Does red blood cell (RBC) storage duration affect transplant failure in patients who received kidney transplants and early posttransplant transfusions?In this cohort study including 12 559 kidney transplant recipients, longer RBC storage was associated with longer transplant survival among patients receiving early posttransplant transfusion.Preferential use of the RBC unit with the longest storage duration might reduce the deleterious association between transfusion and kidney graft survival. This cohort study evaluates associations between duration of red blood cell storage and kidney transplant outcomes among patients receiving early posttransplant transfusion. Red blood cell transfusion (RBCT) is frequently required in the early post–kidney transplant period, but long-term outcomes associated with RBCT is controversial. Therefore, it may be relevant to investigate the association between RBCT characteristics and transplant outcomes.To study the association between RBC storage duration and transplant outcomes.This was a nationwide retrospective cohort study based on data linking between 2 prospective French nationwide registries. Clinical transplant parameters, outcomes, and RBCT characteristics were extracted from the CRISTAL registry of the Agence de la Biomédecine and the national database of the Etablissement Français du Sang. All 12 559 patients having received a first kidney transplant in France between January 1, 2002, and December 31, 2008, were included. Patients were followed up from transplant to graft loss, death with a functional graft, or data retrieval in June 2016. Data were analyzed from April 2019 to June 2022.Clinical outcomes of transplant recipients who underwent early RBCT were analyzed considering transfusion characteristics.Cox proportional hazards regression models were fitted to evaluate transplant failure defined as graft loss or death with a functional graft.P = .06). Patients transfused with at least 1 RBC unit stored for more than 20 days had a 5% absolute decrease in transplant failure at 3 years and 7% at 5 years compared with those who received RBC stored for less than 20 days.Among 12 559 patients who underwent kidney transplant, 3483 received an RBCT during the first 14 days posttransplant. The median (IQR) age of patients was 53.0 (41.5-61.2) years, and 1929 patients (55.4%) were male. Median (IQR) follow-up was 7.8 (7.6-8.0) years. In multivariable analysis, longer (vs shorter) storage duration of transfused RBC was associated with a decrease in risk of transplant failure (hazard ratio, 0.99; 95% CI, 0.98-1.00 for each additional storage day; In this study, longer RBC storage duration was associated with a decreased risk of transplant failure among patients who received kidney transplants and RBC transfusions. Preferential use of RBC with longer storage duration might improve kidney graft survival following transplant and transfusion. Several contradictory publications have focused on the impact of posttransplant transfusion, questioning transfusion-mediated development of anti–human leukocyte antigen (HLA) antibodies and antibody-mediated rejection in presensitized patients.6 Using a national cohort of more than 12 000 patients, we recently reported7 that red blood cell transfusion (RBCT) early after transplantation was associated with transplant failure.Patients who undergo kidney transplant frequently require blood transfusion in the early period after transplantation.Nevertheless, this question may seem trivial. Indeed, when indicated, RBCT is likely to be unavoidable. Consequently, evaluating the characteristics of the RBC units seems to be a more pragmatic strategy to reduce the potential harmful effects of transfusion.10 The settings directly related to the method of preparation, storage conservation, or rejuvenation of the RBC units have also been the subject of numerous studies in clinical settings.12Regardless of the number of RBC units transfused, which also remains a required parameter, characteristics of blood donors, including age, sex, and blood group, have been studied.15 In most jurisdictions, RBC can be stored up to 42 days before transfusion. Longer storage induces biochemical and morphological modifications of RBC units and accumulation of soluble components that may be deleterious, notably by impairing oxygen delivery to tissues.17 Consistent with this, some studies suggested that longer RBC storage was associated with worse outcomes in different clinical settings.19 However, these results have not been consistent, and the benefits of using fresh RBC have been called into question.23Duration of storage is one of the most studied and debated product characteristics.24 Moreover, in the specific setting of transplantation, some immunosuppressive effects of RBC may be enhanced by storage.26 Yet, to our knowledge, no data concerning the putative impact of storage duration of transfused RBC units are available in kidney transplantation.Indeed, fresh RBC units contain increased quantity of different mediators, including damaged leukocytes and platelets, cell-free DNA, and microvesicles, that can result in inflammation, coagulation, endothelial injury, and organ damage as well.The principal aim of this study was to investigate the association between duration of RBC storage and transplant outcomes. To perform this study, we linked 2 national databases including all first kidney transplant recipients and all transfusions between 2002 and 2008.7 Detailed patient characteristics and blood product characteristics for each unit of transfused blood were extracted from national databases. This study was approved by all French regulatory authorities . The exemption of written informed consent was guaranteed by the Advisory Committee on Information Processing for Research in the Field of Health. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.We conducted a national longitudinal study to investigate the association between RBC storage duration and transplant outcomes after early posttransplant RBCT in France.6 leucocytes/RBC unit). Data collected included blood donor demographic characteristics (including age and sex) as well as blood product characteristics for each RBCT.Transfusion within 14 days posttransplant was completed for each first kidney transplant graft between January 1, 2002, and December 31, 2008. Demographic and clinical data were extracted from the national kidney transplant database CRISTAL. Patients were followed up from inclusion on the transplant waiting list to graft loss, death, or data retrieval in June 2016. Early graft failures, within 15 days posttransplant, were excluded from analysis. All RBC concentrates were produced by the Etablissement Français du Sang and underwent prestorage deleukocytation  and 95% CIs for factors associated with transplant failure.Medians with IQRs, means with SEs, and frequencies with percentages were provided for continuous and categorical variables as appropriate. Transplant failure–free survival was estimated using the Kaplan-Meier method and described using median or rate at specific time points with 95% CIs. Follow-up duration was calculated using a reverse Kaplan-Meier estimation.P values of less than .05 were entered into a final multivariable Cox regression model after considering collinearity among variables with a correlation matrix. A final multivariable Cox regression was proposed. The assumption of proportionality was checked by plotting log minus log survival curves and by cumulative martingale process plots.The association of baseline parameters with transplant failure was first assessed using univariate Cox analyses, and then parameters with Sensitivity analyses with a frailty approach by using a random component for the hazard function based on the transfusion region was applied in the final multivariable Cox model and by considering only the subset of patients having experienced a single transfusion episode of 1 or 2 RBC units.To model the association of parameters of interest identified in the multivariate model for the primary composite end point  with each of considered events (graft loss and death during transplant), the Fine and Gray subdistribution hazards approach was applied to address competing risks between graft loss and death during transplant. Cumulative incidence function estimate with subdistribution hazards approach proposed by Fine and Gray was used to model the association of parameters with graft loss–free survival and survival with functional graft.P values less than .05 were considered statistically significant, and all tests were 2-sided. P values were not corrected for multiple tests and should be interpreted as exploratory except for the primary objective . Details on the interpretation of important statistical concepts are given in the eMethods in All analyses were performed using SAS version 9.4 (SAS Institute) and R version 4.1.2 (R Foundation). Our database identified 3483 of 12 559 (28%) patients who received an early posttransplant RBCT. Most had 1 transfusion episode (n = 2512 [72%]), most often consisting of 1 or 2 RBC units   age of patients was 53.0 (41.5-61.2) years, and 1929 patients (55.4%) were male. The median (IQR) body mass index was 23.6 (20.9-26.6), calculated as weight in kilograms divided by height in meters squared. Most patients (n = 2997 [86.3%]) were on dialysis before transplant (977 had glomerulopathy [28.1%]), 1433 had CMV [63.8%]), 2192 did not have preimmunization before transplant [87.1%]), and 3310 received an organ from a deceased donor [95.0%]). Median (IQR) follow-up was 7.8 (7.6-8.0) years.Patient characteristics have been previously described.7 the frequency of patients receiving at least 1 RBC unit after transplant remained unchanged throughout the study period.Characteristics of RBC units are summarized in eTable 1 in P < .001). Similar results were obtained using the maximum, median, or mean storage time of RBC transfused per patient and in multivariable analysis with all transfusion characteristics with a P value less than .05 in univariate analysis or by selecting the parameters of interest in parsimonious model  A correlation matrix was used to detect significant correlations between investigated parameters to select the most relevant variables , we studied all available parameters related to transfusion and included them in our model. The number of RBCT episodes and units per patient, the delay between transplant and first RBC unit transfusion, and the mean delay from transplantation to issue of RBC units for transfusion were also associated with an increase in transplant failure . In the P = .01) (P = .003) compared to transfusion with RBC units stored for less than 20 days  . Surviva 20 days A.Results were similar with frailty model analysis based on geographic region (eTable 2 in P < .001)  C.Furthermore, the number of transfusion episodes was inversely associated with transplant survival D. KaplanIn univariate analysis, the delay between transplant and first RBC unit transfusion, the mean delay from transplant to issue of RBC units for transfusion, and shorter storage duration were also associated with risk of graft failure. As for the overall population, we used a correlation matrix to select the most relevant variable for final multivariable analysis  in competitive risk analyses A and B, 13 Randomized clinical trials published since 2013 revealed similar conclusions.23 Nevertheless, the Age of Blood Evaluation (ABLE) study20 suggested a trend toward an increased mortality with fresh RBC units. To our knowledge, no data have been reported in kidney transplantation. In liver transplantation, the association of RBC preservation on outcomes is variable but the context is obviously different.31 The conflicting results may suggest that the differential association of RBC storage duration on outcomes could depend on clinical context. In our study, a storage time longer than 20 days was associated with a reduced risk of transplant failure at 5 years by 6% compared to a newer RBC unit . This association was robust and persisted in all sensitivity analyses. Moreover, the size of the association is large, since such a transfusion policy may spare 1 graft loss in the first 5 years posttransplant for 14 patients receiving transfusions during the first 2 weeks after transplant.In this cohort study, we report that among patients with kidney transplant and RBC transfusion, those who received RBC with longer storage had better transplant survival. Associations between RBC storage and patient outcomes after transfusion have been long debated. Contrary to our findings, existing literature mainly focuses on deleterious associations between conservation and different end points.32 Macrophage phenotype switching, reduced expression of class II major histocompatibility complex molecules, and Treg cell activation are some of them.33 The degree of immunosuppression is related to the concentration of soluble HLA class I molecules and Fas ligand in the supernatant, which are both increased by storage duration.34 Supernatants of whole RBC inhibit ex vivo phytohemagglutinin-induced tumor necrosis factor–α and interleukin-2 secretion proportionally to the storage time.35 Moreover, concentration of many proinflammatory cytokines decreases when storage duration increases.26 Accumulation of apoptotic white blood cells during RBC storage may also contribute to immunomodulation.36 Some clinical outcomes of transfusion-induced immunosuppression have been previously described. Indeed some studies suggest that RBCT favor recurrence of cancers.38 Moreover, several studies showed that longer RBC storage is associated with an increased rate of infection.40 Together, these data suggest that longer stored RBC may induce sustained immunomodulation that can favor graft survival.The mechanisms underlying the association of RBC storage on graft survival remain speculative. Longer stored RBC may have immunomodulatory properties that would favorably influence graft survival. Different mechanisms are at the origin of this phenomenon, called transfusion-related immunomodulation.4Alternatively, longer stored RBC may be less likely to cause HLA immunization. RBC units still contain white blood cells even after deleukocytation. White blood cells disappear from RBC units in the first days of storage. However, fresh RBC units containing a greater amount of white blood cells are likely to further expose patients to HLA immunization and subsequent humoral rejection.Transfusions on the day of transplant seem to be less deleterious than those performed after. This may be explained by different causes for transfusion in the 2 posttransplant periods. Transfusions on the day of transplant are likely to concern acute bleeding and to be based on clinical appreciation rather than on hemoglobin levels. Those occurring on a later date may be more often related to clinical complications.41 Indeed, RBCT from male donors to female recipients may induce immunization against minor histocompatibility antigen H-Y and drive subsequent alloimmune response.42 Nevertheless, few data support the clinical relevance of this hypothesis.15 In the present study, no association was found between blood transfusion sex mismatch and transplant failure.Some studies suggest that transfusion sex mismatch might carry a harmful effect.46 The association between the need for a massive transfusion and severe posttransplant complications is obvious. However, the deleterious association of the transfusion starts with the first transfusion episode (1 or 2 RBC units). In previous studies, this association only appeared after the third RBC unit.45 The difference may either be related to a smaller number of patients or different transfusion practices in these studies. The association of time elapsed between transplant and transfusion is also probably influenced by differences in the context and indication of transfusion.This study has limitations. The distribution strategy of RBC favors the oldest unit. In this way, multiple transfusions may increase the likelihood of receiving a fresher RBC unit. Nevertheless, the association of storage duration was adjusted for the number of RBC units transfused as well as the number of transfusion episodes. Moreover, the same association of storage duration was observed in patients who had a single episode of RBCT. Although most transfusions (72%) concerned 1 or 2 RBC units, we and others reported that the harmful association of the transfusion was proportional to the number RBC unit transfused.38 Likewise, other unmeasured parameters, such as organ donor age, delayed graft function, or the presence of donor-specific antibodies, may have an impact on graft failure. However, these factors do not explain the differences observed in this population.In addition, we have not taken into account an exhaustive list of all the parameters related to blood donors, such as race and ethnicity, previous pregnancies, or genetic characteristics . These parameters may influence the probability of alloantigen formation as well as the quality of preserved blood, impacting the state of conservation of RBCs.19 Nevertheless, we did not observe any differences in the rate of transfusion or in the quality of delivered blood products between regions.The method of whole blood processing (red-cell filtered RBCs or whole-blood filtered RBCs) is variable from one blood transfusion center to another. Some studies suggest that RBC processing methods may influence RBC quality and patient outcomes.The findings in this study show an association between longer RBC storage duration and improved graft survival. These results may support the use of the oldest RBC available for transfusion following kidney transplants.


We propose BPClip, a less than $ 1 USD blood pressure monitor that leverages a plastic clip with a spring-loaded mechanism to enable any smartphone with a flash LED and a camera to measure blood pressure. Unlike prior approaches, our system measured systolic, mean, and diastolic blood pressure using oscillometric measurements that avoid cumbersome per-user calibrations and does not require specialized smartphone models with custom sensors. HyperWhile high-income countries have stable rates, hypertension prevalence rates are increasing in low- and middle-income countries (LMICs) due to the aging of the population and increases in exposure to lifestyle risk factors including unhealthy diets and lack of physical activity. Control of blood pressure (BP) in these countries continues to be poor, often less than 10%, 6. MigrSmartphone-based digital biomarkers leverage the ubiquity of smartphones to improve access and resources for preventative medicine practices far beyond typical clinical resources. Based oBPClip, an ultra-low cost universal smartphone attachment that enables smartphones to measure blood pressure. Our proposed system uses an oscillometric method to measure blood pressure, the same method utilized by typical automated blood pressure monitors. This is consistent with the proposal by the American Medical Association and American Heart Association, which jointly released a statement supporting at-home blood pressure measurements for more reliable monitoring  was used to measure BP on the left arm. The average of the two cuff measurements was used as the reference.3.2BPClip is designed with SolidWorks CAD software and printed with a resin 3D printer (Any-cubic Photon Mono X with Hard Tough Resin - Black). The clip dimensions are 5.1x4.1x2.3 mm. The clip is clamped onto the smartphone , with a 3D-printed screw. The clip consists of 3 main components: the base clip, the pressing platform, and the compression spring.The base clip is a 3D-printed clip-shaped piece that is mounted to the smartphone. It also includes a 3D-printed screw and nut which can tighten to help fix the clip in position. To ensure a firm and non-slip interface, a silicone pad is used to increase the friction between the clip and the phone screen. The bottom piece is flush with the camera and flashlight LED.The pressing platform is also 3D-printed and wraps around the bottom piece. It comes in contact with the user’s finger and is displaced as the user applies force to it. The contact area is a circular protrusion with a diameter of 10 mm. To ensure an even surface for the finger contact area, clear acrylic pieces are placed over the openings of the illumination slot and pinhole. Two flanges are used to constrain the angle of the index finger. Two notches are used to help users align their index finger with the pinhole.Interfacing the top and bottom is a compression spring with a k-constant of 0.49 N/mm, placed in between the pressing platform and base clip. It renders the pressing platform the ability to move up and down, depending on the amount of force applied by the finger. The spring is pre-loaded with a force of 0.1 N. 6.7 mm more space is allowed for the spring to compress, rendering the potential range of force applied to the finger from 0.1 N to 3.3 N. With an area of a circle of 10mm diameter, the pressure would range from 9.5 mmHg to 315 mmHg. Because the prototype is constructed with 3D printing, surface finishes are not perfectly smooth compared to injection molded plastic parts. Two pairs of guiding rods and tubes, with lubricants applied, are added to the pressing platform and base clip respectively to allow for smooth uniform displacement.A light guide and an imaging path are designed to maximize the light transfer and minimize light leakage. The light guides direct the flash into the protrusion and into the finger. To maximize light transfer from the flash to the finger, chrome spray paint is applied to the inner surface of the light guide. A pinhole projects the light from the finger onto the camera via the imaging path. At the end of the light guide and imaging path, two O-Rings were respectively padded in between the bottom piece and the phone to reduce the external light influence.3.3We developed an Android smartphone application to be used with BPClip. The application has 3 main features. First, it infers the applied finger force from the size of the pinhole reflected on the image captured by the camera. The pinhole is projected to the camera sensor as a circle. For each frame, the area of the circles is calculated from the number of pixels with a value above 20 (the image is encoded with unsigned 8-bit integers). To account for different baseline values within the circle due to different amounts of blood circulation, a histogram equalization operation was applied to the raw image before area calculation. The diameter of the circle is then calculated from the area of the circle. The force is plotted in real-time in the force plot UI. To avoid unnecessary confusion for the user, the force signal was processed with a low pass filter to remove the PPG artifact before being plotted.Second, the application can extract the PPG signal from the pixel values within the circle. For each frame, the average value of the pixels within the circle that have a value between 20 and 254 is calculated to be the PPG signal. The PPG is plotted in real-time in the PPG plot UI.Third, the application has a UI that helps the user maintain the applied finger force at a specific level. This UI consists of a brightness adjustment feature and a feedback feature. Because the brightness depends on the amount of total blood circulation as well as the skin tone, the size of the circle projected onto the camera at each force level changes depending on the person. To adjust for this, a simple brightness adjustment is performed before each measurement. To perform an adjustment, at the beginning of a measurement round, the circle size when the user rests the finger on the clip with no force is recorded , as well as the circle size when the clip is completely pressed down. . By capturing the 0% and 100% circle sizes, the ensuing measurement can be performed in proportion. 