion, Table A greater GLP-1 response during the OGTT (iAUCGLP-1 resulted in a non-significant difference in PWV of − 0.04 m/s (P = 0.3).A doubling in iAUCAnalyses were adjusted for age and sex and PWV analyses was additionally adjusted for blood pressure and heart rate. The association between GLP-1 response and central and peripheral blood pressure remained significant when adjusting for fasting glucose, iAUC insulin response, and for HOMA-IR  . When adjusting for BMI, the association remained significant for central systolic blood pressure and peripheral diastolic blood pressure, Fig. The participants were divided into quartiles according to their iAUC GLP-1 response. The group with the highest quartile of GLP-1 response was associated with significant lower central systolic (− 4.94 (95% CI − 8.56 to − 1.31) mmHg) and diastolic (− 3.05 (95% CI − 5.29 to − 0.80) mmHg) blood pressure as well as significant lower brachial systolic (− 5.18 (95% CI − 8.94 to − 1.42) mmHg) and diastolic (− 2.96 (95% CI − 5.26 to − 0.67) mmHg) blood pressure, compared to the group with the lowest quartile of GLP-1 response.This study of 837 people at risk of diabetes and thereby CVD shows that there is a clinically relevant relationship between greater endogenous GLP-1 hormone response during an OGTT and lower blood pressure measures in a normotensive population. The quartile of individuals with the highest GLP-1 response had a ~ 5 mmHg lower blood pressure compared to the quartile of individuals with the lowest GLP-1 response. This degree of blood pressure lowering has been associated with lower risk of cardiovascular event, all-cause mortality and cardiovascular mortality. Thus indicating beneficial effects on the cardiovascular system with greater endogenous GLP-1 secretion in agreement with the observations of lower cardiovascular mortality and decreased blood pressure with GLP-1 RA treatment , 5, 16.Several parameters have been proposed to affect the secretion and concentration of GLP-1 including glucose , fat 1919, bile We find that there is an association between a greater GLP-1 response during an OGTT and lower central and peripheral blood pressure. Our results remain significant even after adjusting for iAUC insulin, fasting glucose, and for most analyses also for BMI and HOMA-IR, which are all factors known to have an impact on GLP-1 secretion. Interestingly, when dividing participants into quartiles according to their GLP-1 response we found that the group with the highest GLP-1 response was associated with approximately 5 mmHg lower blood pressures compared to the group with the lowest GLP-1 response. Many individuals with obesity and/or type 2 diabetes have decreased GLP-1 secretion , 24, 25 We observe that the quartile of individuals with the highest GLP-1 response have a ~ 5 mmHg lower blood pressure compared to the quartile of individuals with the lowest GLP-1 response. A large meta-analysis found that the degree of blood pressure reduction was proportional to the risk of major cardiovascular disease events, stroke, heart failure, and all-cause mortality . InteresThe GLP-1 receptor has been located on endothelial cells in the vasculature  and a diOnly few studies have previously analysed the association between endogenous GLP-1 levels and cardiovascular disease. In agreement with our findings, an inverse correlation  between GLP-1 secretion and systolic blood pressure was found by Yoshihara et al. . HoweverOur physiological study includes more than 800 participants making its size a major strength, outnumbering previous studies , 58. TotWe found that greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressure. Thus, it is likely that endogenous GLP-1 response has a beneficial impact on vascular function, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality.