We also assessed the relationship between the change of rSO2 and the changes of mean arterial blood pressure (MAP), heart rate (HR), arterial carbon dioxide tension (PaCO2), arterial oxygen tension (PaO2), or arterial oxygen saturation (SaO2).We evaluated the change of cerebral regional tissue oxygen saturation , every 5 min after the onset of pneumoperitoneum, before the Trendelenburg position. After the onset of the Trendelenburg position, rSO2, MAP, HR were recorded at 5, 10, 20, 30, 45, and 60 min, and PaCO2, PaO2, and SaO2 were measured at 10, 30, and 60 min.Forty-one adult patients who underwent a robotic assisted endoscopic prostatic surgery under propofol and remifentanil anesthesia were involved in this study. During the surgery, a pneumoperitoneum was established using carbon dioxide. Measurements of rSO2 were 67.9 ± 6.3% and 68.5 ± 7.0%. Ten minutes after the onset of pneumoperitoneum, significant increase in the rSO2 was observed . During the Trendelenburg position, the rSO2 increased initially and peaked at 5 min , then decreased. Multiple regression analysis showed that change of rSO2 correlated with MAP and PaCO2.Before the pneumoperitoneum, left and right rSOPneumoperitoneum and the Trendelenburg position in robotic-assisted endoscopic prostatic surgery did not worsen cerebral oxygenation. Arterial blood pressure is the critical factor in cerebral oxygenation.UMIN000026227 (retrospectively registered).Japan Primary Registries Network (JPRN); UMIN-CTR ID;  In robotic-assisted endoscopic prostatic surgery, a carbon dioxide pneumoperitoneum and the Trendelenburg position are essential. In the pneumoperitoneum and the Trendelenburg position, intracranial pressure was reported to increase . In addi2) using near infrared spectroscopy can allow to assess cerebral circulation [Measurement of cerebral regional tissue oxygen saturation values , arterial carbon dioxide tension (PaCO2), arterial oxygen tension (PaO2), or arterial oxygen saturation (SaO2).We tested the following hypotheses. Firstly, rSOThis study was approved by the institutional review board of University of Yamanashi (study No. 488), and and was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) under study number UMIN000026227. Written informed consent was obtained from all patients.2. A pulse oximeter was used to monitor percutaneous arterial oxygen saturation (SpO2). A bispectral index (BIS) sensor was also attached on the forehead . An earphone-type infrared tympanic thermometer  was used to monitor body temperature. Non-invasive arterial blood pressure, HR, rSO2, SpO2, and body temperature were measured before induction of general anesthesia while the patient breathed room air . Fluid was infused at 6 ml/kg/hr. Anesthesia was induced and maintained with propofol using target controlled infusion and remifentanil. Tracheal intubation was facilitated with rocuronium. After the induction of anesthesia, radial arterial catheter was placed to allow continuous monitoring of MAP and blood gas analysis . The patient’s lungs were mechanically ventilated in a volume controlled mode  with a positive end-expiratory pressure of 3 cm H2O. Peak airway pressure was controlled below 22 cmH2O. PaCO2 was maintaind between 35 and 45 mmHg. Fraction of inspired oxygen was adjusted to maintain PaO2 between 150 and 250 mmHg. Position of the blood pressure transducer was standardized to place at the level of the ear for every patient. Mean arterial blood pressure was controlled within 60–120 mmHg. If MAP fell below 60 mmHg, ephedrine or phenylephrine was given. If MAP went up over 120 mmHg, the infusion rate of remifentanil was increased. Bispectral index (BIS) was adjusted between 40 and 60 by controlling the target of propofol infusion. If rSO2 went down below 50%, or by 20% of the preanesthetic value, inspired oxygen was increased.Fifty-six adult patients  who underwent robotic-assisted endoscopic prostatic surgery were recruited. Patients having history of cerebral diseases such as cerebral infarction, cerebral hemorrhage, transient ischemic attack, or subarachnoid hemorrhage were excluded. No premedication was given. In the operating room, two sensors of near infrared spectroscopy  were attached on the patient’s forehead to measure the left and right rSO2, MAP, HR, SpO2, SaO2, PaO2, and PaCO2 were made. Pneumoperitoneum with intra-abdominal pressure of 10–15 mmHg was established and measurements were repeated every 5 min. Approximately 15 min after the establishment of the pneumoperitoneum, the Trendelenburg position with 30° head-down tilt was started. Before the start of the Trendelenburg position, rSO2, MAP, HR, SpO2, SaO2, PaO2, and PaCO2 were measured. Measurements of rSO2, MAP, HR, and SpO2 were made at 5, 10, 20, 30, 45, 60 min after the start of Trendelenburg position. After the onset of the Trendelenburg position, blood