The aim of this study is to identify a possible link between macrovascular hemodynamic status and microvascular hemodynamic indices in patients with periodontal disease.  Seventeen adult patients are recruited on a voluntary basis at the Dentistry Department of the “Mater Domini” University of Catanzaro, with sampling that determines the lipid profile, blood glucose, inflammatory mediators, blood plasma viscosity: anamnesis, blood pressure measurement, and detection of anthropometric parameters: eco-Doppler of the carotid arteries and brachial arteries with noninvasive measurements of hemodynamics and evaluation of inflammation and periodontal circulation with a noninvasive spectroscopic technique. The subjects underwent a dental inspection with periodontal proves. The different indices of periodontal disease were evaluated.  The sites with high probing depth differ from the healthy ones, showing low oxygen saturation and a notable increase in tissue edema, but no correlation between macro- and microvascular values was found.  Periodontal probing and spectroscopic examination showed the correlation between low oxygen saturation levels and tissue edema values with probing depth; however, no correlation between macrovascular hemodynamic status and microvascular hemodynamics indices was found probably given the heterogeneity of the population under consideration, the low number of data gathered, and the small sample size. The association between dental and cardiovascular diseases has been arousing much interest in the recent years.Some authors have investigated the correlation between the levels of some chronic inflammation mediators present in the blood and saliva and the severity of periodontal disease.Recently a study wanted to analyze and identify the association among salivary interleukin-6 (IL-6) levels and periodontitis (PT) and to determine the significant trend of this association in PT patients.Patients in the PT group had significantly higher median salivary IL-6 levels compared to the HS group. Salivary IL-6 levels were negatively correlated with C-reactive protein, with the number of teeth and with clinical attachment loss (CAL), probing pocket depth (PPD), and bleeding sites (FMBS). Furthermore, in patients with PT, salivary IL-6 levels were inversely associated (P-trend) with the number of teeth, and directly associated with the proportional extent of PT; these results so showed that PT patients presented significant higher salivary IL-6 levels compared to HS. Moreover, in the analyzed sample, a significant p-trend among PT, tooth loss, and increased salivary IL-6 levels was found .Another study from the same group of authors aimed to analyze the association and impact of periodontitis and coronary heart disease (CHD) on salivary and serum galectin-3 in patients with periodontitis and CHD; the results showed that patients with periodontitis and periodontitis + CHD presented significant higher serum and salivary galectin-3 levels in comparison with CHD patients and healthy subjects. Periodontitis and ET-1 were the significant predictors of serum and salivary galectin-3 levels, respectively. .Another study found increased leukotriene concentration in the gingival crevicular fluid from subjects with periodontal disease and atherosclerosis. .Various studies have reported that there is a correlation between CHD risk factors or metabolic syndrome and related diseases  and periodontal disease, and this is very interesting due to the potential clinical implications , 5.Hemodynamics is that branch of cardiovascular physiology that analyzes and studies the behavior of blood moving in the vessels, therefore allowing reducing the danger of forming pathologies related to blood circulation.The functioning of the cardiocirculatory system can be explained using the physical principles derived from the laws of hydrostatics-hydrodynamics, although the cardiocirculatory system has features that prevent a precise quantitative description.elastic and nonrigid ductstracts (capillaries) that allow the leakage and the entry of liquidsa pump (heart) with intermittent activityexternal pressure in the ducts which can determine changes in the caliber due to its elasticitya non-Newtonian fluid in motion (blood), with viscosity varying with variation of speedIn fact, the cardiocirculatory system presents−1 s−1 at a temperature of 37°C and a hematocrit of 45. Basically, the viscosity can be considered as a resistance in flow, given that the layers of fluid subjected to intermolecular attractions oppose a deformation.The blood is a complex fluid consisting of a suspension of particles in liquid form (plasma) and, as such, subject to variations in viscosity. The blood viscosity depends on the temperature and hematocrit. Usually, we consider the blood viscosity to be around 4·103 kg mThe monitoring of hemodynamic forces in patients with periodontal disease could be important for an accurate evaluation of the overall cardiovascular risk for periodontal therapy .The wall shear stress is the frictional force that is generated by the blood when flowing tangentially to the endothelial surface, strongly influencing the arterial remodeling and, if low, promotes the formation of plaques.It is known that the wall shear stress is lower in elder people and in those with high blood pressure, high body mass index, or affected by diabetes , 8. Moreα, produced by the inflamed oral tissues [The way in which periodontitis affects hemodynamics could be the systematic inflammation , with an tissues , can act tissues . FurtherThe calculation of the hemodynamic forces is based on the eco-Doppler measurements: this method is fast, repeatable, of low cost, valid, and vastly applied in this field.The aspect investigated in this study is the association between local carotid hemodynamics, microvascular hemodynamics indices, and periodontal disease, and the purpose is to identify the link between periodontal indices and micro- and macrovascular hemodynamics values, in particular the wall shear stress, suggesting that the alternation of the hemodynamic profile could contribute to atherosclerosis in subjects with periodontal disease.Seventeen adult patients who meet the inclusion criteria are sequentially recruited on a voluntary basis at the dentistry crime of the “Mater Domin” University Hospital of Catanzaro; those who meet the inclusion criteria signed written consent.Patients with periodontal disease requiring dental therapy Atrial fibrillationSignificant hemodynamically carotid stenosisUse of drugs with an antihypertensive effectNonmenopausal women or neoplasm in actInformative consent is signed by each subject before the spectra are collected. The periodontal sites are defined as those with periodontal probing depth ≥5 mm and a loss in clinical attachment of ≥3 mm. Gingivitis sites are defined as those with periodontal probing depth <3 mm and bleeding on probing. Healthy sites are defined as those with probing depth <3 mm and no bleeding on probing. The spectra were obtained from the contralateral healthy sites or the closest contralateral site closest to the diseased site. The spectra measurements were acquired in the following site: Mea-Buccal, Mid-Lingual, Mesio-Buccal, Mesio-ingual, Disto-Buccal and Disto-Lingual.blood sampling in order to determine the lipid profile, glycemia, inflammatory mediators, and blood and plasma viscosityanamnesis, blood pressure measurement, and detection of anthropometric parameterseco-Doppler ultrasound of the brachial carotid arteries with noninvasive measurement of hemodynamicsevaluation of the inflammation and periodontal circulation with a noninvasive spectroscopic techniqueThe observational study clinic is based on the addition of a cardiovascular screening along with macro- and microvascular hemodynamic measures of selected dental patients. It is made up ofSystolic and diastolic blood pressures were measured by using a standardized sphygmomanometer on the right arm of the participants, after having rested for at least 5 minutes. An average of the second and third reading is then calculated.The observational clinic study is, therefore, based on the addition of cardiovascular screening and of macro- and microvascular hemodynamic measures towards selected dental patients. It consists of blood sampling in order to determine the lipid profile, glycemia, and inflammatory mediators with blood and plasma viscosity; anamnesis, blood measurement, and detection of anthropometric parameters; Doppler ultrasound of the carotid and brachial arteries with noninvasive measurements of hemodynamics; and evaluation of inflammation and periodontal circulation with a noninvasive spectroscopic technique. Weight and height are measured with routine methods. The body mass index (BMI) was calculated as weight (kg) divided by the height squared. Patients with values higher than 29.9 kg7 m2 were considered to be obese. Glucose and lipids present in the blood were measured with kits available on the market. The eco-Doppler exam was conducted with an ATL 3000 activated ECG instrument equipped with a 5–0 MHz multifrequency linear probe.The common carotid artery, the carotid bulb, and the internal and external carotid artery have all been studied longitudinally and transversally, with anterior, lateral, and posterior approaches. Each segment has been classified as normal, with plaque, and with stenosis. A segment with plaque showed a localized laceration which invaded the lumen by >1,3 mm, without enlarging the spectral or only in the deceleration phase of the systole, with systolic and peak flow velocity of <120 cm/s. The segments with stenosis showed a spectral enlargement during the systole or a peak flow in systolic velocity of <120 cm/s .ηVSP\IDTPeak: 4ηVM\IDRAverage: 4The peak and mean of the wall shear stress were measured in the common carotid 1-2 cm next to the bulb with the following formulas:The gingival plaque was calculated using the Silness and Loe plaque index, while the gingival inflammation was assessed using the gingival index.The depth of the pocket is evaluated. The gingival margin was taken as reference point when reading the values during probing.Subjects underwent dental inspection with periodontal probes.As it is known, the periodontal indices are usually a sum of each dental element score, divided by the number of teeth, resulting in an average value for the patient. In this work, the sum of the values was calculated for each periodontal index of each patient. The staff performing the tests was unaware of the other measurements.The 17 patients in this preliminary phase presented an age range with varied from 23 to 74 years with an average of 49.8 years. The group was made up of 9 males and 8 females. Looking at the comparison between the periodontal probing and the spectroscopic examination, as already occurred in previous works of Liu , 14, thep > 0.1).The variability in measurements of macro- and microvascular hemodynamics was not correlated in the population under examination (The statistical analysis applied was a multiple linear correlational analysis made with SPSS v.17.0.The comparison between periodontal probing and spectroscopic examination showed, as in the past, the correlation between low oxygen saturation levels and tissue edema values with probing depth; in fact, the sites with high probing probability differ from the healthy ones, showing a low oxygen saturation and a notable increase in tissue edema. However, no correlation between macrovascular haemodynamic status and microvascular haemodynamic indices was found in the small population under examination. The negative result of the study could be attributed to numerous reasons. The most likely hypothesis is that, also given the heterogeneity of the population under consideration, the low number of data gathered affected the result. The statistic test used should correct these factors but probably not with great effectiveness given the small sample size. The other hypothesis is that the spectrophotometric measurements, indirect for hemodynamics, were represented very little by the gingival microcirculation for there to be a strong and, therefore, visible association with the already few macrovascular hemodynamics. Finally, it is possible that the two circulatory districts were not strongly connected in the gingival pathology, and due to the enlargement of the local gingivopathy, it was only the systematic inflammation which gave the verified worsening of the carotid hemodynamic situation in patients with periodontal disease.