20 force levels are then equally divided from 5% to 95%. During the trial, a green line representing the current target force level appears in the force plot. An additional red indicator line showing the current force applied helps guide the user to adjust the applied force to meet the target force. While the applied finger force does not yet match the target, the indicator line remains red. As soon as the force is in the range close to the target (±2%), the indicator turns yellow. The user is then expected to hold their finger in position to maintain a constant applied force. If the force stays within the range, after 2 seconds the indicator turns green from yellow, where the data is collected for 5 seconds. If the force goes out of the range (±2%) anytime when the indicator is yellow or green, the indicator changes back to red, and any data collected will be discarded. The data for the current force level then needs to be recollected.3.4This section elaborates on the process of preprocessing raw data recorded on the smartphone. As thoroughly explained in the prototype hardware section, the camera images contain a pinhole projection. The diameter of the pinhole projection corresponds to the force exerted on the finger. The pixel intensity fluctuations of the pinhole projection correspond to blood flow through the palmar arch artery.For the data analysis, we only use data captured during the 5-second intervals at the specified force levels from the smartphone application. For the applied force, this smartphone application ensures ±2% tolerance on each force level. At each of the 20 force levels, the 5 seconds of recording allows for approximately 3-7 complete pulses of blood flow, as measured by the pixel intensity of the pinhole projection. For each of these force levels, we applied a 0.5 to 10 Hz band pass filter and then averaged the peak-to-trough amplitude of all complete pulses using peak prominence. This results in one average peak prominence value for each of the 20 force levels. These 20 points make up the subsampled blood volume oscillogram used to calculate blood pressure.During the data preprocessing, we excluded participants for the following reasons:The participant did not have sufficient perfusion to create a PPG signal with significant enough prominence values for interpretation. (N=4)The participant had abnormal blood pressure with more than 80mmHg difference between the reference systolic and diastolic BP measurements. (N=1)This resulted in N=24 participants for the data analysis and validation steps of the study.3.5This section describes our process of using pre-processed data to predict blood pressure. In estimating systolic and mean BP from the 20-point blood volume oscillogram, we exclude the lowest and highest force levels, because when at the lowest force, the finger can sometimes leave the clip, and at the highest force, the spring is fully compressed and the applied finger force may exceed the spring load. From the remaining 18 oscillogram points, we normalize the points between 1 and 0. We use the 18 oscillogram points as the input into a Least Absolute Shrinkage and Selection Operator (LASSO) Regression to estim3.6The data that support the findings of this study are available from the corresponding author upon reasonable request.3.7The code that supports the findings of this study is available from the corresponding author upon reasonable request.4A key finding in our work is that there is no need to perform a per-user or per-device calibration. This is enabled by the simple top-bottom brightness adjustment that is included at the beginning of a measurement. By asking the user to hold the clip at the furthest compression and then once again at the closest compression, our system adjusts for the total brightness as reflected by a person’s finger. Thus, no matter the skin tone (where darker would absorb more light) or with a dimmer flash , the brightness adjustment equalizes the proportional amplitude of the PPG accordingly.As with all optical-based pulse sensing systems, skin tone needs to be considered. Although a formal skin tone study was not performed, our approach does not have a fundamental limitation due to skin tone beyond signal strength. Darker skin tones can absorb more light, thus leading to less total light reflected. However, unlike calculating oxygen saturation (SpO2), our method does not depend on the distribution of absorbed light at different wavelengths, but rather only depends on the total amplitude of the signal. Our current prototype addresses this sufficiently through chrome-painting the light guide from the flash, which channels a significant amount of light from the phone flash. Additionally, for darker skin tones, we can increase the sensitivity of the camera without compromising the sampling rate. Increasing the exposure time, however, is not a good solution because that would interfere with the sampling rate of the pulse signal.More importantly, our method requires adequate blood circulation in the finger to capture a strong pulse signal. To ensure an adequate amount of blood circulation in the finger, we provided a hand warmer for participants to warm their hands prior to measurement. Additionally, the participants’ perfusion index (PI) was checked using a pulse oximeter  before the data collection. If the PI ≤ 1%, the participants continue to warm their hands to raise the PI to above 1%.A key contribution of our work is that the design of this ultra-low cost blood pressure monitoring attachment is suitable for almost all smartphones on the market. The studies presented in this paper were conducted using the Google Pixel 4 smartphone, however, because BPClip only relies on the smartphone camera and flashlight, our approach is suitable for almost all phones. BPClip can be expanded to other smartphone models with minimal changes, as most phone models would only require changes in the distance between the flashlight and the camera. Our current design already takes that into account and uses a bend in the light guide to bring the flashlight to the finger from various distances.A limitation of our system, compared to a fully automated cuff is that the user needs to have a reasonable level of finger dexterity to be able to use BPClip as the user needs to be able to hold the index finger steadily while exerting various amounts of force. Therefore, for some older adults with weakened grip and/or hand tremors, it can be difficult to use BPClip. However, we find that our middle-aged participants had no trouble using the device.5Health monitoring should be available to everyone, no matter their country of origin, their skin tone, their sex, and most of all, their income. In this paper, we propose a solution to democratize blood pressure (BP) monitoring by converting the billions of smartphone cameras, even the cheapest ones, into BP monitors with an ultra-low-cost plastic clip that can be produced at-scale for mere cents. Our current prototype costs less than $1USD to manufacture at low quantities, but at scale, we expect that a blood pressure monitor will reach the cost of less than a US quarter. So cheap, in fact, our goal is that BP monitors should be provided to anyone who needs them, much like the way a pack of floss is given out at dentists or stress balls at fairs.


The results showed that the differences in BP between the arms had a strong positive relationship with CVD. Therefore, inter-arm blood pressure could be considered a marker for the prevention and diagnosis of CVD for physicians.The inter-arm blood pressure difference has been advocated to be associated with cardiovascular mortality and morbidity. Our study aimed to investigate the association between Inter-arm systolic and diastolic blood pressure differences and Cardio Vascular Disease (CVD). A total of 10,126 participants aged 35–70 years old were enrolled in a prospective Fasa Persian Adult Cohort. In this cross-sectional study, the cutoff values for inter-arm blood pressure difference were less than 5, greater than 5, greater than 10, and greater than 15 mm Hg. Descriptive statistics and logistic regression were used to analyze the data. Based on the results the prevalence of ≥ 15 mmHg inter-arm systolic and diastole blood pressure difference (inter-arm SBPD and inter-arm DBPD) were 8.08% and 2.61%. The results of logistic regression analysis showed that inter-arm SBPD ≥ 15 and (OR According to the latest guidelines for managing high blood pressure, blood pressure should be measured in both arms2. Inter-arm blood pressure difference can be easily measured in outpatient clinics3, and in most cases, there is a difference between the blood pressure of each arm4. 10 mmHg and above is defined as an increase in inter-arm SBPD difference5 and it can be found in more than 24% of healthy people6. Detection of this difference is important for diagnosing and treating hypertension7. The prevalence of inter-arm blood pressure difference varies in different populations and this difference tends to increase in the presence of high blood pressure8. The inter-arm blood pressure difference is reported in 7% of diabetic patients, and 11% in high blood pressure patients9. In a study conducted by Essa et al., inter-arm systolic blood pressure difference greater than 10 mmHg was observed in 26.1% of study participants3. In addition, this difference is more prevalent in those with a history of high blood pressure2. The results of the study conducted by Sharma et al. showed that 46% of the participants had a systolic blood pressure difference of 10 mmHg and more10. Based on previous studies, there is a positive and significant relationship between the inter-arm blood pressure difference and the occurrence of cardiovascular diseases12. In Iran, few studies with sufficient sample size have investigated the relationship between the difference in inter-arm systolic and diastolic blood pressure and the occurrence of cardiovascular diseases. Therefore, this study aimed to determine the relationship between Inter-arm systolic and diastolic blood pressure differences and CVD in Iran.Systolic and diastolic blood pressure are important risk factors for CVDThe current research data is related to Fasa Adults Cohort Study (FACS) data on 10,126 residents of Sheshdeh City, which is located 40 km from Fasa City. This longitudinal study is one of 22 ongoing cohorts in Iran, which is based on the population and aims to investigate the risk factors of cardiovascular diseases.The criteria for inclusion in the study are people over 35 to 70 years of age who have lived in the Shashada and Qarabalag region for at least 10 years and have consent to participate in the study, the exclusion criteria are people unable to answer questions and mentally and physically disabled.People were invited to participate in the study by telephone through a list that included people covered by