gas analysis was performed at 10, 30, 60 min. The measurements were not blinded to the anesthesiologists.Before pneumoperitoneum, baseline measurements of rSO2. Change in rSO2, MAP, HR, SpO2, SaO2, PaO2, and PaCO2 were examined via analysis of variance and Tukey post hoc comparisons. Multiple regression analysis was performed to estimate the relationship between rSO2 and MAP, HR, SpO2, SaO2, PaO2, or PaCO2. For multiple regression analysis, rSO2 data were averaged. When statistical significances were obtained after the multiple regression analysis, we performed linear regression analysis. Values are represented as means ± SDs; a p value < 0.05 was considered statistically significant.We used Stat Flex version 6.0  for statistical analysis. Power analysis revealed that the sample size of 41 patients was sufficient to provided 80% power with an α level of 0.05 to detect mean differences of 5% in rSOn = 8), position of blood pressure transducer error (n = 2), and blood pressure measurement failure  (n = 3). Therefore, we enrolled 41 patients . No patients have comorbidities such as chronic obstructive pulmonary disease, heart failure, or uncontrolled hypertension. BIS before anesthesia was 93 ± 6. Propofol was infused at 2.8 ± 0.5 μg/ml and remifentanil was infused at 0.37 ± 0.10 μg/kg/min. BIS was maintained at 44 ± 6 during the study period. Body temperature before anesthesia was 36.3 ± 0.4 °C, and was maintained at 36.5 ± 0.5 °C during the study period.Of 56 eligible patients, two patients failed to meet the inclusion criteria, and 13 patients developed the protocol fault such as data acquisition failure (2 before anesthesia (Pre) was 98.0 ± 1.4%, and increased to 99.0 ± 1.0% throughout the study period  after the induction of anesthesia. They were treated with ephedrine 5 mg and phenylephrine 0.05 mg. As shown in Fig. 2 before the pneumoperitoneum was 167.4 ± 43.9 mmHg. PaO2 decreased after the pneumoperitoneum, and increased after the Trendelenburg position. PaCO2 before the pneumoperitoneum was 40.3 ± 3.5 mmHg , and decreased to the baseline value afterwards but the change was not statistically significant.Before general anesthesia, left Fig.e and rig2 was correlated with MAP (p < 0.05) and PaCO2 (p < 0.0001) , and rSO2 = 45.3682 + 0.60127 × PaCO2, r = 0.3059 .Multiple regression analysis showed that change of rSOp < 0.000  . A previerfusion . Therefogulation . In acutgulation , 13. Howgulation . If bloo2 pneumoperitoneum, rSO2 increased initially. Some studies reported that central venous pressure increased by 10–16 mmHg during the Trendelenburg position combined with CO2 pneumoperitoneum [2 pneumoperitoneum in the previous studies [2 pneumoperitoneum compared with that before the pneumoperitoneum. Change in cerebral perfusion pressure immediately after the Trendelenburg position was 16–18 mmHg (MAP change) minus 10–16 mmHg (assumed CVP change) [2 pneumoperitoneum. Cerebral perfusion pressure was not involved in the transient increase in rSO2 just after the Trendelenburg position combined with CO2 pneumoperitoneum. Schramm et al. reported that cerebral autoregulation deteriorated with Trendelenburg position combined with pneumoperitoneum [2 initially increased after the Trendelenburg position combined with CO2 pneumoperitoneum.After the Trendelenburg position combined with COritoneum –17. On t studies , 17. In  change) –17. The  change) . The valritoneum  reported2. We recently reported that changes in rSO2 significantly correlated with changes in PaCO2. [2 at 40 ± 5 mmHg. However, PaCO2 increased significantly after the pneumoperitoneum. Thus, rSO2 increased along with the rise in PaCO2. rSO2 gradually decreased after the pneumoperitoneum combined with the Trendelenburg position. Nevertheless, PaCO2 remained high level during the pneumoperitoneum combined with the Trendelenburg position. Although there was a correlation between rSO2 and PaCO2, PaCO2 may be less involved in the change of rSO2. On the other hand, MAP was observed highest at 5 min after the Trendelenburg position (T5 in the Fig. 2 changes with alterations in mean blood pressure rather than change of PaCO2.Cerebral blood flow varies with PaCOn PaCO2. . Abdomin2 [2 in this study. According to the manufacturer, rSO2 reflects 25% arterial and 75% venous portion of blood. If cerebral oxygen consumption decreased, venous blood oxygen could be increased. As a result, rSO2 may have increased. However, BIS was unchanged after the induction of anesthesia. There were no factors that involved the decline in cerebral oxygen consumption after the pneumoperitoneum. Furthermore, PaO2 was significantly decreased after pneumoperitoneum. Therefore, oxygenation status was unlikely to participate in the rise of rSO2.Cerebral oxygenation can be monitored by rSO2 . Cerebra2 before anesthesia was significantly higher than that after