P = 0.003] and lower urine output . 72 h mean IAP was an independent risk factor for delayed graft function , postoperative complications , and absence of graft function recovery . Increased IAP was highly prevalent after transplantation and was independently associated with delayed graft function, postoperative complications, and absence of graft function recovery. Routine IAP monitoring should be considered post-transplantation to facilitate early recognition of relevant complications.Increased intra-abdominal pressure (IAP) is common among post-surgical patients and may cause organ dysfunction. However, its impact after kidney transplantation on early postoperative complications and graft recovery remains unclear. We designed a prospective, observational cohort study to describe the prevalence and determinants of IAP, as well as its effect on delayed graft function, postoperative complications, and graft recovery. IAP was measured in 205 kidney transplant recipients every 8 h during the first 72 h after surgery using the urinary bladder technique. Intra-abdominal hypertension was defined as IAP ≥ 12 mmHg. Patients were followed for 6 months or until graft failure/death. Mean IAP was 12 ± 3.3 mmHg within the first 24 h. 78% of subjects presented with intra-abdominal hypertension during the first 72 h. Increased IAP was associated with higher renal resistive index [r = 0.213;  However, the rising prevalence of chronic kidney disease produces a continuous increase in the allograft demand/supply ratio2. Early recognition of complications should be key to maximize the longevity of each organ, improving long-term results and reducing future demand for new allografts. In fact, postoperative complications are common after kidney transplant surgery; delayed graft function (DGF) can affect up to 30% of all deceased-donor transplant recipients3, renal artery or vein thrombosis produces 45% of early graft losses4, while bleeding that requires further intervention occurs in 4.4% of patients5.In 2018, 21,227 kidney transplantations were performed in the European Union (3313 of them in Spain)6. Intra-abdominal hypertension (IAH) and abdominal compartment syndrome are clinical entities characterized by a sustained increase of IAP above normal values, which, in healthy subjects are < 5–7 mmHg. The abdominal compartment syndrome is a sustained elevation of IAP > 20 mmHg with new organ dysfunction7.Intra-abdominal pressure (IAP) is defined as the steady state pressure concealed within the abdominal cavity, according to the 2013 World Society of the Abdominal Compartment Syndrome guidelines (WSACS)12, associating higher rates of complications and mortality and longer hospital stay15. IAH has also been established as an independent cause of acute kidney injury following abdominal surgery in mixed intensive care unit (ICU) populations18. Depending on the context, incidence and prevalence rates of IAH/abdominal compartment syndrome vary, ranging from 14 to 83% in the case of IAH and between 0–56% for abdominal compartment syndrome19. Obesity, sepsis, abdominal surgery, or large volume fluid resuscitation have been correlated with higher risk of IAH/abdominal compartment syndrome22.IAH and abdominal compartment syndrome are common among the critically ill24. In subjects with hepatorenal syndrome and tense ascites, paracentesis was associated with a significant decrease in IAP and RRI and increased renal blood flow, creatinine clearance and urine output25. In kidney transplantation, RRI is a strong predictor of DGF, especially when measured in the early postoperative period26.Moreover, the severity of IAH has been linearly correlated with renal artery resistive index (RRI) both in experimental models and humans27.Despite IAH is a widely recognized cause of kidney injury and death, its impact on kidney transplant outcomes has not been completely characterized. Recently, the impact of IAP changes on outcomes after kidney transplantation, specifically third-day serum creatinine (SCr), DGF or 30-day estimated glomerular filtration rate, has been reportedThis study aimed to describe the effect of increased IAP on outcomes after transplantation, including its relationship with DGF, postoperative complications, a composite outcome of in-hospital graft failure or death and graft function recovery throughout the first 6 months post-transplantation.This single-center prospective cohort study was conducted in the Nephrology Department of a tertiary referral university hospital  from March 2017 to January 2020. During the study period, all consecutive patients ≥ 18 years-old who received a deceased-donor kidney transplant were asked to participate and give their written informed consent. The transplant unit where the study took place in does not perform living donor or multi-organ transplantation. Patients were excluded if they were unwilling to participate or if transplantectomy had to be performed during implantation surgery. Two hundred eleven patients received a kidney transplant in our unit during the study period. Three patients declined to participate. Transplantectomy had to be performed during implantation surgery in three cases due to incoercible hemorrhage. The final cohort included 205 kidney transplant recipients .28. Ureterovesical double J stenting was used as standard procedure. All but two patients were weaned from ventilator support in the operation room and transferred to the nephrology unit. Hemodynamic monitoring during the first 72 h included measurement of mean arterial pressure, central venous pressure, blood loss volume, and urine output. Cold ischemia time was dichotomized using 16 h as a cut-off point, as described by Debout et al.29. Abdominal binders were not employed after transplantation.The anesthesia technique was the same in all cases. Surgery was performed according to local protocol. Allografts were perfused with cold University of Wisconsin solution and placed in cold storage. A modified Gibson or para-rectal incision with an extra-peritoneal approach of the iliac fossa was performed, with anastomosis of the renal vein to the external or common iliac vein, or inferior vena cava. The renal artery was anastomosed to the external iliac artery or common iliac artery. All vascular anastomoses were performed in an end‐to‐side fashion. No significant intra-abdominal adherences were found in any of the patients. All kidney allografts were placed in the retroperitoneal space. Anastomosis between donor ureter and recipient bladder was performed as described by Lich–GregoirStandard immunosuppressive medication typically consisted of basiliximab induction, corticosteroids in a tapering regimen and tacrolimus alone or in combination with mycophenolic acid or everolimus. Intra- and postoperative fluid administration  was managed according to central venous pressure and hourly urine output. No cases of prolonged postoperative ileus were observed. No patient was treated with abdominal binders.30 using the UnoMeter Abdo-Pressure kit , a closed sterile circuit that connects between the patient’s Foley catheter and the urine collection device. IAP measurement using the urinary bladder technique is currently considered the gold standard method for IAP monitoring31. The Foley manometer was placed between the catheter and the urine collection device and was primed with 20 mL of saline. With the patient in supine position, the “0 mmHg” mark of the manometer tube was placed at the symphysis pubis, the filter was elevated vertically above the patient and the clamp was opened. The end-expiration value for the bladder pressure was read after stabilization of the meniscus. After the measurement the clamp was closed, and the Foley manometer was placed in its drainage position. All measurements were performed after ensuring the absence of abdominal muscle contractions. The Foley catheter was kept in place for at least the first 72 h after transplant surgery in all cases. IAP values were registered immediately after transplantation and every 8 h during the first 72 h after surgery or until reoperation due to graft vascular thrombosis or other surgical complications. Overall, of the expected 1845 IAP measurements that should have been performed, 1788 (96.9%) were carried out.We monitored IAP following WSACS guidelines6. IAH was defined as the highest grade registered using daily mean values during the first 72 h after surgery for each subject. 72 h average IAP was chosen as a potential predictor of post-transplant outcomes rather than the first 24 h average IAP to consider a larger number of IAP measurements. Thus, we aimed to avoid potentially higher mean values that could be associated with surgical wound-associated pain, which is more common during the first hours after transplantation.Daily mean IAP, mean arterial pressure , 24 h fluid balance and urine output values were calculated during the first 72 h after implantation surgery, which were defined as day-0, day-1 and day-2. 72 h average IAP, mean arterial pressure and accumulated fluid balance were calculated as the average of all available values measured during the first 72 h after surgery. IAH was graded according to WSACS recommendations Measurements were performed by nurses from the transplant unit and not by the research team to ensure a pragmatic approach. All nurses received proper training in this procedure to reduce measurement bias. The frequency of measurements was not changed based on IAH diagnosis or severity.32. All examinations were performed by trained radiologists. Peak systolic and end-diastolic velocities were measured in two or three representatives renal interlobar arteries. RRI was calculated using the following equation and the average values of all performed measurements:RRI was measured using Doppler ultrasound 24 h after transplant surgery, employing a Canon Aplio a550 ultrasound system Detailed demographic and clinical data such as age, chronic kidney disease etiology, time on dialysis or additional comorbidities, and donor information were gathered from the medical records. Hemodynamic parameters, laboratory and surgery-associated data were extracted from the patient’s charts and the electronic laboratory database.Describing the prevalence of IAH immediately after surgery.Characterize the association between mean IAP, RRI, mean arterial pressure, fluid balance and urine output during the first 24 h after surgery.The primary outcome was to describe the impact of increased IAP on transplant results, such as DGF, postoperative complications, graft function recovery and a composite outcome of in-hospital graft failure or death. Secondary outcomes included:33. Postoperative complications included need for re-intervention due to intra-abdominal hemorrhage, lymphocoeles or wound dehiscence (defined as Grade III-b or more severe according to the Clavien Dindo classification)34, graft artery or vein thrombosis or need for blood transfusion. The Kidney Donor Profile Index (KDPI) was calculated using the allocation calculator available at the US Organ Procurement and Transplantation Network website .DGF was defined as the use of dialysis within seven days of transplantation. Graft function recovery was defined as reaching a SCr < 2.0 mg/dL off-dialysisP value ≤ 0.05 was considered statistically significant. IAP measurements showed no data outliers upon screening with the Grubbs’ test .According to data distribution, demographics were summarized using mean and standard deviations (SD) or median and range for continuous variables and counts with percentages for binary variables. Continuous data were assessed using T-test, Mann–Whitney U test or Kruskal–Wallis test. Binary data were analyzed using the Chi-square test. Analysis of correlations was performed using Spearman Rho tests. A two-sided P values were adjusted for multiple comparisons using the Benjamini & Hochberg procedure.Binary logistic regression analysis was used to find which variables were associated with IAH grade II/III, DGF and postoperative complications using odds ratios (OR) with 95% confidence intervals (CI). Cumulative survival curves of the 6-month follow-up were estimated with the Kaplan–Meier method, and the effect of IAH grade of graft function recovery was compared between groups using the log-Rank test. The Cox proportional hazards model with hazards ratios (HRs) with 95% confidence interval (CI) was used to evaluate potential risk factors of absence of graft function recovery. The proportional hazards assumption was tested using Schoenfeld residuals. Variables included in the adjusted regression models were selected due to their potential clinical relevance, considering potential multicollinearity issues, and a rate of at least 8 events per predictor variable. Statistical analysis was carried out using the Statistical Package for Social Sciences software, version 20.0 , Stata version 14.1  and GraphPad Prism, version 7.04 for Windows .2. Median donor KDPI was 75%. Most patients (59.5%) had received hemodialysis as renal replacement therapy. In the whole cohort, the mean IAP value was 12.2 mmHg throughout the first 72 h after transplantation. Immediately after implantation, 94 subjects (45.9%) had IAP < 12 mmHg, 73 (35.6%) between 