each health center and provided to the staff. An average of 25 people were invited to the cohort center daily and demographic information, job type, physical activity level, information related to anthropometric examination , medical examination including oral and dental hygiene, blood pressure and the history of infectious and non-infectious diseases, biological samples including blood, hair, urine, and feces were recorded.Demographic information and socioeconomic status of people were collected by general interviewers, biological samples were collected by laboratory experts, and medical information was collected by five trained nurses. Resting heart rate and blood pressure were measured using calibrated devices in both arms consecutively after 15 min of rest and with a time interval of 5 min, and its average was recorded. Other medical information including the history of infectious and non-infectious diseases; Oral and dental hygiene and anthropometric measurements including  and duration of sleep in 24 h).In this cross-sectional study, the difference in systolic and diastolic blood pressure between the two arms was calculated, and individuals were grouped into 4 groups with blood pressure differences of less than 5, greater than 5, greater than 10, and greater than 15 mm Hg. Finally, the relationship between these groups of cardiovascular diseases was evaluated.Dependent variable: having cardiovascular diseases except for high blood pressure.Systolic and diastolic blood pressure differences between the two arms.2), waist circumference (WC), and non-alcoholic fatty liver.Gender, age, triglyceride glucose (TyG), triglyceride to high-density lipoprotein cholesterol (TG-HLD-C), smoking, opium use, diabetes, triglyceride (TG: mg/dl), high-density lipoprotein (HDL-c: mg/dl), depression, socioeconomic status, BMI (kg/mDescriptive statistics were reported in the form of a number (percentage) or mean ± standard deviation based on the presence or absence of CVD. An independent t-test was used to compare quantitative variables between the two groups, and a chi-score was used to examine the relationship between qualitative covariates and cardiovascular disease. Multiple logistic regression was used to investigate the relationship between the difference in systolic and diastolic blood pressure between the two arms and having cardiovascular diseases and to control the effect of other study covariates. All analyses consider a level of significance below 0.05. STATA version 14.0 . was used to analyze the data.Ethical issues including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc. were completely observed by the authors. This study was performed according to the ethical guidelines expressed in the Declaration of Helsinki and the Strengthening of the Reporting of Observational Studies in Epidemiology (STORB) guideline. The study was also approved by the Research Ethics Committee of Fasa University of Medical Sciences (IR.FUMS.REC.1401.144). Informed consent was also waived by the Research Ethics Committee of Fasa University of Medical Sciences (IR.FUMS.REC.1401.144).The prevalence of CVD in this study was 11.73%. Of the 10,126 participants in the study, 5283 (52.17%) were female. The majority of patients  were identified in the inter-arm SBPD < 5 mmHg group, followed by 96 (8.08%) patients who belonged to the inter-arm SBPD group ≥ 15 mm Hg. Also, inter-arm DBPD ≥ 10 mm Hg was reported in 146 (12.29%) patients. A few 31 (2.61) patients were inter-arm DBPD ≥ 15. The mean age (55.55 ± 9.17 years) and body mass index (26.47 ± 4.85) were raised in those with CVD. There were 443 (9.69%) male patients and 745 (13.41%) female patients. Out of the total  who had cardiovascular disorders, 289 (24.33%) and 189 (15.91%) patients presented with diabetes and Non-alcoholic fatty liver. Furthermore, people with depression are at increased risk of CVD compared to healthy (P < 0.05)  had a difference of ≥ 10 mm Hg (systolic BP), and about 5.04% (n = 511) were at high risk for CVD events (difference ≥ 15 mmHg). Regarding the difference in diastolic BP for both arms, it was observed that 8.21% (n = 832) had a difference of ≥ 10 mm Hg and where as 2.04% (n = 207) had a difference of ≥ 15 mm Hg. , while there was no significant association found between inter-arm SBPD ≥ 10  and inter-arm SBPD ≥ 5  with CVD.Table <5/≥10 = 1.518; 95%CI = 1.238–1.862; P < 0.001), while there was no significant association found between inter-arm DBPD ≥ 15  and inter-arm DBPD ≥ 5  with CVD.Table 2 .Hypertension is a well-known non-communicable disease that has received public health attention. High blood pressure screening using a blood pressure measuring device is one of the simplest and easiest methods to identify people with high blood pressure. However, the concept of measuring blood pressure in both arms to identify the difference in blood pressure has not yet been considered in public health. It is necessary to identify people who have a significant difference in blood pressure between the two arms to prevent cardiovascular diseases13 Therefore, consecutive measurement of blood pressure in each arm with a Sphygmomano is not correct. As a result, in recent studies, the difference in blood pressure between the arms is measured simultaneously with an automatic oscillometric device14 Accordingly, it is preferred to measure blood pressure simultaneously from both arms to obtain the blood pressure difference between the arms.In the previous cohort studies, the inter-arm blood pressure difference was determined by consecutive measurements rather than simultaneous measurements. By inflating the cuff on one side during measuring blood pressure, blood pressure increases in the opposite arm2 The results of the Seethalakshmi et al. study showed that 46% of the participants had an inter-arm SBPD of 10 mmHg or more and 35% of them had an inter-arm DBPD of 5 mmHg or more15 . Additionally, another study showed that 26.1% of the participants had an inter-arm SBPD of 10 mmHg or more16 . According to the studies, the difference in systolic blood pressure between the two arms is more observed in the elderly18 . Several studies have reported that in patients with inter-arm blood pressure differences, the blood pressure in the right arm is higher than in the left arm, which may be related to the anatomical difference in the left and right blood circulation19 .In this study, the prevalence of inter-arm SBPD is reported to be 10 mm Hg and more than in 43.5% of participants. Also, a diastolic blood pressure difference of 5 mmHg and more was observed in 57.2% of them. Due to the high prevalence of the blood pressure difference between the arms, it should be considered to measure blood pressure in both arms. These people are at risk of developing cardiovascular diseases in the future, so they need to be observed and followed up20 .The results of this study indicated that the inter-arm SBPD and DBPD between the arms was 15 mm Hg and more in 5.04% and 2.04% of the participants, respectively. According to the study of Kranenburg et al., 16% of the participants had an inter-arm systolic blood pressure difference of 15 mmHg or more21.In this study, the prevalence of cardiovascular diseases in women was significantly higher than in men. Based on current knowledge, it seems that the risk of cardiovascular diseases in women is increased compared to men due to factors such as diabetes, blood pressure, and obesity. Also, the occurrence of these diseases in women is influenced by socioeconomic and psychosocial factors. Therefore gender aspects should be more intensively considered23. Long-term drug use leads to changes in plasma fibrinogen levels, coagulation, atherosclerosis, development or exacerbation of coronary artery disease (CAD), hypertension, cardiac arrest, and stroke24.In this study, an inter-arm DBPD of more than 10 mmHg was associated with CVD, while an inter-arm DBPD of more than 15 mmHg was not. But with the increase in the inter-arm SBPD between the arms, the prevalence of CVD increased. The results of previous studies show that recently there is a significant difference between inter-arm SBPD and cardiovascular outcomes25 . The results of the meta-analysis study conducted by Clark et al. suggested that a blood pressure difference of 10 mmHg and more or 15 mm Hg and more is related to peripheral vascular disease26. Peripheral vascular disease has been identified as a risk factor for cardiovascular events and mortality due to it27. and based on studies conducted, peripheral vascular disease is the cause of the inter-arm SBPD between the two arms28. Also, it is notable that, a difference greater than 15 mm Hg is associated with evidence of carotid angiography or aortic artery disease and vascular disease caused by high blood pressure8. In addition, results from multiple logistic regression analysis demonstrated that inter-arm SBPD > 10 mm Hg was positively related to cardiovascular disease Risk factors including SBP and BMI, and negatively related to ankle-brachial index(ABI)17.The present study showed a significant relationship between substance use and cardiovascular disease, which is consistent with the results of other studies6. In addition, the difference in systolic blood pressure between the arms is related to all-cause mortality and cardiovascular diseases29. In a prospective study of 230 hypertensive patients who were followed up for 8–9 years, inter-arm SBPD was observed in 33% of the patients, and each millimeter of increase in this difference increased the mortality rate by 5–6%8.In a study with 6743 participants without a history of cardiovascular disease, the inter-arm SBPD of 15 mmHg and more was reported in 4.5% of participants, which was associated with the occurrence of cardiovascular disease20.In patients without specific cardiovascular disease, every 5 mm increase in the inter-arm SBPD increases the risk of vascular events by 12%. Also, this difference is related to the occurrence of stroke in the futures affects the inter-arm blood pressure difference but this relationship was not observed for blood lipid and blood-sugar-lowering medications30. In the present study, we could not consider this issue due to the missing and incompleteness of the type of medicine for CVD patients.Medicine in CVD patients can affect the inter-arm blood pressure difference. Miyashima et al. showed that the use of antihypertensive drugs in patients with CVDIn this study, the relatively large sample size ensured that the findings are to some extent representative of all Iranian adults. The cross-sectional nature of the study serves to provide evidence for the relationship between independent variables and CVD and does not establish causality. Also, due to missing information on the medicines of cardiovascular patients, we could not investigate their effect on the inter-arm blood pressure difference.Our findings suggest an association between inter-arm SBPD and CVD. After adjusting for covariates, we observed a relationship between inter-arm SBPD ≥ 15 and inter-arm DBPD ≥ 10 mm Hg with CVD. Hence, inter-arm blood pressure could be considered a marker for the prevention and diagnosis of CVD for physicians. It is worth mentioning that despite the recommendation of most guidelines to measure blood pressure in both arms, this measure has not yet been implemented in primary care. Therefore, it is necessary to measure blood pressure from both arms when measuring blood pressure for the first time, and detecting the difference in blood pressure between the arms can help in predicting the occurrence of cardiovascular diseases in the future.