the induction of anesthesia. Mean arterial blood pressure also declined after the induction of anesthesia. In addition, cerebral metabolic rate decreases after the induction of anesthesia that results in decrease in cerebral blood flow [2 is firmly affected by MAP and cerebral blood flow rather than arterial oxygenation status in this study situation.In this study, data before anesthesia were obtained under room air breathing and other data were measured under oxygen inspiration. Therefore, arterial oxygen saturation before anesthesia was significantly lower than that after the induction of anesthesia. However, rSOood flow . This ph2 altered along with the change of MAP though decrease in blood pressure below the lower limit of autoregulation was not observed in this study. Nevertheless, individual variation in MAP while anesthetized and the lower limit of autoregulation might make the rSO2-MAP relationship different for different individuals.Cerebral autoregulation, which is expected to keep cerebral blood flow constant, mainly depends on cerebral perfusion pressure . If cere2 decreased after pneumoperitoneum. A previous study suggested that pneumoperitoneum elevated diaphragm that can lead to basilar atelectasis, with resulting right to left shunt formation [2. After the Trendelenburg position, PaO2 increased. Some studies reported that peak and mean airway pressure increased after the Trendelenburg position [2 increased.In this study, PaOormation . Atelectposition , 26. Ele2. Davie et al. reported that the extracranial contamination potentially affected rSO2 [2 [2 in this study.This study has some limitations. First, we did not measure central venous pressure because central venous catheterization is an invasive method and not always necessary for robotic-assisted endoscopic prostatic surgery. In many studies, central venous pressure was increased after pneumoperitoneum , 9 and tted rSO2 . They al rSO2 [2 . TrendelIn conclusion, pneumoperitoneum and the Trendelenburg position in robotic-assisted endoscopic prostatic surgery did not aggravate cerebral oxygenation. Changes in rSO2 were associated with the alteration of MAP and PaCO2, but did not correlate with the changes of HR, PaO2, or SaO2, indicating that arterial blood pressure is the critical factor in the cerebral oxygenation.


Dietary intake of anthocyanins (ACNs) is associated with a reduced risk of cardiovascular and coronary heart disease. While the anti-inflammatory, antioxidant, and lipid-lowering effects of ACN consumption have been consistently reported, their effect(s) on blood pressure regulation is less consistent and results from human studies are mixed. The objective of this review is attempting to identify potential patterns which may explain the variability in results related to blood pressure. To do so, we review 66 human intervention trials testing the effects on blood pressure of purified ACN or ACN-rich extracts, or whole berries, berry juices, powders, purees and whole phenolic extracts, from berries that are rich in ACN and have ACNs as predominant bioactives. Several factors appear to be involved on the mixed results reported. In particular, the baseline characteristics of the population in terms of blood pressure and total flavonoid intake, the dose and duration of the intervention, the differential effects of individual ACN and their synergistic effects with other phytochemicals, the ACN content and bioavailability from the food matrix, and individual differences in ACN absorption and metabolism related to genotype and microbiota enterotypes. Hypertension is a known risk factor of cardiovascular disease (CVD), which is the leading cause of death worldwide . The rolAnthocyanins (ACN) are a large class of water-soluble plant metabolites belonging to the flavonoid family of phenolics, responsible for the red, blue, and purple pigmentation of many flowers, fruits, and vegetables. They are the glycosylated forms of highly reactive and relatively unstable molecules characterized by a flavylium cation structure, called anthocyanidins . AlthougStrong epidemiological evidence associates ACN intake with a reduced risk for cardiovascular disease and coronary heart disease . While AAronia melanocarpa) (over 400 mg/100 g) [To try to identify potential patterns explaining such variability in results related to blood pressure, we decided to review clinical trials testing purified ACN or ACN-rich extracts, or whole berries, berry juices, powders, purees, or whole phenolic extracts from berries that are rich in ACNs and have ACNs as predominant bioactives. Among berries, a higher ACN content can be found in chokeberries (g/100 g) , blackcug/100 g) ,13. Instg/100 g) ,14. ThusACNs have been consistently shown to increase endothelial-derived nitric oxide (NO), via modulation of endothelial NO synthase (eNOS) expression and