12 and 15 mmHg, 36 (17.6%) between 16 and 20 mmHg and 2 (1%) between 21 and 25 mmHg. During the first 24 h after surgery, 103 recipients (50.2%) had some form of IAH. According to maximal IAH grade achieved during the first 72 h after transplantation, 117 patients (57.1%) were classified as grade I IAH, 38 patients (18.5%) grade II IAH and five patients (2.4%) grade III IAH  of 25.9 kg/mSubjects who suffered IAH during the early post-transplant period were more commonly males, had higher BMI, had spent a longer time on dialysis before transplantation and received more frequently hemodialysis as renal replacement therapy. Patients without IAH received organs from donors with lower KDPI Table .Table 1DRecipient male sex, higher BMI and longer time on dialysis were independently associated with IAH grade II/III in adjusted binary logistic regression analysis. Although subjects that had received peritoneal dialysis as renal replacement therapy of choice suffered IAH less frequently, dialysis modality failed to predict IAH grade II/III Table .Table 2PP = 0.003; Males: Rho = 0.222; P = 0.011; Females: Rho = 0.162; P = 0.184]   .Day-0 IAP was correlated with RRI and day-0 urine output but not with day-0 mean arterial pressure or fluid balance Fig. . RecipiePatients who suffered IAH grades II and III had substantially higher RRI Fig. .Figure 3Recipients with IAH experienced higher rates of DGF and postoperative complications and needed longer hospital length of stay Table . In multOut of five patients who suffered grade III IAH, three had to be reoperated due to renal vein thrombosis (two patients) or intraabdominal hemorrhage (one patient) and consequently lost graft function. Both subjects with renal vein thrombosis died due to postoperative complications. The two remaining grade III IAH patients died after hospital discharge due to cardiovascular complications and cytomegalovirus pneumonia.In addition, duration of dialysis before transplantation and 72 h mean IAP were associated with increased odds of delayed graft function Table .Table 4RP value < 0.001; No IAH vs. IAH Grade I: 12.981, P value < 0.001; IAH Grade I vs. IAH Grade II/III: 5.530, P value = 0.019; No IAH vs. IAH Grade II/III: 27.931, P value < 0.001)  than among female patients. .IAH severity was associated with graft function recovery  Fig. . This asP value = 0.044). DGF was also an independently associated with absence of graft function recovery   developed IAH during the first 24 h after surgery, a proportion that increased to 78% when considering the first 72 h after transplantation. Although reported incidence and prevalence rates of IAH are highly variable, depending on the clinical setting, the method and frequency of measurements or the use of mean or maximum IAP values to define IAH, this was not an unexpected finding. The only evidence available regarding IAH and kidney transplant outcomes comes from a small study by Dupont et al., who have recently described that IAH occurred in 74.5% of 55 kidney transplant recipients in the early postoperative period37. We found that male patients suffered more frequently IAH. Reintam-Blaser et al. reported a borderline significant association between male sex and IAH among critically ill patients35. Additionally, it has been recently described that female rats develop better hemodynamic response after exposure to increased IAP and higher survival than their male counterparts, suggesting a possible role of sex hormones in the hemodynamic adaptation to IAH38. Patients that received peritoneal dialysis as renal replacement therapy suffered IAH less commonly when compared to hemodialysis subjects, a finding that has also been described in another transplant cohort27. However, dialysis modality failed to predict IAH grade II/III in adjusted regression analysis in our study. Increased intra-peritoneal pressure, a surrogate of IAP is a common finding among peritoneal dialysis patients and has been related to several complications such as hernia or dialysate leakage40. Nevertheless, repeated peritoneal dialysis leads to abdominal wall expansion, explaining the lower prevalence of postoperative IAH among these patients. Additionally, intra-peritoneal pressure is directly correlated with actual infused volume40 and recipients are left with a dry abdomen immediately before transplant surgery, thus removing the main driving determinant behind increased intra-peritoneal pressure in this subset of subjects.Higher BMI, male sex and longer time on dialysis were independently associated with IAH grade II/III in our cohort. BMI constitutes one of the strongest risk factors for IAH and its effect on IAP has been described in the critically ill, cardiothoracic surgical patients or those subjected to coronary artery bypass43. Only two patients required mechanical ventilation for 48 h or more after surgery and none suffered clinically significant abdominal distension or infection. Aggressive fluid administration was common in our sample, with average 72 h fluid gains over 3.5 L. Nevertheless, fluid balance was not associated with IAH in our study. As Mohmand et al.41 proposed, several conditions that are common among the critically ill, but not in kidney transplant recipients, such as sepsis, coagulopathy or polytransfusion could increase capillary permeability and fluid accumulation in the interstitium, facilitating the development of fluid balance-associated IAH. These factors may be common in the ICU setting but are considerably rarer after kidney transplantation.Other factors, such as aggressive fluid resuscitation, mechanical ventilation, abdominal infection, or distension have been previously described as significant risk factors of IAH27. Reduction of abdominal wall compliance due to recent abdominal surgery, increased intra-luminal and intra-abdominal contents due to postoperative ileus, abdominal distension, and graft placement in the retroperitoneal space may facilitate the rise of IAP. In addition, patient-related risk factors, such as high BMI and certain pre-existing pathologies such as hypertension or diabetes that may act in conjunction with common complications in kidney transplant patients such as metabolic acidosis, facilitating the development of ischemia–reperfusion associated endothelial dysfunction and capillary leakage, which may further exacerbate the growth of IAP. Endothelial dysfunction is closely related to chronic kidney disease. Certain risk factors for endothelial dysfunction, such as chronic volume overload, anemia, abnormal calcium-phosphate metabolism, increased oxidative stress and inflammation44, are common among subjects with end-stage chronic kidney disease. Several of these factors have also been linked to the development of IAH45. Longer dialysis duration may act in this setting as a surrogate marker of the maintenance of these risk factors over time.IAH may occur in the transplant setting due to the joint action of transplant- and patient-related factors27. However, contrary to what has been done in that study, we chose to use IAP as a continuous rather than categorical predictor variable because IAH and abdominal compartment syndrome only represent specific cut-off points on a spectrum of increasingly harmful pressure that can alter intra-abdominal tissue perfusion and reduce organ viability19. Moreover, these cut-off points were developed using data from critically ill subjects and were not specifically designed for the transplant setting. We also chose to extend follow-up in our cohort up to the first 6 months after transplantation to analyze if IAP might influence graft function beyond immediate recovery.Besides, we found that 72 h mean IAP was independently associated with DGF in adjusted binary logistic regression analysis. 72 h mean IAP also predicted graft function recovery in adjusted Cox regression analysis. These results support the notion that higher IAP not only exerts a pernicious effect on outcomes immediately after surgery but can also affect graft function days after transplantation. IAH grades III/IV have been associated with increased risk of DGF and lower day-30 eGFR in a previous report41. Indeed, we observed that higher IAP during the first 24 h after transplantation was significantly associated with higher RRI and lower urine output during that timeframe. RRI measurement, an easy-to-reproduce Doppler ultrasound study, has been used to predict AKI in ICU and postoperative settings47, as well as DGF, acute rejection or long-term mortality in renal transplant recipients50. We hypothesize that, in the early post-transplant period, augmented IAP may compress the inferior vena cava and renal vasculature, reducing cardiac output and venous return while increasing the RRI, a relationship that has already been observed in humans24. As a consequence, the reduction in renal blood flow can extend in time the post-operative acute tubular necrosis, impairing the urine output, facilitating the development of DGF, and providing a pathological link between increasing IAP and absence of recovery of kidney graft function. Nevertheless, an organ-centric view of the RRI should be avoided; the index is, in fact, the product of multiple interactions between hemodynamic, renal and systemic vascular factors, many of which may not be correlated with IAP.Although the pathological processes involved are not completely understood, several IAP-induced kidney injury mechanisms have been proposed, such as direct parenchymal and vascular compression or exacerbation of renal tubular necrosisOf note, 72 h mean IAP was the only variable independently associated with postoperative complications in adjusted regression analysis. Low urine output can be common early after transplantation, especially in patients with little to no pretransplant residual renal function, while transient hypotension and mild or moderate abdominal pain are frequent findings in this setting. Close IAP monitoring can offer, in combination with the rest of hemodynamic parameters and clinical findings, an early warning sign in case of postoperative complications that may allow faster diagnostic and therapeutic approaches immediately posttransplant. Short-term results after transplantation have vastly improved in the last decades thanks to advancing of surgical techniques and the optimization of immunosuppression therapy. However, these improvements are marred by the inclusion of older and higher-risk recipients in transplant programs. IAP measurements might help define recipients at greater risk of postoperative complications and/or absence of graft function recovery, to adopt preventive measures aimed to minimize this risk, such as tighter monitoring of immunosuppressive drug levels to avoid potential nephrotoxicity or repeated imaging tests to control intra-abdominal bleeding.The present study entails limitations. Its single-centered nature potentially limits external validity. The study sample was mostly composed of Caucasians, limiting the extrapolation of results to other ethnic groups. Furthermore, WSACS guidelines advocates for IAP measurement every 4–6 h in critically ill patients. However, the department where the study was conducted was not an ICU and we chose to measure IAP every 8 h to facilitate patient care. Finally, the severity of IAH observed in this study was, in most cases, mild or moderate. Very few patients developed severe IAH, with only five subjects suffering maximal IAH grade III and none developing IAH grade IV. As such, our study is not sufficiently powered to adequately describe the effects of IAH grades III/IV on early transplant outcomes.However, we also recognize several strengths. This is one of the first prospective studies designed to analyze the consequences of increased IAP early after transplantation. We applied WSACS consensus guidelines in kidney transplant patients using a standardized and widely accepted method to measure IAP. The extended follow-up enabled us to describe the influence of IAP on DGF and graft function recovery and early posttransplant complications. Measurements were performed by trained nurses instead of research staff to increase their real-world applicability and to avoid relying on personnel with high commitment or experience in this subject. Most planned IAP measurements (> 96%) were completed, reflecting high compliance rates to the protocol. IAP measurement is an easy to implement and standardized process that requires only bladder catheterization. Systematic measurement of IAP during the first hours after surgery may allow a faster diagnosis of severe postoperative complications that could affect graft and patient survival, allowing early treatment initiation and improving results after transplantation.In sum, the present study describes increased IAP as a promising predictor of postoperative complications and absence of renal function recovery in the early kidney post-transplant period. The present report complies with WSACS guidelines using a pragmatic approach in a prospective cohort of incident kidney transplant recipients. Future studies should analyze the impact of IAP-guided interventions on the early postoperative care of kidney transplant recipients and their impact on patient and graft outcomes.