Time-activity curves, as averaged standardized uptake values (SUVavg), were extracted from dynamic PET for spleen and liver. Maximum SUVavg, stress and rest spleen-to-liver ratio (SLR), and the splenic activity concentration ratio (SAR) were computed. Optimal cut-off values for SSO assessment were estimated from receiver operating characteristics (ROC) curve for maximum SUVavg and SLR. Also, differences between coronary artery disease, myocardial ischemia, beta-blockers, and diabetes were assessed. Data are presented as median [interquartile range].Thirty patients underwent H2O PET perfusion and used as a marker for adequate adenosine-induced vasodilatation response. In contrary to other PET perfusion tracers, adenosine-induced SSO is time dependent with [15O]H2O.SSO can be quantified from [ Adequat studies . Adenosi studies . However studies .13N]ammonia and rubidium-82 tracers with adenosine and dipyridamole for stressors [15O]H2O perfusion after adenosine stress [The SSO effect has also been previously described in PET perfusion imaging using [tressors –8. Objece stress . However15O]H2O PET perfusion imaging. We describe the feasibility and cut-off values of SSO in [15O]H2O perfusion for further use in clinical practice and research.In our study, we quantitatively assess the clinical utility of SSO as a marker for adequate vascular vasodilator response to adenosine stress on [15O]H2O PET perfusion at rest and adenosine stress at Helsinki University Hospital for evaluation of myocardial ischemia. A history of coronary artery disease, diabetes, hypertension, smoking, and hypercholesterolemia was collected from hospital records. The exclusion criteria were the inability to complete the standard PET perfusion protocol. Written informed consent was obtained from all participants. The study was performed according to the Declaration of Helsinki, and the study protocol was approved by the local ethics committee (HUS/1226/2019) and the Helsinki University Hospital’s institutional research board.The study population consisted of a retrospective cohort of 30 consecutive patients who underwent [15O]H2O myocardial PET perfusion protocol. The patients were instructed to abstain from caffeine for 24 h prior to the PET study. Sequential acquisition of helical low-dose computed tomography (CT) for attenuation correction and PET perfusion scans were performed using a digital 4-ring detector time-of-flight PET/CT system . Rest perfusion was performed first, and after a 10-min pause for radiotracer clearance stress perfusion was obtained. The target dose was 600 MBq per PET scan (range 416–715 MBq). A standard 6 min adenosine stress was used during the stress perfusion with radiotracer injection 2 min after the initiation of adenosine infusion at 140 µg/kg/min. The scan parameters were identical in both scans. List mode PET data were acquired and reconstructed as dynamic and divided into frames as 14 × 5 s; 3 × 10 s; 3 × 20 s; 4 × 30 s . PET images were reconstructed with the iterative Q.Clear algorithm  with 256 × 256 matrix size. The pixel size and slice thickness were set to 2.73 mm and 2.79 mm, respectively.All patients were imaged using a standard clinical  cm3) and spleen , and then activity concentration (kBq/ml) TAC as average values from the VOI region were exported in a tabular format (.csv).The assessment of SSO was done retrospectively for research purposes only from the time-activity curves (TACs) extracted from the dynamic PET data using Syngo.via  software’s MM Oncology package. Spherical volumes of interest (VOI) were manually drawn in the liver (mean: 116 cmSUVavg) using the administered tracer dose and patient weight. The following parameters were extracted from the SUVavg TAC: Time to peak SUVavg in rest spleen, Maximum SUVavg value from the spleen TAC, Spleen-to-liver SUVavg ratio (SLR) both during stress and rest (SLR = Maximum splenic SUVavg/Maximum liver SUVavg) and the splenic SUVavg ratio (SAR = Maximum splenic activityStress/Maximum splenic activityRest).Further processing of the ta TAC values was performed in Python v. 3.8 using custom codes. The average activity concentration values from PET data were transformed into average standardized uptake values  for the SSO assessment was available. However, in our patient population, the spleen maximum Quantitative global left ventricular myocardial perfusion values were obtained for rest and stress PET scans using Carimas™  software package . PET imaN = 30), a nonparametric Wilcoxon signed-rank test was chosen for comparison of stress and rest spleen SUVs at different time points and SLRs. TACs were used to evaluate the optimal time-points for quantification of the SSO phenomenon. Spleen rest TAC was compared with spleen stress TAC to evaluate the adenosine-induced SSO phenomenon during stress imaging. In addition, boxplot analyses were performed to investigate possible differences in SSO reaction in patients with diabetes, previously known coronary artery disease, or myocardial ischemia at PET perfusion. Boxplots displayed a sample median as horizontal line, a first and third quartiles as boxplot edges, whiskers, which were set to first quantile—1.5 ⋅ interquartile range and third quantile + 1.5 interquartile range, and outliers, i.e., values outside whiskers as circles. The statistical differences between these groups were assessed using Welch’s t-test. Correlations were analyzed using Pearson’s correlation.Continuous variables are reported as mean ± standard deviation (SD) and median [interquartile range] for normally distributed and skewed data. Categorical variables are reported as numbers and percentages. Due to sample size (A receiver characteristics operating curve (ROC) analysis was used to evaluate the optimal cut-off value to differentiate rest perfusion images from the stress perfusion. Area under ROC curve (ROC AUC), sensitivity, and specificity were calculated, and the optimal cut-off point was determined from Youden's index maximum.p < 0.001. All statistical analyses were conducted in Python using SciPy (v. 1.10.0) and Pandas (v. 1.5.2), scikit-learn (v.1.2.1) libraries [The limit for statistically significant differences was set to ibraries .15O]H2O PET perfusion imaging. Patient characteristics are shown in Table The study population consisted of 30 patients who underwent 5OH2O PETSUV values   and 1.57 (0.93 specificity and 0.9 sensitivity) for maximum SUVavg and SLR, respectively  was found between SLR and global myocardial blood flow (MBF)   patients with myocardial ischemia of which three patients had global balanced reduction in myocardial perfusion. These three patients received a diagnosis of diffuse atherosclerosis and/or microvascular disease and two of them showed SSO response as a lower maximum SUVavg and SLR in the spleen during stress.A strong negative correlation (BF) Fig. a. HoweveFR) Fig. b. There SAR and SLR  to the patients with positive SSO with adenosine stress [13N]ammonia PET  [13N]ammonia and rubidium-82 SLRStress values ≤ 0.92 and 0.71, respectively, were proposed as normal positive splenic response. We observed a quite similar SLRStress values (≤ 1.57) to the previous [13N]ammonia threshold. It should be noted that the [15O]H2O does not accumulate in the liver similar to[13N]ammonia and has relatively rapid perfusion as shown in Fig. SLRStress values were similar in [15O]H2O and [13N]ammonia, the dynamic kinetic process between the tracers is different which might affect the spleen-to-liver ratio comparisons.Previous studies have investigated the SSO effect on adenosine stress ) . For 13313Nammon13N]ammonia, high SUV values were reported for the spleen over a whole dynamic rest perfusion PET study (up to 7 min) compared to a stress study [15O]H2O is more rapid due to tracer wash out  hybrid imaging would be good modality to cross-validate SSO phenomenon and to evaluate our quantitative PET measures. We did not perform laboratory tests for blood caffeine levels in our study. Interestingly, one previous study showed that SSO imaging failed to detect the effect of caffeine consumption on splenic stress response, which should be explored further in another study using quantitative PET [15O]H2O PET perfusion. Three patients had balanced ischemia and received diagnosis of microvascular and/or diffuse atherosclerosis, and one of them had poor SSO, which confounded the assessment of coronary adenosine response. A larger patient cohort should be used to validate and assess the diagnostic implications of SSO thresholds derived from our study and assess its impact on patient management. The sample size of our study was small, and we cannot study small differences in quantitative SSO in coronary risk factors such as diabetes or peripheral atherosclerosis possibly affecting the portal blood flow. We were unable to study the associations between hemodynamic parameters, symptom severity, and SSO phenomenon during adenosine stress due to our retrospective study setting, and it should be explored in a further prospective study.The main limitation of this study was the lack of reference standard for PET measured SSO phenomenon. However, we included 30 clinical PET perfusion patients who were screened for caffeine consumption before imaging. Furthermore, comparison with CMR might be problematic due to the superior flow properties of H2O PET perfusion during adenosine stress. [15O]H2O tracer kinetics were rapid in the spleen, and the statistically significant differences found between rest and stress time-activity curves revealed that the splenic switch-off was most apparent at 40–160 s after tracer injection. In this study, spleen maximum SUVavg value < 12.6 and spleen-to-liver ratio < 1.57 were found as a simple and clinically useful thresholds to evaluate the adequate vascular response in adenosine stress.Splenic switch-off can be observed and quantitatively measured in [


Cerebral hyperperfusion syndrome (CHS) is a relatively rare but life-threatening complication following a carotid recanalization procedure. It was first described by Caplan in 1978 and still remains a matter of ongoing debate due to its vague definition, complex pathophysiology, and lack of cutoff points for defining hyperperfusion .CHS is traditionally considered to be a combination of clinical features with evidence of hyperperfusion and is defined as an increase in cerebral blood flow (CBF) of more than 100% over the baseline value .Although this complication occurs most often after carotid revascularization procedures, CHS has been associated with other procedures as well. It is possible to develop CHS after intracranial stenting, mechanical thrombectomy, high-flow superficial temporal artery to middle cerebral artery bypass, and cardiac procedures that augment cardiac output such as heart transplantation or congenital aortic stenosis , 5.The exact mechanism of this phenomenon is unclear, but it is thought that CHS is a result of impaired cerebral autoregulation. In settings of chronic low flow, due to severe carotid stenosis, cerebral autoregulation will result in maximum vasodilatation downstream. These vessels will eventually lose their ability to autoregulate and after the restoration of blood flow, it will not be able to constrict in response to systemic blood pressure increases, resulting in cerebral hyperperfusion, loss of vessel integrity, disruption of the blood–brain barrier (BBB), and eventually cerebral edema and/or intracerebral hemorrhage (ICH). Autoregulation disorder usually recovers within a few days to a few weeks, which overlaps with the occurrence of the syndrome; most cases of CHS will develop within the first few days, but delayed presentation is also possible .The incidence of CHS after recanalization procedures is reported to range from 1.16 to 4.6% in previous studies. This variability in incidence between studies is most likely due to different inclusion criteria and different definitions of CHS. A retrospective meta-analysis of 13 studies, including 4,689 patients undergoing carotid endarterectomy (CEA), revealed that cerebral hyperperfusion, which is defined as an increase in flow without any clinical symptoms, hyperperfusion syndrome, and ICH occurred in 12.5, 1.9, and 0.37% of patients, respectively , we can also reduce CBF –10.Although it is quite clear that BP treatment is the mainstream in preventing CHS progression, there are no clear guidelines for BP regulation in these patients. It is considered optimal to maintain BP below 140/90 mmHg, and in a high-risk group (listed below) even below 120/80 mmHg. Few studies have shown that reducing the BP until