activity. Nitric oxide is one of the major contributors to endothelium-dependent vasorelaxation. It causes vascular smooth muscle relaxation following activation of soluble guanylate cyclase, which in turn increases cGMP. This blocks the release of intracellular calcium, preventing it from causing vascular smooth muscle contraction .Reactive oxygen species damage NO, thus promoting vasoconstriction and hypertension. Due to their strong antioxidant activity, ACNs act to prevent NO oxidative damage and radical-induced NO conversion, such as the reaction caused by NADPH oxidase .ACNs have been shown to reduce synthesis of vasoconstricting molecules, such as angiotensin II via inhibition of the angiotensin-converting enzyme (ACE) activity, endothelin-1, and thromboxanes via inhibition of the cyclooxygenase (COX) pathway .High blood pressure can be caused by an increased cardiac output or by a higher systemic vascular resistance, which in turn results either from a narrower diameter of blood vessels or by their lower elasticity. An excess of vasoconstricting stimuli, or a lack of vasodilator stimuli, can both result in hypertension . ACNs haWhile most of these mechanistic observations come from in vitro and animal model studies , the praEpidemiological data appears to confirm the existence of a link between ACNs and blood pressure regulation. A prospective epidemiological study on 34,489 postmenopausal women from the Iowa Women’s Health Study, analyzing the effects of total flavonoids or seven different individual flavonoid subclasses on cardiovascular health over 12 years, found a significant inverse association between ACNs and CHD and CVD and total mortality, while total flavonoids and the other individual subclasses had no significant effect . AnalyziSeveral meta-analyses have been conducted using data from clinical trials involving sources of ACNs, with mixed results. A meta-analysis of 128 clinical trials on different sources of ACN and ellagitannins, with a total of 5538 participants, found that both systolic and diastolic blood pressure (DBP) were significantly lowered by consumption of berries, red grapes, and red wine—the main sources of ACN investigated in the study . Per conIn light of such mixed results, we searched the literature for clinical trials, testing the effects on blood pressure of ACNs or ACN-rich berries and examined the results individually to attempt to identify potential patterns explaining the variability in results related to blood pressure.A search of the literature for human acute and chronic intervention studies was carried out on multiple databases  with the keywords (anthocyanin* OR blueberr* OR raspberr* OR bilberr* OR blackberr* OR blackcurrant OR açai OR cherr* OR aronia OR elderberr* OR chokeberr*) AND . Abstracts and full texts were screened, and reference lists were also searched for related articles. Further details about the literature search process are provided in Of the 14 single-dose interventions which were identified and reviewed; six found a significant effect on blood pressure, as summarized in All single-dose studies were performed on healthy participants, with the exception of the study by Keane et al. which was conducted on 15 subjects with early hypertension: both SBP and mean arterial pressure, but not DBP, were significantly lower at 1, 2, 3, 4, 5, 6, 7, and 8 hours after a serving of tart cherry juice providing 73.5 mg ACN . Del Bo Fifty-two long term interventions were identified and summarized in Several factors appear to influence the effects of ACNs on blood pressure regulation in humans, and they are discussed in the following subsections.A consistent observation is that the effect on blood pressure is only detectable in subjects with high blood pressure baseline value. Of the six studies targeting specifically prehypertensive or hypertensive subjects, five found an effect on blood pressure ,58,67,83After a six-week intervention with high bush blueberries on 25 adults, McAnulty et al. did not find a significant effect on DBP for the whole group, but the reduction became significant when considering only the subset of nine prehypertensive subjects . SimilarAnother interesting observation comes from the study of Cook et al. on 13 healthy participants receiving a blackcurrant extract providing 315 mg ACNs for a week . While nBased on these findings, future studies should aim to identify with more precision which population segments may benefit from ACN intake, possibly relating the findings to the new American Heart Association guidelines’ blood pressure categories of normal (<120/<80 mmHg), elevated (120–129/<80 mmHg), stage 1 hypertension (130–139/80–89), stage 2 hypertension (≥140/≥90 mmHg), and hypertensive crisis (>180/>120 mmHg).Another potentially relevant factor is the baseline total flavonoid intake of the population