To evaluate retinal thickness and capillary density in patients with type 2 diabetes (T2D) and their association with diabetic kidney disease (DKD) using swept-source optical coherence tomography (SS-OCT).A cross-sectional study was conducted with T2D patients with mild or no diabetic retinopathy (DR) and nondiabetic controls. Inner retinal layer thickness was measured with SS-OCT. Retinal capillary density and the foveal avascular zone (FAZ) were measured with SS-OCT angiography (OCTA). SS-OCT parameters were compared in patients with and without diabetic kidney disease (DKD) and nondiabetic controls.131 DKD eyes showed decreased ganglion cell layer plus (GCL+) , retinal nerve fiber layer (RNFL) (p = 0.003), and central retinal thickness (CRT) (p = 0.032), as well as foveal avascular zone (FAZ) enlargement (p = 0.003) and lower capillary density in the superficial vascular plexus , compared to controls. No statistically significant changes were found between diabetic patients without significant DKD and controls.Our findings suggest early neurovascular damage in patients with T2D; these changes were more significant in patients with DKD. Larger longitudinal studies are warranted to determine the role of early neurovascular damage in the pathophysiology of severe DR. Diabetic retinopathy (DR) is the leading cause of vision loss and the most important ocular complication of diabetes mellitus . Major rOptical coherence tomography has become an important tool for management and follow-up of retinal diseases such as diabetic macular edema. Although most studies use the spectral domain OCT (SD-OCT), the recently introduced swept-source OCT (SS-OCT) has improved image penetration using a wavelength of 1050 nm, higher imaging speeds , higher detection efficiency, improved imaging range, and improved depth with reduced sensitivity roll-off that is capable of generating images of both the vitreous and choroid simultaneously . SS-OCT The role of retina neurodegeneration in the pathogenesis of microangiopathy remains unclear but recent studies pointed that diabetic neurodegenerative abnormalities could play an important role in the pathogenesis of early stages of DR in a large proportion patients T2D . Lynch aNeuroretinal alterations in patients with diabetes without DR or with early-stage DR have been detected by OCT, and include decreased retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) thickness . Recent The term neurovascular unit (NVU) was first applied to the blood–brain barrier and, subsequently, to the retina, to describe the intricate communication between neurons, glial cells, and vascular cells that together coordinate the retinal vascular flow with metabolic activity . The micTherefore, the aim of this study was to detect structural and vascular retinal changes in patient with type 2 diabetes (T2D) with or without kidney disease (DKD) using SS-OCT and OCTA. Our hypothesis was that T2D and DKD would be associated with early neurovascular damage.This cross-sectional study was conducted at a public teaching hospital in Southern Brazil between July 2018 and July 2019. The protocol was reviewed and approved by the Hospital de Clínicas de Porto Alegre Ethical Committee (registration number 20180186), adhering to the tenets of the Declaration of Helsinki, and written informed consent was obtained from all patients.The inclusion criteria were confirmed T2D according to the standards of the American Diabetic Association (ADA) , age aboThe control group was composed of health volunteers above 45 years old, who had recent (maximum 3 months) normal glycated hemoglobin (HbA1c) values (< 5.7%), no prior history of diabetes, and no prior or current history of kidney disease. Controls also could not present any ophthalmologic condition that could interfere on images evaluation as opacities and spherical equivalent outside ± 3 diopters.2) [2 and/or UAC < 14 mg/L or higher) and DKD (eGFR < 60 mL/min/1.73 m2 and/or UAC ≥ 14 mg/L).In the T2D group, DKD was defined by the presence of a urinary albumin concentration (UAC) > 14 mg/L and/or reduced estimated glomerular filtration rate  . Estimat2) , 19. To Both eyes of eligible T2D patients and controls were included in this study. All patients were subjected to a complete ophthalmologic examination that included slit-lamp biomicroscopy, indirect ophthalmoscopy, fundus photography, best corrected visual acuity (BCVA), SS-OCT, and OCTA. Age, gender, diabetes duration, HbA1c, and systemic hypertension were recorded. Diabetic retinopathy was graded by a masked experienced ophthalmologist as none, mild, moderate, severe nonproliferative, or proliferative, with or without macular edema, based on the International Clinical Diabetic Retinopathy classification system using fundus color images acquired with a Topcon DRI OCT Triton device .SS-OCT and OCTA images were performed with a Triton DRI OCT plus scanner , which uses a swept-source laser with a center wavelength of 1050 nm and scan speed of 100,000 A-scans per second. Images were analyzed using Triton Imaginet 6 (software version 1.22). In this study, the 3D(H) wide macula + line protocol was used with simultaneous color fundus picture of the posterior pole  grid centered at the fovea . Automated segmentation of retina and choroid was performed in nine ETDRS areas plus average thickness, center thickness, and total volume. Ganglion cell layer plus (GCL+), from nerve fiber layer (NFL)/ganglion cell layer (GCL) to inner plexiform layer (IPL)/inner nuclear layer (INL) and GCL++ complex, from inner NFL interface to IPL/INL, and retinal nerve fiber layer (RNFL) segmentation was performed in six standard areas: superior (S), nasal superior (NS), temporal superior (TS), inferior (I), temporal inferior (TI), and nasal inferior (NI), plus total volume. An active eye tracker was used to reduce motion artifact.2) was measured using manual delineation in the superficial and deep plexus using native SS-OCT software.OCTA scans were acquired using the DRI OCT Triton system based on the Topcon OCT angiography ratio analysis (OCTARA) algorithm. OCTA software uses the proportion of bright pixels to the proportion of dark pixels to derive a measure of vascular density. Capillary density values were obtained by applying a 6 mm × 6 mm ETDRS grid overlay centered at the fovea. Vascular density is derived from the percentage of the area occupied by bright pixels in a segmented area. Boundary layer segmentations were defined as superficial capillary plexus (SCP), from 2.6 μm below internal limiting membrane to 15.6 μm below the junction between IPL and INL (IPL/INL); deep capillary plexus (DCP), from 15.6 μm below the IPL/INL to 70.2 μm below the IPL/INL; choriocapillaris (CC), from Bruch’s membrane (BM) (0-μm offset) to 10.4 μm below the BM. Foveal avascular zone (FAZ) area . Demographic and descriptive data were expressed as mean and standard deviation. For continuous variables, data were presented as the mean ± standard deviation; categorical variables were presented as percentages. Differences between groups were assessed with generalized estimating equations (GEE) and were adjusted by age and use of both eyes, excluding missing values.Demographics and clinical characteristics of T2D patients and controls are summarized in Table 2, p < 0.001).Table Retinal layers in patients with T2D were thinner than in controls in the following ETDRS locations Table : inner rMean capillary density values of superficial, deep plexus, and choriocapillaris are shown in Table Significant FAZ enlargement was observed in the diabetic group compared with control eyes in the superficial  and deep plexus  Table . AnalyzeT2D patients with DKD has presented difference compared to controls, namely thinning of retinal central and inner temporal ETDRS quadrant, GCL+ temporal inferior and inferior quadrants, GCL++ temporal inferior quadrant, RNFL total, temporal, temporal superior, and temporal inferior quadrants. DKD and nDKD groups have presented independent differences compared to controls as registered on Table OCTA showed a lower capillary density in superficial plexus, central quadrant  in the DKD group compared to controls   mode. In our study, we used SS-OCT and OCTA to analyze retinal thickness and macular capillary density and the association of these findings with DKD in T2D patients and controls. Our results showed significant thinning of the inner retina of T2D patients, especially the GCL+/++ layer and RNFL; enlargement of the FAZ ; and lower capillarity in the superficial retinal plexus compared with controls. These findings suggest that neurovascular changes are an ongoing component of DR that may precede clinically moderate to severe microvascular changes.The inner blood–retina barrier (iBRB) comprises the capillary endothelial cells which regulate blood flow in response to the metabolic demands of the retina, surrounded by pericytes, astrocytes and microglia; this complex is the neurovascular unit (NVU) . iBRB inOur study population with T2D had a mean disease duration of 13.2 ± 6.0 years in the nDKD group and 15.0 ± 8.0 years in the DKD group. Mean levels of HbA1c were 8.4% ± 1.8 in subjects without DKD and 8.3% ± 1.5 in the DKD group, which represents a long period of hyperglycemia that appears to be sufficient to induce disruption of NVU elements, but more severe DR elements such as IRMA, venous beading, and neovascularization were absent. However, the T2D group showed a significantly worse BCVA compared to controls, which could reflect functional consequences of this early damage to the neuroretina. Bao et al. described visual field defects in patients with diabetes and no clinically detectable DR, and suggested that early neuroretinopathy could precede the classical microvascular disease .Along with these neurodegenerative findings, OCTA images showed a decrease of capillary density in the superficial plexus of the retina and an enlargement of the FAZ in patients with T2D. Reduction of capillary density and FAZ disruption are findings related to reduction of blood flow, caused by microvascular damage diabetes These findings corroborate previous descriptions of microcirculatory impairment, both in retinal and choroidal vasculature of diabetic eyes, before more severe findings of DR , 26, andOur findings suggest that reduction of superficial blood flow may be affecting primarily the ganglion cells and their axons (RNFL), corroborating that the NVU is subjected to early changes due to chronic hyperglycemia and that OCTA could be used along with fundus imagining for screening and follow-up of DR. These results can corroborate the potential of OCTA as a clinical tool for earlier detection of DR , 27.RNFL was significantly thinner only among T2D patients with some degree of DKD, not in T2D patients without DKD or controls. A recent meta-analysis suggested that the retinal microvasculature signs can be associated with kidney diseases, provide significant data on concurrent kidney disease status and predict future risk for kidney disease development and progression .The causal relationship between DR and DKD has already been more explored and evaluated. Most research data came from studies involving diabetic patients with DR diagnosed in more advanced stages (moderate to proliferative) , 30.The scarcity of data on structural alterations in the retina of T2D patients with early DR or no DR and its link with kidney damage can be attributed, at least in part, to the sensitivity of the diagnostic devices used to examine for presence of DR, such as color fundus photography or fundoscopy. SS-OCT has a higher sensitivity than previous methods and offers a more accurate analysis of the retinal layers, even compared to SD-OCT . Early aOur study had potential limitations, including its cross-sectional design and limited sample (composed mainly of white women). Also, there are natural age-related changes and thinning of neuroretinal parameters , hence wWe reported that patients with kidney microvascular damage (DKD group) showed more retinal neurovascular alterations compared to patients without kidney disease (nDKD). However, these results of a cross-sectional design do not allow us to establish a causal relationship between kidney disease and diabetic retinopathy and it remains unclear whether diabetic neurovascular changes are a predictive, modulating, or causative factor in DR.Longitudinal studies are necessary to evaluate if presence of early retinal neurovascular changes is associated to an increased risk of kidney disease or if presence of diabetic kidney disease can drive a worse retinal prognosis or even both conditions run independently.Longitudinal studies are also warranted to determine the role of these early neurovascular changes in predicting the development of severe non-proliferative and proliferative DR. These findings are potentially useful for screening, follow-up, and treatment of patients with T2D, and may positively impact their visual and systemic outcomes.In conclusion, this study used swept-source structural OCT and OCTA and detected early changes in retinal thickness in the GCL+, GCL++, and RNFL, as well as FAZ enlargement and decrease of superficial retinal capillary density, in T2D patients—most notably, those with DKD—compared to controls. DKD was associated with inner retinal and superficial plexus vascular changes in T2D patients with mild or no DR, suggesting an association of eye and early kidney changes.