CHS symptoms resolve, even to the level of induced hypotension, is safe and effective in eliminating the occurrence of ICH . TherefoDifferent imaging modalities could be used to detect or screen patients for CHS. Cerebral perfusion imaging, such as single-photon emission computed tomography (SPECT), CT perfusion, or perfusion-weighted imaging, enables us to directly estimate CBF , 5. ThesOne of the most available and most commonly used is transcranial color Doppler (TCD) . TCD monThe utility of TCD monitoring for the evaluation and prediction of CHS was investigated in multiple studies . DiffereAt first, studies were focused on intraoperative MCA blood flow velocity measurements, usually at 2- or 3-time points  .An increase in MCA blood flow velocity or PI >100% over the baseline values, immediately after the restoration of the flow, was considered a hemodynamic definition of cerebral hyperperfusion, and this cutoff value was used to identify high-risk patients for the development of CHS .However, this cutoff point for hyperperfusion is completely arbitrary, and few researchers have recently questioned its validity for routine clinical practice. They have demonstrated that more than 50% of patients would have been underdiagnosed if this traditional definition of CHS to be used .Moreover, intraoperative MCA velocity measurements yielded the lowest positive predictive value (PPV) for the detection of CHS, ranging from 8 to 18 % in different studies –19. ThisIn 2015, the velocity blood pressure index (VBI) was introduced as a new prognostic parameter for CHS. This parameter combines BP and velocity changes in the perioperative phase. VBI cutoff value of 2 yielded a sensitivity of 83.3% and a PPV of 62.5% in predicting CHS development, but this has not yet been validated in a larger study  will help to more precisely identify high-risk patients for CHS . One stuMany open questions regarding CHS remain, but it is clear that the early recognition and treatment of CHS are crucial to prevent devastating complications such as ICH. Therefore, we need to have a high level of awareness for CHS in every patient undergoing a revascularization procedure, especially in a high-risk group. TCD is considered the most suitable imaging modality for monitoring these patients, primarily because it provides us with real-time information on CBF and can be repeated as many times as needed.However, validated TCD protocols for the detection and prediction of CHS are still lacking, thus an individual approach to each patient is needed. Once hyperperfusion has been established, we should monitor our patients more closely and treat them appropriately, until the symptoms resolve and blood flow normalizes. We should not use strict cutoff values of CBF to establish the diagnosis of hyperperfusion because this may lead to the underdiagnosis and undertreatment of these patients. In addition, we should not try to predict CHS based on single TCD measurements. Any patient at risk of developing CHS requires an individual approach with vigilant monitoring and careful therapeutic decision-making based on MCA velocity dynamics, BP values, and clinical context.Finally, we emphasize the need for continued research in this area, preferably through a larger multicenter prospective study that would provide a significant number of patients, give a better insight into the dynamics of these patients, and perhaps shed some new light on this complex issue.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Background: The aim of this study was to assess the prevalence, characteristics, and determinants of apparent treatment-resistant hypertension (aTRH) in an unselected large population of patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD) throughout the country. Methods: A database of 5879 patients  was obtained from the biggest provider of hemodialysis in the country. Hypertension and aTRH were defined using pre- or/and post-dialysis BP values. Patients with and without aTRH (non-aTRH) were compared. Results: Using pre- and post-dialysis criteria, hypertension was diagnosed in 90.7% and 89.1% of subjects, respectively. According to pre- and post-dialysis blood pressure criteria, aTRH incidences were 40.9% and 38.4%, respectively. The hypertensive patients with aTRH versus non-aTRH were younger, had a higher rate of cardiovascular disease, lower dialysis vintage, shorter time on dialysis, higher eKt/V, higher ultrafiltration, higher pre- and post-dialysis BP and HR, and higher use of antihypertensive drugs. Factors that increase the risk of aTRH according to both pre- and post-dialysis BP criteria were age—OR 0.99 [0.98–0.99] and 0.99 [0.98–0.99], the history of CVD 1.26 [1.08–1.46] and 1.30 [1.12–1.51], and diabetes 1.26 [1.08–1.47] and 1.28 [1.09–1.49], adjusted OR with 95% CI. Conclusions: In the real-life world, as much as 40% of HD patients may have aTRH. In ESKD HD patients, aTRH seems to be multifactorial, influenced by patient-related rather than dialysis-related factors. Various definitions of aTRH preclude easy comparisons between studies. What is already known about this subjectHypertension is the most common finding in hemodialyzed patients; however, data based on large cohorts are limited.The currently established definitions of resistant hypertension are not directly applicable to the end-stage kidney disease setting.Apparent true resistant hypertension prevalence is unknown, and target blood pressure in patients on hemodialysis is still a matter of debate.What this study addsApparent treatment-resistant hypertension, defined as uncontrolled blood pressure on three or more antihypertensive medication classes or the use of four or more medications regardless of blood pressure level, affects as much as 40% of HD patients in real-world settings.What impact this may have on practice or policyDetermination of how and when blood pressure should be measured in the group of dialysis patients.Revision of target blood pressure values in this group of patients is to be considered, as well as the definition of resistant hypertension or, rather, switch to apparent treatment-resistant hypertension is to be recommended.Apparent treatment-resistant hypertension seems to be multifactorial, influenced by patient-related rather than dialysis-related factors; therefore, using standardized procedures may help to manage it.Hypertension (HTN) affects the great majority of end-stage kidney disease (ESKD) on hemodialysis (HD), with a prevalence ranging from 82 to 89% depending on the criteria and technique of blood pressure (BP) measurement ,2,3.According to the current guidelines, treatment-resistant HTN (TRH) is defined in the general population as uncontrolled blood pressure on three or more antihypertensive drugs in adequate doses or when patients on four or more antihypertensive drug categories irrespective of the BP control, providing that antihypertensive treatment included diuretics ,5.True TRH occurs in 10–20% of people with hypertension ,7. DemogThe currently established definitions of resistant hypertension are not directly applicable to the ESKD setting . The diaSince most epidemiological studies lack the key elements  to define true resistant hypertension, an additional category of HTN was proposed—namely, apparent treatment-resistant hypertension. According to American Heart Association, apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled blood pressure with concurrent use of three antihypertensive medication classes or four or more antihypertensive medication classes regardless of blood pressure level when pseudoresistance cannot be excluded .The prevalence of aTRH in the general population of patients with hypertension is estimated to be 0.5–14% and 1.6–42% in pre-dialysis chronic kidney disease (CKD) patients ,13,14,15In our recent review , we discTherefore, the aim of this study was to assess the prevalence, characteristics, and determinants of aTRH in an unselected large population of patients with ESKD treated with HD throughout the country.We performed a retrospective analysis of a fully anonymized database of 5879 unselected, consecutive prevalent patients  receiving hemodialysis from the biggest provider of hemodialysis in non-tertiary centers in Poland. The database included demographic data, the etiology of CKD, data on concomitant diseases and antihypertensive medication groups, pre- and post-dialysis BP and HR, and data regarding HD. Patient history and physical examination were generally used to assess the optimal target dry weight. The patients were questioned about interdialytic symptoms that suggested orthostatic hypotension (such as lightheadedness) and intradialytic symptoms such as muscle cramps. The reduction in dry weight was performed gradually. The target weight was reduced over days to weeks; the older the patient, the longer period of time was needed to achieve dry weight (in some cases up to 12 weeks). The target dry weight was reduced by 0.5 L per session. In patients who are unable to tolerate this, 0.2 L per session was attempted. If increasing the dialysis time was ineffective, the dialysate sodium concentration was reduced. The dialysate sodium was reduced gradually  to approximately 136 mEq/L. To assess volume status, body composition has been checked every 12–13 weeks by using a bioimpedance measurement device body composition monitor (BCM) as required by dialysis unit rules.We analyzed the database updated on 6 October 2022, which included averaged data from a full 4-week period from 29 August 2022 to 25 September 2022.The characteristics of the patients are depicted in BP measurements were performed by a dialysis nurse using a free-standing BP cuff in the sitting position according to the current guidelines using only sphygmomanometers that were certified and periodically validated by hospital technical authorities. We define hypertension and aTRH in each subject using two separate BP criteria, pre- or post-dialysis BP values. The normotension was defined as BP < 140/90 mm Hg in patients not using antihypertensive treatment. Hypertension was defined as BP ≥ 140/90 mm Hg and/or using antihypertensive medication.Apparent treatment-resistant hypertension was defined as BP ≥ 140/90 while on 3 or more antihypertensive drugs or using 4 antihypertensive drugs, irrespective of BP values.We adopted the definition used for the general population of hypertensives. This definition does not include volume status.We analyzed the frequency of hypertension in the studied population according to these above-mentioned criteria. In patients with hypertension, we assessed the incidence of aTRH using pre- and post-dialysis BP values. We compared the hypertensive patients with aTRH and without aTRH (non-aTRH). The comparison included demographic data , BMI, data on concomitant diseases . Cardiovascular disease (CVD) was defined as the diagnosis of at least one of the following: heart failure, coronary artery disease, peripheral artery disease, and cerebrovascular disease.t-test. Categorical variables were compared using the chi-square test.Group differences in continuous variables were calculated using the We calculated unadjusted and adjusted odds ratios with 95% CI for risk factors for the presence of aTRH that included age, sex, BMI, CVD history, diabetes mellitus, dialysis vintage, effective weekly treatment time, eKt/V, and ultrafiltration.https://www.r-project.org) (accessed on 1 August 2023).Risk estimates were calculated using a multivariable logistic regression model with binary outcomes for aTRH. The statistical analysis of the data was performed using R  according to pre-dialysis BP criteria and by 5240 pts. (89.1%) according to post-dialysis BP criteria. The characteristics of all patients, and those with/without hypertension, are presented in The incidence of aTRH according to pre-dialysis BP criteria was 40.9%, and 38.4% according to post-dialysis BP criteria. The hypertensive patients with aTRH compared with the non-aTRH group were younger and more frequently men; had higher BMI and Charlson comorbidity scores; higher frequency of CVD, congestive heart failure, cerebrovascular disease, and diabetes; lower dialysis vintage; shorter time on dialysis; higher eKt/V; higher ultrafiltration rates; higher pre- and post-dialysis BP values; lower pre- and post-dialysis heart rates; and higher use of antihypertensive drugs disregarding the criteria of aTRH used. The comparison of these groups is depicted in However, the multivariate analysis revealed that the only significant, independent factors that increase the risk of aTRH were lower age, higher BMI , a history of CVD, and diabetes .It has been reported that over 50 to 60 percent of hemodialysis patients (up to 85 percent in some reports) and nearly 30 percent of peritoneal dialysis patients are hypertensive ,19,20,21In the classical study performed on 369 HD patients in the US, Agarwal et al. noted that hypertension control assessed with 44 h ABPM was achieved only in 38% of patients receiving antihypertensive drugs; however, the authors did not assess aTRH . In anotHowever, the estimated prevalence of aTRH in patients with HD reported in recent studies was lower ,18. Tana2 from two large US health care systems by An et al. estimated aTRH for 23–55% depending on the definition [The Chronic Renal Insufficiency Cohort (CRIC) study that included 3367 hypertensive non-dialysis CKD patients revealed the high prevalence of aTRH assessed for 40.4% , and anafinition .The aTRH incidence estimation in ESKD patients may be confounded by numerous factors, including the selected population, the method of BP estimation, and the cut-off values for uncontrolled BP.A potential limitation of our study was using peridialytic BP measurements instead of 44h ABPM. The diagnosis of resistant hypertension requires the confirmation of poor BP control with ABPM . AlthougAlthough standardized BP measurement is recommended in CKD patients by the current KDIGO guidelines, the specific recommendations for ESKD patients on dialysis are still lacking . TraditiInterdialytic BP measurements, compared with peridialytic recordings, correlate better with target organ damage  and are Data from a study by the European Cardiovascular and Renal Medicine (EURECA-m) working group of the ERA-EDTA published in the Sarafidis et al. study comparing pre-hemodialytic BP and 48 h ABPM in 396 HD patients revealed a similar incidence of hypertension assessed by these two techniques (89.4% versus 84.3% respectively) and a similar percentage of the patients with controlled BP (28.2% versus 28.7% respectively), but the BP status was misclassified in about 1/3 patients due to white-coat hypertension (18.2%) and that of masked hypertension (14.1%) [However, in the analysis based on the European Renal and Cardiovascular Medicine (EURECA-m) registry, pre-dialysis BP fairly well identified TRH compared with 44 h ABPM with high sensitivity (87%) and very high specificity (99%), and the discriminatory power of pre-dialysis BP for the same diagnosis was good  .The good discriminatory value of pre-dialysis BP was explained by the authors by the fact that patients with TRH represent a subpopulation with BP values well above the hypertension thresholds of the two BP metrics , and for this reason, TRH patients were less frequently misclassified by pre-dialysis BP . Of noteThe use of a lower cut-off obviously increases the incidence of aTRH. Vareta et al. reported an increase in aTRH prevalence from 30% to 32.1% (for ABPM 130/80 vs. 125/75 mmHg and 27.9% to 32.9% (for office BP 140/90 vs. 130/80 mmHg) in ESKD patients treated with PD .Most patients show a progressive increase in BP during the interdialytic interval and a gradual decline during the dialysis session, whereas a minority (5–15%) present a BP rise during or immediately after the dialysis session .In a classical meta-analysis of Agarwal et al.  comparinTherefore, to minimize the potential discrepancies between them, we used both timepoints to assess BP to minimize the potential influence in the aTRH incidence assessment. Not surprisingly, the estimated aTRH incidence in our cohort with the use of pre-dialytic BP values was higher compared to the post-dialytic BP; however, the difference was small.It is worth mentioning that most previous studies used only pre-dialytic BP, and in some studies, the exact timing of peridialytic BP measurement is not provided .We are aware that the BP assessment in the peridialytic period in ESKD patients may encounter numerous methodological difficulties resulting from the presence of arteriovenous fistula or former multiple vascular access surgeries (preventing BP measurement on both or any arm), anxiety and discomfort during dialysis and severe vascular calcifications .Studies assessing aTRH incidence among ESKD patients on HD are scarce and often performed on a limited number of patients from selected centers, often tertiary centers participating in multicenter studies. The discrepancy in the aTRH incidence in HD may result also from the differences in the population studied. Preselection bias is an important issue since aTRH occurs in a higher percentage of the population- and clinic-based samples when an at-risk group is selected and among treated hypertensive adults in clinical trials, which is likely explained by the selection of patients with demographic and comorbidity characteristics that place them at high risk for the fatal and nonfatal CVD outcomes of interest . PatientOur cohort is similar to that of Mallamaci et al. study regarding age and gender distribution, BMI, CVD, and diabetes incidence . HoweverDue to residual renal function loss and anuria, diuretics have limited effectiveness in dialysis patients ,38. SomeSince most studies did not include the assessment of the volume, many of the patients classified as aTRH may have had volume-mediated hypertension and no true resistance to antihypertensive treatment ,16,18,19Risk factors for the development of TRH in the general population of patients with HTN include older age, obesity, diabetes, smoking, increased dietary sodium intake, heart and kidney failure, and long duration of hypertension ,39.The strengths of our study were a high volume of unselected patients representing 30% of all dialyzed in the country according to the standard protocol using the same hardware by one of the largest European providers. To our knowledge, our cohort presents the largest one among studies assessing aTRH in ESKD treated with HD. We are fully aware that BP medication compliance is difficult to ascertain, and some assessment of medication compliance should be introduced. Prescription of hypotensive medication is feasible to assess; however, there is no possibility to cross-check the prescription with pharmacy delivery of these drugs. A body composition monitor is used to assess the volume status on a regular basis, i.e., every 12–13 weeks, to adjust dry weight and ultrafiltration rate.The limitations are the lack of the ABPM and compliance assessment as well as some clinical features potentially increasing the risk of aTRH, including duration of hypertension, smoking habits, target organ damage, dietary sodium intake, and volume assessment.We are aware that including both the Charlson score and some of its components  in the model may be considered over-adjustment. However, despite the potential collinearity of the data in the model, age, cardiovascular disease, and diabetes were still statistically significant covariates.Our study suggests that in the real-life world, using pre- and post-dialysis BP values, as much as 40% of HD patients may have aTRH. In ESKD patients treated with HD, aTRH seems to be multifactorial, influenced by patient-related factors rather than dialysis-related factors. Various definitions of aTRH preclude easy comparisons between studies. We could suspect that if the chronic HD units ensured medication compliance and fully lowered fluid volume, the prevalence of resistant hypertension would be very much less than the 38–40% found in our population, and maybe it contributes to lowered all-cause and/or cardiovascular mortality.


There has been conflicting evidence on the association between multimorbidity and blood pressure (BP) control. This study aimed to investigate this associations in people with hypertension attending primary care in Canada, and to assess whether individual long-term conditions are associated with BP control.This was a cross-sectional study in people with hypertension attending primary care in Toronto between January 1, 2017 and December 31, 2019. Uncontrolled BP was defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. A list of 11 a priori selected chronic conditions was used to define multimorbidity. Multimorbidity was defined as having ≥1 long-term condition in addition to hypertension. Logistic regression models were used to estimate the association between multimorbidity  with uncontrolled BP.A total of 67 385 patients with hypertension were included. They had a mean age of 70, 53.1% were female, 80.6% had multimorbidity, and 35.7% had uncontrolled BP. Patients with multimorbidity had lower odds of uncontrolled BP than those without multimorbidity . Among the long-term conditions, diabetes , heart failure , ischemic heart disease , schizophrenia , depression/anxiety , dementia , and osteoarthritis  were associated with a lower likelihood of uncontrolled BP.We found that multimorbidity was associated with better BP control. Several conditions were associated with better control, including diabetes, heart failure, ischemic heart disease, schizophrenia, depression/anxiety, dementia, and osteoarthritis. Globally, blood pressure (BP) control is still suboptimal, with control rates of approximately 20% for people with hypertension. Poor BP control can increase the risk of heart failure, coronary heart disease, peripheral artery disease, renal failure, stroke, and dementia, and therefore, increase the risk of developing multimorbidity in people with hypertension. Multimorbidity, defined as having 2 or more chronic conditions, has become a primary healthcare concern.5Hypertension is a risk factor for cardiovascular disease and other chronic health conditions. The prevalence of hypertension increases with age, with a prevalence of only 27% in people younger than 60 years, but 74% in people aged 80 years and older. A systematic review of 45 studies showed that the overall prevalence of multimorbidity was 66.1% (when multimorbidity was defined as having ≥2 chronic conditions), and 44.2% (when multimorbidity was defined as having ≥3 chronic conditions) in older adults in high-income countries. In the United States, 81 million adults were estimated to have multimorbidity in 2020. In Canada, the prevalence of multimorbidity is also high, with a reported prevalence ranging from around 30% to 70% in primary care settings, and around 17% to 59% in the general population. Multimorbidity increases healthcare costs and healthcare utilization including hospitalizations.11Two out of 3 people with hypertension have additional long-term condition.17 While some studies show that the presence of multimorbidity was positively associated with BP control,16 other studies suggested that people with more comorbidities had poorer management and control of hypertension.17 There is minimal evidence of this association in the Canadian population. Therefore, this study aimed to investigate the association between multimorbidity and BP control in patients attending primary care in Canada, and to assess if individual comorbidities are associated with BP control.Several studies have examined the impact of multimorbidity on BP control, and there has been conflicting evidence on the association between multimorbidity and hypertension control. Data include de-identified patient-level information on various factors including demographics, medical diagnoses, procedures, medications, immunizations, laboratory test results, vital signs, risk factors, and clinical notes.This study used data from the University of Toronto Practice-Based Research Network (UTOPIAN), a primary care electronic medical records (EMRs) database. The UTOPIAN database contains de-identified records from participating family medicine clinics in Ontario, Canada, with most providers practicing in the Greater Toronto Area.This is a cross-sectional study using the UTOPIAN 2021Q4 database with a start date of January 1, 2017 and an end date of December 31, 2019. This end date was chosen to avoid the COVID-19 pandemic-related effects on the data. We identified a cohort of patients who met the following selection criteria; had hypertension before December 31, 2019; had blood pressure recorded between January 1, 2017 and December 31, 2019; and were at least 45 years old when their blood pressure was measured. Supplemental Appendix 2):We defined the hypertension phenotype using the following criteria (Free text documentation of hypertension was found within the (past or present) health condition section of the cumulative patient profile, including the following terms: hypertension, hypertensive, htn; ORAnti-hypertensive medication was prescribed and an elevated blood pressure reading was