Tai Chi exercise has been reported to enhance physical and mental health in the older adults; however, the mechanism remains elusive.We recruited 289 older adults practicing Tai Chi for over 3 years, together with 277 age-matched older and 102 young adults as controls. 168 Tai Chi practitioners were successfully matched to 168 older controls aged 60–69 based on a propensity score for statistics.Cerebrovascular function was evaluated by measuring the hemodynamics of the carotid artery. Spearman correlation was performed to validate the age-associated physiological parameters.P = 0.002), mean blood flow velocity (P = 0.014), maximal blood flow velocity (P = 0.04) and minimum blood flow velocity (P < 0.001), whereas the age-related increases in pulse wave velocity (P = 0.022), characteristic impedance (P = 0.021) and peripheral resistance (P = 0.044) were lowered.Cerebrovascular function in older adults significantly degenerated compared with the young, and was substantially correlated with age. Compared with the older control group, Tai Chi practitioners showed significant improvements in CVHI  Score  A combination of remarkable increases in life expectancy and declining fertility rates results in a larger elderly population, a problem challenging economic development globally . AlthougOne major issue impeding the development of this field is the lack of reliable healthspan indicators or biomarkers. Age is an independent risk factor for cerebrovascular diseases, which dominate common health problems in the older adults . DeclineRegular physical activity is associated with improvement in physical health and protection against cerebrovascular diseases , 12. TaiHere we conducted a cross-sectional study to investigate the impact of Tai Chi practice on age-associated declines of cerebrovascular function by measuring the hemodynamics of the carotid blood flow. Our study provides direct evidence for the anti-ageing effect of Tai Chi through improving blood supply in the brain.http://www.chictr.org.cn; ChiCTR1900025187), and performed in accordance with the principle of the Helsinki Declaration II. Written informed consent was obtained from all participants in advance. Inclusion criteria were based on the following: healthy older people (60–69 years old), regular practice of Tai Chi more than three year for the Tai Chi group; healthy physical active older people (60–69 years old) for older adult control group; healthy young adults (21–25 years old) for young adult control group. Exclusion criteria included: cancer, surgery history, cognitive impairment, pregnant females, gastrointestinal diseases or had gastrointestinal surgery before, abnormal liver and kidney function, evidence of acute or chronic inflammatory or infectious diseases. This is a cross-sectional study. Data were collected in a double-blinded manner.From December 2017 to March 2018, we recruited older adult Tai Chi practitioners, together with age-matched older adults and young adults as controls in Wuhan, China to evaluate the effects of Tai Chi on age-related changes in cerebrovascular functions. This study was approved by Ethical Committees from both Renmin Hospital of Wuhan University and Wuhan Sports University. This study was registered on Chinese Clinical Trial Registry . One day before testing, all participants were advised not to consume caffeine or alcohol, smoke or engage in vigorous exercise. Blood pressure in the arms was measured using an automated oscillometric device . We recorded the sex, age, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate and calculated body mass index (BMI).Left internal carotid artery hemodynamics were measured using a cerebrovascular function tester GT-3000 . The instrument has two probes: the Doppler probe and the pulsation pressure sensing probe. Both probes record parameters at the level of the internal carotid. Doppler probe records cerebral blood flow, cerebral blood flow rate and average blood flow. Pulse pressure sensing probe records cerebrovascular elasticity, external resistance, pulse wave velocity and other related indicators. The subjects were in a lying flat position. Cerebral vascular hemodynamics indexes (CVHI) were calculated. The recorded or calculated parameters include CVHI score, mean blood flow rate (Qmean), mean blood flow velocity (Vmean), maximum blood flow velocity (Vmax), minimum blood flow velocity (Vmin), pulse wave velocity (Wv), characteristic impedance (Zcv), dilatability (DI), resistance vascular (Rv), dynamic resistance (DR), critical pressure (CP) level, and diastolic pressure and critical pressure difference (DP).α/2+Zβ) × σ/ δ]2×(Q1− 1+Q2− 1). To carry out stratified analyses, we performed the propensity score matching process while simultaneously forcing an exact match of sex, BMI, and age between older adult control group and the Tai Chi group. Then we compared matched groups within clinical parameters. All continuous variables were summarized as mean ± standard deviation (SD), and non-normally distributed continuous variables were summarized as median (25th - 75th ). The statistical difference in continuous variables normally distributed data between the two groups was compared using the student’s t test. The Mann-Whitney U test was used for comparisons between groups for non-normally distributed continuous variables. A correlation Spearman test was used to test the coefficients of non-normally distributed continuous variables. P < 0.05 was considered statistically significant. All statistical analyses were two-tailed.All data were processed using SPSS 22.0  and GraphPad Prism software 8.0 . Sample size was predicted by the following formular n=, and also significantly decreased in the older adults compared with young controls   Table .Table 2P = 0.002], which almost approached the level in young control group [92.25 (86.63–97)] (Table P = 0.014), Vmax (P = 0.04) and Vmin (P < 0.001). Wv and Zcv are indicators of the atherosclerosis degree of the brain, and associated with the overall elasticity of the arterial wall; and Rv reflects the degree of flow of small blood vessels and capillaries. We found that Tai Chi practice significantly reduced arterial resistance indices   in Tai Chi group and 91 (81.25–98.31) in older adults control group; Ageing and age-related diseases have become the major threaten to human health . MaintaiSince cerebrovascular ageing is associated with cognitive decline, dementia and brain pathology, it is crucial to unveil the predictors of cerebrovascular function status for early detection and prevention . PreviouArterial hemodynamics indices Vmean, Vmax, and Vmin are main parameters reflecting diastolic blood flow velocity. Cerebral dynamic Wv and Zcv are related to the elasticity of the arterial wall. Lowered Wv and Zcv indicate the better overall elasticity of the arteries. Rv is a quantitative indicator of the degree of the flow of small blood vessels and capillaries. Compared with the older adult controls, those who have practiced Tai Chi for 3 years showed alterations in most of the cerebrovascular parameters towards the young controls (Table Tai Chi has many positive effects on the health of the older adults, including improved motor ability, exercise efficiency and emotional state , 25. In This study also has some limitations. Firstly, this is a cross-sectional study involving a cohort of Tai Chi practitioners with variable durations of Tai Chi practicing. The impact of duration or intensity of Tai Chi practicing on cerebrovascular function need to be further investigated. Secondly, we did not select another style of exercise as a strict control for Tai Chi. Thus, the observed changes would also reflect a general impact of regular physical activity. Thirdly, we did not discriminate the subtypes of Tai Chi they practiced, and could not calculate the session volume or duration during each practice. It would be impossible for them to insist on a constant manner to exercise during such a long period. Finally, the conclusions need to be further validated by a longitudinal cohort with well-controlled Tai Chi training.Taken together, in this cross-sectional study, we found that the age-related decline in cerebrovascular hemodynamics in the older adults is significantly improved by Tai Chi practice. Our findings provide novel insights into healthy ageing and anti-ageing strategies.


The prevalence rate of CKD was 25.3%  and increases with age (34.0% in ≥65 years-olds). 24.9% of patients with CKD were in the very-high risk category for cardiovascular events (6.3% of the diabetic population). If CKD were diagnosed without requiring sustained eGFR <60 mL/min/1.73 m2 and/or sustained UACR ≥30 mg/g (as it is frequently found in the literature) this would overestimate the prevalence of CKD by 23%.Diabetes mellitus (DM) is one of the leading causes of chronic kidney disease (CKD). We analyzed the prevalence of CKD in the population with diabetes in Extremadura (Spain). retrospective observational study was carried in the diabetic population attended in the Extremadura Health System in 2012–2014. A total of 38,253 patients, ≥18 years old were included. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation. CKD was defined as follow: an eGFR <60 mL/min/1.73 m Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are highly prevalent chronic diseases, and both represent major public health problems. The estimated prevalence of CKD in the world population over 30 years of age is 7.2% , and in Patients with DM and renal impairment are a group of patients with higher morbidity and mortality, mainly cardiovascular, in addition to having a higher risk of hypoglycemia. The incidence of cardiovascular events in patients with CKD is very high and similar to that of patients with coronary heart disease. Indeed, it is accepted that CKD behaves as an equivalent of coronary risk, and therefore CKD patients are candidates for secondary cardiovascular prevention measures . On the Given this background, the objective of this study was to establish the prevalence of CKD in the diabetic population of Extremadura (Spain), using the diagnostic criteria proposed in the KDIGO 2012 guidelines  .We performed an observational, retrospective, prevalence study, with the information gathered, during 2012, 2013 and 2014, in two databases from the Extremadura Health System: one about medication dispensed in pharmacies, and another about clinical analyses (CORNALVO). Patients, ≥18 years old with DM criteria were identified as previously reported . And so,The glomerular filtration rate (eGFR) was estimated using the equation developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) . The uri2 and/or an UACR ≥30 mg/g, confirmed in a previous determination separated by at least 3 months [Any patient with DM was considered to have CKD if he had, at his last analytical control during the study period, an eGFR value below 60 mL/min/1.73 m3 months ,16. The 3 months .Extremadura is one of Spain’s Autonomous Communities and, in 2013, had a total population of 1,104,004 inhabitants  . 95.3% oSince anonymised electronic records were used as a data source, written informed consent was not required.t-test for independent samples was used for quantitative variables and a Chi-squared test for categorical variables.Data processing and analysis were performed using SPSS 22.0 for Windows. Results were stratified by age group and by sex. In bivariate analyses, a p < 0.001). Slightly more than half of that percentage (12.8%) corresponded to stage 3 CKD (eGFR between 59–30 mL/min/1.73 m2). The higher prevalence of CKD was found in the group ≥65 years old , followed by the group 40–64 years (13.6%)  was 25.3%  .p < 0.001), with a single eGFR <60 mL/min/1.73 m2 and/or a single UACR ≥ 30 mg/g. Accordingly, if this were accepted as a true diagnose of CKD, the prevalence rate would be overestimated by 23% .The distribution of the diabetic population with a single eGFR or UACR test is shown in 2) and 11.7% to patients with an A2 category of kidney damage (UACR between 30–300 mg/g). The prevalence of CKD increases with age, so that 34.0% of those ≥ 65 years of age have stage 3 or higher CKD. 24.9% of patients with CKD are included in the very-high risk category for cardiovascular events (6.3% of the diabetic population).The estimated prevalence of CKD in the diabetic population of Extremadura ≥18 years of age is 25.3%, with slightly more than half of that percentage (12.8%) corresponding to stage 3 CKD , users of the Public Health System, and that it uses as diagnostic criteria for CKD those recommended by the National Kidney Foundation K/DOQI clinical practice guidelines , which r1C values and not through the review of patients’ medical history [This study also has limitations. The identification of patients with diabetes was carried out with diagnostic criteria based on hypoglycemic drug use and hemoglobin A history . This st history . MoreoveThe prevalence of CKD in the diabetic population in our study (25.3%) is in the prevalence range found (23.0–27.9%) in our country ,13,14. H2 and/or a single UACR ≥ 30 mg/g as the definition of CKD, the prevalence would be 31.0% , accepting the criteria defined in the K/DOQI clinical practice guidelines of the National Kidney Foundation. On the other hand, the high percentage of patients without eGFR and UACR determinations is in line with the topic of clinical/therapeutic inertia which concerns both nephrologists and diabetologists, since glomerular hyperfiltration and albuminuria are often the first marker of a progression towards CKD . An earl


Aims: Despite the prognostic value of coronary microvascular dysfunction (CMD) in patients with ST-segment-elevation myocardial infarction (STEMI), its assessment with pressure-wire-based methods remains limited due to cost, technical and procedural complexities. The non-hyperaemic angiography-derived index of microcirculatory resistance (NH IMRangio) has been shown to reliably predict microvascular injury in patients with STEMI. We investigated the prognostic potential of NH IMRangio as a pressure-wire and adenosine-free tool.Methods and Results: NH IMRangio was retrospectively derived on the infarct-related artery at completion of primary percutaneous coronary intervention (pPCI) in 262 prospectively recruited STEMI patients. Invasive pressure-wire-based assessment of the index of microcirculatory resistance (IMR) was performed. The combination of all-cause mortality, resuscitated cardiac arrest and new heart failure was the primary endpoint. NH IMRangio showed good diagnostic performance in identifying CMD (IMR > 40U); AUC 0.78  with an optimal cut-off at 43U. The primary endpoint occurred in 38 (16%) patients at a median follow-up of 4.2 (2.0–6.5) years. On survival analysis, NH IMRangio > 43U  was equivalent to an IMR > 40U in predicting the primary endpoint (hazard ratio comparison p = 0.91). NH IMRangio > 43U was an independent predictor of the primary endpoint .Conclusion: NH IMRangio is prognostically equivalent to invasively measured IMR and can be a feasible alternative to IMR for risk stratification in patients presenting with STEMI. This can be achieved by measuring the index of microvascular resistance (IMR) with a conventional pressure-wire and thermodilution technique  is biologically  and progechnique . Our groechnique , 5. Contechnique , 7. Receechnique , 9.angio)  . This inomplete. , 13. In th STEMI . Thus, wangio in patients with STEMI.The aim of this work was to evaluate the prognostic performance of NH IMRPatients with a diagnosis of STEMI presenting between January 2010 and March 2020 with STEMI at the Oxford Heart Centre were enrolled in the prospective OxAMI  cohort study . The curPrimary percutaneous coronary intervention (pPCI) was performed in standard fashion with the use of adjunctive therapies  and choice of stenting technique at the operator's discretion. ST-segment resolution was calculated using surface electrocardiography acquired before and at 90 min after pPCI as described previously , and defThe study protocol was approved by the local ethics committee (10/H0408/24) and conducted in accordance with the Declaration of Helsinki.angio and its reproducibility have been published previously . In brief, three-dimensional quantitative coronary angiography and quantitative flow ratio (QFR) analyses were performed using QAngio® XA 3D software . NH IMRangio was computed using the following formula:The methodology for the derivation of NH IMReviously . AccordiPa was the post PCI mean aortic pressure at resting conditions, Nframes was the number of angiographic frames from contrast dye to travel from the guiding catheter to a distal reference  in resting conditions and fps was the frame-acquisition rate  by independent operators blinded to physiology and clinical outcome data.Invasive assessment of coronary physiology indices on the IRA was performed with pressure-wire technology  and thermodilution technique at the end of the pPCI as previously reported  15). We. We15). The primary clinical outcome of the study was the composite endpoint of all-cause mortality, resuscitated cardiac arrest and new heart failure diagnosis. The secondary clinical outcome of the study was the composite endpoint of cardiac mortality, resuscitated cardiac arrest and new heart failure diagnosis. Heart failure was defined as the development of new heart failure symptomatology and/or prescription of diuretics in conjunction with supporting new non-invasive imaging findings of left ventricular systolic dysfunction (LVEF) < 50% and/or raised levels of brain natriuretic peptide. Outcome data was collected from scheduled study follow-up visits and annual telephone calls and review of electronic case records and contacting the participants' General Practitioners.2 or Fisher's exact test as appropriate, while continuous variables were compared using Student's t-test, Mann-Whitney U test or Kruskal-Wallis test. Correlations between variables were expressed using Spearman rho coefficients.We tested the normality assumption of continuous variables with statistical (Shapiro-Wilk test) and graphical (histogram) means. We expressed continuous variables as mean ± standard deviation or median (25–75 percentile) as appropriate and categorical variables as numbers (percentage). Between-group comparisons for categorical variables were performed using Pearson's χangio to predict an IMR > 40U. We then selected the optimal NH IMRangio cut-off value by identifying the value that maximizes the Youden's J statistic.We used receiver operator characteristic curve analysis to explore the diagnostic utility of NH IMRangio, (ii) IMR and (iii) CFR (expressed as dichotomous variables) using Kaplan Meier and Cox proportional hazard regression modeling methods. We compared the hazard ratios of dichotomised NH IMRangio, IMR and CFR with paired Student's t-tests  NH IMR t-tests .angio (as a dichotomous variable) for our primary endpoint we constructed multivariate Cox regression models adjusted for clinical, procedural, angiographic and echocardiographic variables. We measured the goodness of fit using concordance (C-statistic) statistics. By adding NH IMRangio in a baseline multivariate model, we assessed for improvement in model performance by performing a likelihood ratio test.To evaluate the prognostic utility of NH IMRsurvival, survminer, forestplot and survcomp packages). All tests were two-sided and α was set at 0.05.Statistical analyses were performed with SPSS version 26 (IBM Inc. New York USA) and R studio version 1.3  with a median follow-up of 4.2 (2.0–6.5) years. Baseline clinical, procedural, imaging and post pPCI coronary physiology data are reported in angio values at the end of the procedure were 33 (20–55) and 43 (30–59) units respectively.A total of 262 patients with both post pPCI invasive IMR and NH IMRangio was significantly correlated with IMR  and predicted an IMR > 40U with an AUC of 0.78   coinciding with the median NH IMRangio value of 43U observed in the overall study cohort. Patients with a high NH IMRangio (>43U) were characterized by longer ischaemic times, worse post pPCI TIMI flow grade, lower occurrence of complete ST-segment resolution, and lower left ventricular ejection fraction at discharge than patients with a low NH IMRangio (angio (>43U) was associated with a significantly higher degree of invasively assessed microvascular dysfunction  than a low