recorded at any point in the EMR (elevated blood pressure reading is defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg); ORAnti-hypertensive medication was prescribed and a billing record with the diagnosis code for hypertension (ICD-9 code 401) was recorded at any point in the EMR; ORA billing record with the diagnosis code for hypertension (ICD-9 code 401) and an elevated blood pressure reading was recorded at any point in the EMR (elevated blood pressure reading is defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg)20 A list of 11 a priori selected chronic conditions was used to define multimorbidity, in alignment with the Centers for Disease Control and Prevention (CDC) recommendations for defining and measuring multiple chronic conditions when using Medicare claims. These long-term condition are: ischemic heart disease, heart failure, atrial fibrillation, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, cancers, osteoarthritis, dementia, depression and/or anxiety, and schizophrenia.Multimorbidity was defined as having 1 or more long-term conditions in addition to hypertension. This definition of multimorbidity is similar to definitions used in other studies (REFs).We used the most recent information on Body Mass Index (BMI) and smoking status as of December 31, 2019. BMI was grouped into underweight (≤18.4), normal (18.5-24.9), overweight (25.0-29.9), obese class I (30.0-34.9), obese class II (35.0-39.9), and obese class III (≥40.0). We calculated age (in years) on the date when the blood pressure measurement was recorded between January 1, 2017 and December 31, 2019. We used rurality and neighborhood income quintiles (as an indicator of socioeconomic status) using data from the 2016 Statistics Canada Census.Supplemental Appendix section (i), along with the algorithm used to determine the presence of hypertension in EMRs ).We identified different classes of hypertension medication (including angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blocker (ARBi), calcium channels, beta-blockers, diuretics, and other classes of hypertension medication) that were prescribed during the 6 = months prior to the blood pressure measurement. The full description of drug names for each class of hypertension medication is provided in  The SBP treatment goal is a pressure level of <140 mm Hg (Grade C). The DBP treatment goal is a pressure level of <90 mm Hg (Grade A). These targets were established using Office-based BP Measurements (OBPM). For patients with multiple BP readings recorded on the same day at the same visit , we took the average measurement of the systolic and diastolic blood pressure measures on that day.The primary outcome measurement was the most recent BP measure recorded during the study period . Uncontrolled BP was defined as having either systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg for the last BP measurement prior to December 31 2019. The BP treatment target was chosen to align with the Hypertension Canada’s 2016 Canadian hypertension education program guidelines for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension that reflected the practice during the study period. and the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults.We also conducted a sensitivity analysis, with a BP target of <130/80 mmHg, as recommended by the 2018 ESC/ESH Guidelines for the management of arterial hypertension,t-tests for continuous covariates.We used descriptive statistics to summarize patient demographics and clinical characteristics associated with controlled and uncontrolled blood pressure. We used means, standard deviations, and median, minimum and maximum to summarize continuous variables, while frequencies and percentages were used to summarize categorical variables. To reduce the risk of re-identification, our reports exclude any cell count of 5 or fewer. Comparisons between patients with controlled and uncontrolled BP were assessed using Pearson’s chi-square tests for categorical covariates and using 2-sample Supplemental Figure 1). In GEE models, we adjusted for the following covariates: age, sex, income quintiles, smoking status, BMI, number of primary care visits, along with the multimorbidity status.We fitted logistic regression models using the Generalized Estimating Equations (GEE) with an exchangeable working correlation matrix to assess the association between multimorbidity  on uncontrolled BP. We reported both the unadjusted odds ratios (OR) and adjusted odds ratios. To account for multicollinearity, we fitted separate logistic models using GEE for multimorbidity and different comorbidities, respectively. We a priori specified age, sex, income quintiles, smoking, and BMI as potential confounders  for multimorbidity and for the outcome of BP control, while different classes of hypertension medications were considered potential mediators on the pathway between multimorbidity and BP control  and excluded BMI and smoking status in the regression models to include patients that did not have BMI or smoking status recorded.This study was approved by the Research Ethics Board at the University of Toronto (protocol number 00043354).A total of 67 385 patients who satisfied the selection criteria were included in this study. Patients in the sample had a mean age of 70.1 years (SD = 11.8) and 53.1% were female. The prevalence of overweight and obesity was 66%, with a greater proportion of patients with class II and class III obesity in the uncontrolled BP group compared to the controlled BP group. There was no difference in socioeconomic status between the 2 groups .Supplemental Table 2). As an example, 8.0% of the patients with multimorbidity had more than 9 visits in 2019 compared to 1.9% of patients without multimorbidityThe overall prevalence of multimorbidity was 80.6%. Patients with multimorbidity had a higher number of annual primary care visits than patients without multimorbidity in 2017, 2018, and 2019 (P < .001). Overall, 35.7% of patients had uncontrolled BP . Younger patients had lower odds of having uncontrolled BP than older patients. Obese patients  had higher odds of uncontrolled BP than those with normal BMI. Current smokers had higher odds of having uncontrolled BP compared to non-smokers. Increasing number of visits to primary care doctors was associated with lower odds of uncontrolled BP .Among the long-term conditions, 7 conditions were significantly associated with lower likelihood of uncontrolled BP: diabetes , heart failure , ischemic heart disease , schizophrenia , depression/anxiety , dementia , and osteoarthritis . The remaining long-term conditions  were not associated with uncontrolled BP .Supplemental Tables 3 and 4).Sensitivity analyses showed consistent results , adjusting for age, sex, income quintiles, body mass index, and number of visits.Our analysis in 67 385 Canadians aged 45 years or more with hypertension attending primary care from 2017 to 2019 showed that multimorbidity was associated with approximately 30% lower odds of uncontrolled BP. The individual long-term conditions that were significantly associated with lower likelihood of uncontrolled BP include diabetes, heart failure, ischemic heart disease, schizophrenia, depression/anxiety, dementia, or osteoarthritis. found that multimorbidity was positively associated with BP control among participants with hypertension in the UK Biobank, and the types of comorbidities that were significantly associated with controlled BP included cardiovascular disease , diabetes , migraines , and depression . Another study conducted by Sarkar et al in 31 676 patients with hypertension in primary care in the UK, found that 16 140 (51 %) had multimorbidity, and hypertensive patients with multimorbidity had lower BP than those with hypertension alone. Mini et al also reported that blood pressure control was better in participants who reported any comorbidity  compared to those who did not report any. However, several other studies reported the opposite findings—people with more comorbidities had poorer management and control of hypertension. In a study of 223 286 patients with hypertension in Hongkong, Wong et al found that the proportion of patients having poor BP control increased from 35.0% to 65.0% and 69.1% when the number of medical conditions increased from 0 to 1 and 2, respectively. However, this study enrolled adult patients prescribed their first antihypertensive agents; hence people with comorbidities  who were already on a relevant medication  for these reasons would be excluded from the hypertension cohort. A cross-sectional analysis of the World Health Organization Study of Global Ageing and Adult Health (WHO SAGE) Wave 1 (2007-2010) in 41 557 adults (9778 with hypertension) from 6 middle-income countries  reported that more comorbidities were associated with increased odds of uncontrolled hypertension.Our finding aligns with other studies that examined this association, which reported that multimorbidity was one of the strongest predictors of controlled BP in patients with hypertension. Tapela et al28A possible explanation that would account for the lower odds of uncontrolled hypertension in patients with chronic conditions like diabetes, heart failure, ischemic heart disease, schizophrenia, depression/anxiety, or osteoarthritis may be explained by the fact that patients with these conditions tend to have frequent doctor visits. As with dementia, some studies showed that dementia was associated with lower blood pressure.The results from this study may reflect the achievement of primary care in controlling cardiovascular risk factors in patients with multimorbidity, including regular BP measures and treatment. Comorbidities may be associated with more frequent healthcare utilization and hence increase the monitoring of chronic conditions, including BP measurement and counselling on lifestyle modifications and medication adherence. Another explanation could be the study’s participation selection processes. Among people with hypertension as their only chronic health condition, those with poorer BP control may be more motivated to attend primary care and hence were included in this cohort. Thus, the observed associations could be explained by selection bias—hypertensive patients with no comorbidities, but uncontrolled BP may have been more likely to seek primary care compared to hypertensive patients with no comorbidities and controlled BP. These lead to opportunities to measure BP and obtain scripts, reminders given to them on taking medications, and better lifestyle modifications.This study has several strengths. To the best of our knowledge, it is the first study reporting the association between multimorbidity and blood pressure control in Canada. The study is based on detailed clinical data. It is grounded in real world data from routine primary care practices. The large sample size of this study provides sufficient statistical power, allowing for point estimates with precise confidence intervals.The study data was only collected from patients in Ontario and is not nationally representative. We might be unable to capture all cases of hypertension and/or prescriptions of anti-hypertensive medications in the EMR data. Duration and severity of hypertension, and lifestyle modification, an essential strategy in the management of hypertension and can influence BP control, could not be captured through the EMR data. In addition, BP control was defined based on BP measurement at the clinics, which may be influenced by the white coat effect. Therefore, results should be replicated and cautiously interpreted before generalizing to all patients in primary care.In this large-scale study of patients attending primary care with hypertension, multimorbidity was associated with better BP control. Several long-term conditions were associated with better control, including diabetes, heart failure, ischemic heart disease, schizophrenia, depression/anxiety, dementia, and osteoarthritis. Further large‑scale studies are needed to explore the mechanisms underlying the associations between multimorbidity and BP control, and to understand barriers to BP control in primary care.Click here for additional data file.Supplemental material, sj-docx-1-jpc-10.1177_21501319231215025 for Multimorbidity and Blood Pressure Control in Patients Attending Primary Care in Canada by Tu N. Nguyen, Sumeet Kalia, Peter Hanlon, Bhautesh D. Jani, Barbara I. Nicholl, Chelsea D. Christie, Babak Aliarzadeh, Rahim Moineddin, Christopher Harrison, Clara Chow, Martin Fortin, Frances S. Mair and Michelle Greiver in Journal of Primary Care & Community Health