NH IMRangio (NH IMR 0.0001) . The optIMRangio . A high IMRangio 2.angio >43U was significantly associated with a higher risk of both the primary and secondary endpoints, . A post pPCI IMR >40U was also significantly associated with a higher risk of the primary and secondary endpoints . The comparison of the hazard ratio estimates of NH IMRangio > 43U and IMR > 40U did not yield a statistically significant difference for either endpoint (p = 0.91 and p = 0.85).At 7 years of follow-up, the primary and secondary endpoints occurred in 38 (16%) and 30 (12%) participants respectively. All-cause death occurred in 13 (5%) participants , two (1%) had a resuscitated cardiac arrest and 28 (12%) had a new diagnosis of heart failure. Cox regression analyses showed that a post pPCI NH IMRp < 0.03 and HR 4.56, 95% CI 1.08–19.18, p < 0.04, respectively). Pairwise comparisons of CFR ≤ 2.0 with IMR > 40U and NH IMRangio > 43U hazard ratios were not statistically significant.In an exploratory analysis, a CFR ≤ 2.0 was significantly associated with a higher risk of the primary and secondary endpoints  alongside age, ischaemic time, and discharge LVEF (p = 0.01). The addition of NH IMRangio >43U as a variable to a cox regression model including age, ischaemic time and discharge LVEF% yielded a good model  with a significant improvement in predictive performance .To further evaluate the prognostic utility of NH IMRrge LVEF . NH IMRaangio) for the assessment of CMD in patients with STEMI.This study extends our preliminary findings  and explangio) against pressure-wire-based IMR represented a preliminary dataset  or NH IMRangio (>43U) are not significantly different, further supporting the prognostic equivalence of the two indices. The prognostic equivalence is also maintained when analysing a stricter cardiac endpoint excluding non-cardiac mortality. These findings are consistent with the results and effect estimates reported in the previous work by Fearon et al. on the prognostic role of invasive and pressure-wire based IMR in patients with STEMI  have already “declared” their risk category, whilst it is the majority of “intermediate risk” patients  that may benefit the most from personalized and stratified medicine approaches .angio resulted prognostically equivalent to invasive IMR. Whilst this observation is evident in STEMI patients, we do not anticipate that a non-hyperaemic index will work as well in patients with coronary syndromes characterized by a lesser degree of CMD, as also already recently reported . The patients/participants provided their written informed consent to participate in this study.RAK: methodology, investigation, formal analysis, writing—original draft, visualisation, writing—review and editing, project administration, and funding acquisition. DT-P, FM, RS, JB-W, JL, AL, RC, and RAK: investigation and writing—review and editing. MS: investigation, writing—review and editing, and funding acquisition. OxAMI Study Investigators: investigation, methodology, resources, project administration, and funding acquisition. HG-G: conceptualisation, methodology, and writing—review and editing. KC: conceptualisation, methodology, investigation, resources, writing—review and editing, project administration, and funding acquisition. AB: conceptualisation, methodology, investigation, resources, writing—review and editing, and funding acquisition. GD: conceptualisation, methodology, investigation, resources, writing—original draft, writing—review and editing, supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.This study was Supported by British Heart Foundation , BHF Centre of Research Excellence, Oxford (RG/13/1/30181), Oxfordshire Health Services Research Committee and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. RAK, Academic Clinical Fellow is funded by Health Education England (HEE) /National Institute for Health Research (NIHR) for this research project. MS is in receipt of the Alison Brading Memorial Scholarship in Medical Science, Lady Margaret Hall, University of Oxford.The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care.GD reports grants from Miracor Medical SA, outside the submitted work. In addition, GD has a patent PCT/US20/55240 pending. AB reports grants from Boston Scientific, personal fees from Boston Scientific, personal fees from Abbott, personal fees from Medtronic, personal fees from Phillips, outside the submitted work. HG-G reports institutional research grants from Medtronic, Boston Scientific, Abbott, Biotronik, Neovasc, Corflow, Shockwave, Chiesi, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This review presents the key clinical aspects of cerebral autoregulation and its disruption in SAH: it provides a mechanistic overview of cerebral autoregulation, describes current clinical methods for measuring autoregulation in SAH patients and reviews current and emerging therapeutic options for SAH patients. Recent advancements should fuel optimism that microvascular dysfunction and cerebral autoregulation can be rectified in SAH patients.Subarachnoid hemorrhage (SAH) is a devastating stroke subtype with a high rate of mortality and morbidity. The poor clinical outcome can be attributed to the biphasic course of the disease: even if the patient survives the initial bleeding emergency, delayed cerebral ischemia (DCI) frequently follows within 2 weeks time and levies additional serious brain injury. Current therapeutic interventions do not specifically target the microvascular dysfunction underlying the ischemic event and as a consequence, provide only modest improvement in clinical outcome. SAH perturbs an extensive number of microvascular processes, including the “automated” control of cerebral perfusion, termed “ In this regard, a pronounced secondary ischemic event, termed “delayed cerebral ischemia (DCI)” emerges 3–14 days following SAH. DCI is a significant cause of death and disability in SAH patients who survive the initial aneurysm rupture  an overview of cerebral autoregulation, its mechanistic basis and predictions on how SAH alters autoregulatory function, (2) clinical measures of autoregulation and their relationship to patient outcomes, and (3) current therapeutic interventions for SAH in the context of autoregulation, which explains why alternative approaches are desperately required. In our subsequent discussion, we will examine some emerging therapeutic options that may be capable of correcting dysfunctional autoregulation in SAH.erebral blood flow autoregulation is a regulatory mechanism that maintains constant brain perfusion over a relatively wide range of cerebral perfusion pressures (CPPs). This mechanism originates within the cerebral microcirculation, where resistance arteries actively match their level of constriction and hence, vascular resistance, to the prevalent perfusion pressure . Te. Te26). Since there are no systematic assessments defining the entire autoregulatory range in humans, the generally accepted range is 50-150 mmHg, as originally described by Lassen , 26. How2 and CO2 tensions, lactate, adenosine, nitric oxide, potassium ions, and vasoactive neurotransmitters   has also been used  –52. Thesoupling” –52, altheen used . To avoiin vitro experimental system that directly characterizes a resistance artery's response to pressure in a controlled external environment where confounding metabolic and neural inputs are eliminated.In pathological settings, autoregulatory dysfunction undoubtedly incorporates both intrinsic changes to how smooth muscle cells sense and respond to pressure and their vasomotor responses to the metabolic signals emanating from the external environment. Isolating the effects of SAH on the intrinsic pressure-sensitive mechanisms can only be effectively achieved with an in situ and in vitro  experiments that demonstrated pressure-dependent vasoconstriction and vasodilation (in vitro conditions) inputs, he deemed these responses to be myogenic in nature   . Indeed,f tone.” . Remarkaf tone.” , in partf tone.” . Althougf tone.” , the mecf tone.”  and (ii) and vasodilation in response to a decrease in transmural pressure. Small cerebral arteries (<300 μm in diameter) are myogenically active , 59–62 aAt the molecular level, the myogenic response is the conversion of a mechanical stimulus  into an intracellular biochemical signal; however, reviews over the last 20 years attest to the enormous complexity and mechanistic diversity of myogenic mechanisms , 68–75. v) and calcium-activated large conductance (BK) potassium channels, which play important roles in modulating the depolarization response   , 71. In phatase) : notablephatase) , 20-hydrphatase) , 88, Rhophatase) , 90, andphatase) , 92.ex vivo to investigate the effects of SAH on myogenic reactivity  microcirculatory vasoconstriction  in the absence of angiographic vasospasm, (ii) angiographic vasospasm alone, and (iii) both microcirculatory and large artery vasoconstriction. We propose the following effects on autoregulation:Our first scenario  is consiBecause autoregulation maintains constant CBF at reduced levels, perfusion will not increase unless the CPP passes the upper limit of autoregulation. In severe cases , the autoregulatory range may be small enough that the upper limit can be passed with “moderate elevations” in systemic blood pressure [e.g., an elevation of mean arterial pressure to 140 mmHg ; Figure In our second scenario , large aOur final scenario  combinesCerebral autoregulation has been a focus of clinical assessment in SAH patients for over 50 years. In this subsection, we present distilled descriptions of the most frequently used methods to measure autoregulation in SAH patients, including the key principles, caveats, and conclusions.133Xe clearance, positron emission tomography, thermal diffusion, magnetic resonance imaging arterial spin labeling, and perfusion computed tomography   , (iv) anAlthough autoregulation responds to both increases (vasoconstriction) and reductions (vasodilation) in perfusion pressure, running both protocols in SAH patients is logistically challenging. Thus, studies generally measure responses after a single stimulus in SAH patients, almost always a reduction in blood pressure , 117–121Given that ischemia and perfusion deficits are common in SAH patients, it is not surprising that these studies largely confirm that SAH compromises autoregulation in many SAH patients  20, 101–125. TheTransient Hyperemic Response Test (THRT). The test is scored as a binary measure (intact/perturbed), depending on whether the transient hyperemic BFV is 10% higher than the pre-compression BFV. In the thigh cuff approach, thigh cuffs are inflated to 200 mmHg for 2 min and then rapidly released, resulting in a negative step change in CPP. The autoregulatory BFV response is then mapped to 10 theoretical traces incorporating autoregulatory dynamic gain, a dampening factor and a time constant (Autoregulation Index (ARI), with 0 indicating no autoregulation and 9 indicating “perfect” autoregulation.Dynamic autoregulation assessment refers to a relatively simple TCD-based method that evaluates the autoregulatory response to a transient reduction in perfusion pressure. In brief, middle cerebral artery (MCA) BFV is continuously measured by TCD. Autoregulatory responses are then measured following an alteration in CPP : this is typically achieved in SAH patients by compressing the carotid artery ipsilateral to the insonified MCA –131, altconstant . Each cuAlthough the methods are relatively simple, non-invasive and use readily available TCD equipment, there are some general caveats and limitations: (i) the measurements are highly prone to inconsistency, most likely due to short-term variations in autoregulatory activity, the influence of other physiological variables and noise in the system, (ii) there is an assumption that MCA diameter does not change as a result of the interventions, and (iii) the THRT is graded against a somewhat arbitrary present/absent threshold that oversimplifies the outcome.SAH patients frequently display abnormal THRT results  126–131131. Two There are several practical considerations that hinder the routine measurement of static and dynamic cerebral autoregulation in critically ill patients: (i) static autoregulation measures require the use of vasoactive drugs or mechanical maneuvers that are often contraindicated in critically ill patients, (ii) assessments can be time consuming and consequently, frequent/routine assessment would add a substantial workload burden to neurocritical care staff, and (iii) assessments can be prohibitively expensive, especially if MRI-based methods are used. In a critical care setting, cerebral autoregulation assessments should be fast and inexpensive, minimally disturb the patient and ideally, utilize data that is already collected as part of neurocritical monitoring. Continuous autoregulation measurements largely meet these criteria, as they rely on endogenous variations in blood pressure and utilize continuous monitoring data from widely available equipment.Pressure Reactivity Index (PRx), first described in 1997 by Czosnyka et al. , a U-shaped relationship is observed , these parameters may be measured in SAH patients who are subject to continuous ICP monitoring. However, PRx measurements in SAH patients possesses key caveats: (i) ABP must be a reliable correlate of CPP, which may be problematic in patients with high ICP levels, putatively due to compression of intracranial veins and consequent increase in venous resistance , 139; i; (iii) cPRx measurements are more firmly established as a prognostic indicator for traumatic brain injury patients than they are for SAH patients , 146. Nebelow 90 mmHg  also associated with unfavorable outcome. This potentially identifies a clinically significant augmentation of myogenic vasoconstriction, which would simultaneously induce a leftward shift in the upper limit of autoregulation  and reduce perfusion (promoting ischemia at CPP levels of 60-70 mmHg). In support of this conclusion, Johnson et al., stratified SAH patients into high and low PRx values (≤0.1 vs. >1) and found that the high PRx group associated with lower CBF, despite the fact that both groups possessed similar/normal CPP and ICP levels and Mean Reactivity Index(Mx), as these are non-invasive alternatives to PRx. Both Sx and Mx are similar to PRx, in that they correlate slow waves in CPP and CBF surrogates. For Sx and Mx, systolic blood pressure (Sx) and mean blood pressure (Mx) serve as surrogates of CPP, while MCA BFV serves as a surrogate of CBF. In a setting with intact autoregulation, CBF remains constant despite changes in blood pressure and consequently, MCA BFV remains constant; when autoregulation is compromised, CBF increases with pressure and hence, BFV in the MCA concomitantly increases. Like PRx, the Sx and Mx indices are calculated using a moving Pearson correlation, yielding a U-shaped autoregulatory relationship.Of the other continuous methods for determining cerebral autoregulation, it is worth elaborating on the TCD-based r = 0.36 to 0.58), which likely reflects territorial differences , measurement susceptibility to ICP and differences in model assumptions  the technique is highly operator-dependent and requires expertise for reliable and reproducible measurements ; (ii) thumptions , 142.Only a handful of studies have used Mx or Sx in SAH patients  21, 154154–156. It should be mentioned that slow waves in blood pressure and TCD-based MCA BFV have been also analyzed with a transfer function analysis, instead of the moving Pearson correlation that generates the Mx and Sx values. Simplistically, a transfer function is Fourier decomposition of input and output signals that are transformed into sinusoids with the same frequency, but a different amplitude (gain) and a latency ; a coherence function identifies conditions where estimates of gain and phase are reliable . When ceOxygen ReactivityIndex(correlation between slow waves in oxygen saturation and blood pressure)   deservesressure) , 24 or bressure) , 159. Buressure)  conducteressure) , 159, deressure)  in SAH; Collectively, a large body of clinical data strongly support the conclusion that cerebral blood flow autoregulation is perturbed in SAH patients: this is not necessarily a surprising revelation. However, many issues hamper the overall interpretation of the literature and the utility of autoregulatory assessment as a prognostic indicator. Most notable among these issues are (i) the absence of a “gold standard” autoregulation measurement, (ii) the sparsity of studies utilizing multiple assessment techniques, and (iii) the diversity in patient populations and outcome measures. It can be argued that there is no “gold standard” method for measuring cerebral autoregulation, as every method has limitations . Yet, th2 can profoundly alter autoregulation through direct actions on vascular reactivity , or a decrease of at least 2 points on the Glasgow Coma Scale  that lasts for at least 1 h, is not apparent immediately after aneurysm occlusion and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies.” At present, there are only 2 interventions used to treat DCI: hyperdynamic therapy and the calcium channel antagonist nimodipine (In the distant past (45–50 years ago and beyond), aneurysmal rebleeding was the primary cause of mortality and morbidity in SAH patients who survived the initial aneurysmal rupture. The development of aneurysm clips and effective microsurgical techniques , 164, piAH ictus , 12. It asospasm . Regardlmodipine .Triple H Therapy,” as it includes hypertension, hypervolemia, and hemodilution as core elements   .In summary, hyperdynamic therapy is a “last resort” intervention, because the underlying mechanisms causing the microcirculatory constriction are not understood. Thus, there are few options available to increase CBF when symptoms of ischemic injury occur. Hyperdynamic therapy, therefore, attempts to override the constriction with high pressure: this may increase CBF, but with risks of both systemic and central nervous system injury. The evidence supporting hyperdynamic therapy as an intervention is weak , 202–205Nimodipine is the only FDA-approved medication for use in SAH: it belongs to the dihydropyridine (DHP) class of calcium channel blockers that inhibit L-type, voltage-sensitive calcium channels. The blockade of voltage-gated L-type calcium channels strongly impacts depolarization-stimulated vasoconstriction , 214, a In order to increase cerebral perfusion, cerebrovascular resistance must decrease relative to systemic resistance. Nimodipine is characterized as a “preferential cerebrovascular dilator,” with several reports demonstrating that nimodipine stimulates an increase in cerebral blood flow at concentrations that either do not alter systemic blood pressure or elicit only modest reductions –220. Thiaccumulates in cerebral cell membranes is largely not supported by available evidence: nimodipine possesses a relatively low partition coefficient, can easily wash out of membranes and has a short clinical half-life  is much lower than in plasma (10-250x lower in CSF relative to plasma) –226. It alf-life ; radiolaalf-life . NimodipIn the absence of a distribution effect , the cerebrovascular preference might entail a higher sensitivity to L-type calcium channel inhibition relative to peripheral arteries. This conclusion is primarily based on comparisons of agonist-stimulated responses  in basilar and saphenous arteries , 214. HoFinally, the myogenic response is highly dependent on membrane potential, voltage-gated calcium channels, and calcium influx , 230. ThThe FDA approved nimodipine for use in SAH in 1988. At the time, many of the studies supporting the use of nimodipine were “non-comparative” and relied on historical data to drive conclusions regarding the effect of nimodipine. Some notable examples of these non-comparative studies include Ljunggren et al.  and AuerSince nimodipine possesses vasodilatory properties, a vascular mechanism was presumed. However, there is scant evidence for an effect on cerebral perfusion in SAH patients. Only 2 of the controlled trials (1 placebo controlled) that preceded FDA approval conducted CBF measurements: neither found evidence that nimodipine increased cerebral perfusion , 238. In133Xe clearance) (133Xe clearance), the results are generally unsupportive of a perfusion effect  . For obvearance) , 247, onearance) , 240–242n effect . Rasmussn effect . Hänggi The absence of a clear vascular effect has spurred the search for non-vascular mechanisms of action that could explain nimodipine's beneficial effect in SAH. The attenuation of cortical spreading depolarizations is one potential non-vascular mechanism that has received significant attention . Spreadisteal phenomenon. It should also be noted that since the myogenic response, the basis of autoregulation, depends on L-type calcium channels  would undoubtedly be more effective. However, globally targeting the cerebral microcirculation with a vasodilator has many of the same shortcomings as hyperdynamic therapy. Specifically, there is both normal or pathological heterogeneity in autoregulatory status within the cerebral microcirculation: thus, global treatment could undermine autoregulation in regions where it functions properly, potentially leading to hyperperfusion, edema and/or potentially, a channels , 230, caculation . The autculation . The incIn summary, it appears unlikely that orally administered nimodipine elicits significant and sustained cerebrovascular dilation and increased perfusion. As a consequence, a neuroprotective mechanism is now favored. While it would be preferable to target the vascular mechanism, the global use of vasodilators is problematic and there are currently no alternative approaches available.Cerebral autoregulation is a crucial homeostatic mechanism: its disruption in SAH can profoundly compromise cerebral perfusion and consequently, cause ischemic injury. Autoregulatory status can be measured in a clinical setting: while these measures are generally predictive of outcome, future efforts need to establish a “gold standard” procedure with sufficient numbers in order provide appropriate diagnostic and prognostic guidance. However, the absence of interventions that can correct perturbed autoregulation is a dire problem: a substantial research investment is required on this front, as the number of interventional options at the clinician's disposal is limited.As reviewed by Daou et al., an array of pharmacological interventions have been tested for efficacy in SAH . Many ofThere are few studies that systematically investigate how myogenic reactivity, the underlying basis of autoregulation, changes in SAH , 98–100.2R), Rho-associated protein kinase (ROCK) and the cystic fibrosis transmembrane conductance regulator (CFTR). It is worth considering how these might fare as interventions   , 278 areigabine) , 280. Fu2R, CFTR, and ROCK) may all be functionally linked into a pathological signaling chain  via the activation of the ROCK signaling cascade   cerebrospinal TNF levels rise and peak 4–10 days post-SAH ictus –295, theJTE-013)  or fingoJTE-013) , 303, im benefit –306. Col benefit .2R antagonists. Fingolimod is approved to treat multiple sclerosis . Myogenic reactivity and its systemic counterpart, cerebral autoregulation, are crucial homeostatic mechanisms that are perturbed in SAH. Understanding the molecular basis for this microvascular dysfunction, coupled with advances in clinical monitoring of autoregulation, will provide the best prospect of identifying new interventions that successfully restore autoregulation and perfusion in SAH patients.DL wrote the first draft of this article. All authors contributed equally to the conceptualization, literature research, and revision of the final manuscript.DL is a consultant for Qanatpharma AG . SS-B is executive board member of Qanatpharma AG and Aphaia Pharma AG . Neither Qanatpharma AG nor Aphaia Pharma AG had any financial or intellectual involvement in this article. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.