under study. It is reasonable to hypothesize that the effect of ACN supplementation may be greater in subjects with low baseline flavonoid intake. Unfortunately, this information is rarely collected or reported in studies, making it difficult to identify a pattern.Of the seven studies providing high doses of ACN (>500 mg/day), four studies found a significant effect on blood pressure ,40,49,67It is important to consider, however, that ACN quantification is rather complicated, and only few studies rely on complete ACN profiles of the food under investigation. More frequently, studies measure cyanidin-3-glycoside equivalents, or rely on a quick but approximate spectrophotometric quantification following methanol extraction. In some cases, they only estimate ACN content based on the USDA food composition tables. To further complicate matters, ACNs are rather unstable compounds and sensitive to pH variations, heat, light, oxygen exposure, and enzyme activity, and they are highly reactive with other molecules, sugars, proteins, and other phenolics . Thus, tOnly seven studies investigated specifically the effect of different ACN doses, of which four seem to suggest the existence of a dose-effect. After 12 days consumption of a blackcurrant extract providing either 105, 210, or 315 mg/day of ACNs, with a crossover design, a significant reduction in mean arterial pressure in a group of 15 athletes was only observed with the two higher ACN doses . After aIn contrast, in another 6-week intervention with 66 mostly overweight adults, neither a low nor a higher dose blackcurrant juice  had any effect on blood pressure . An inteAnother interesting observation comes from the study of Kent et al. providing a single dose of cherry juice containing 207 mg ACNs to a group of young or older adults and detecting a significant reduction of both SBP and DBP at two hours after consumption. However, when the same amount of juice was split into three doses provided one hour apart over two hours, the effect on blood pressure was no longer detectable . Thus, a positive effect on blood pressure was found across a wide range of ACN doses, with both dose and time being relevant factors.The study duration does not seem a consistent factor in determining the effect of ACNs on blood pressure. Of the 34 studies with 6 week durations or longer, 15 found a significant effect on blood pressure . Of the It is interesting to note, however, that after 6-week consumption of aronia juice providing 90 mg/day ACNs, a group of 58 male with mild hypercholesterolemia had a significant reduction in DBP but not in SBP, while after another 6 weeks of aronia juice consumption the reduction became significant also in SBP, suggesting that the duration of the intervention may indeed be a relevant factor .Of the 28 studies registering a significant effect of blood pressure, 14 studies reported a reduction in SBP but not in DBP , and 12 Thus, the blood-pressure-lowering effect appears to be more evident on SBP than DBP.Hormonal long-term regulation of blood pressure, mainly via the renin-angiotensin-aldosterone and antidiuretic hormone (ADH) systems, is a potential target of ACN activity, as has been suggested by investigations in the animal model . In humaA group of 23 subjects with untreated metabolic syndrome (MetS) received either aronia extract supplements providing 60 mg ACNs, or ACE-inhibitors. After 8 weeks, the activity of SBP, DBP, and ACE was significantly lower compared to baseline. However, ACE activity was still higher compared to a reference group of healthy controls or MetS controls treated with ACE-inhibitors (reference group was measured only once and did not undertake any intervention) . ConversMore studies on how ACN intake may affect blood pressure hormonal regulatory systems are warranted, and the variability in biological responses should also be considered in view of the recent findings on the M235T polymorphism of the angiotensinogen gene, which has been linked with cardiovascular disease .Many studies which found significant effects on BP used ACN-rich foods or whole extracts, which also contain other bioactive phytochemicals potentially affecting blood pressure. The exact composition of such extract is often unknown in most studies. Of the 14 studies using isolated ACNs or ACN-rich extracts, only one found a significant effect on blood pressure, while the remaining 13 studies did not find any effect. In contrast, of the 11 studies using whole phenolic extracts, eight studies found a significant effect, while only three studies did not find any effect on blood pressure see .It is also interesting to report that while no effect on blood pressure was observed when whole grapes were given for 4 weeks to a group of 60 mildly hypertensive participants, a significant reduction of both SBP and DBP was detected with grape wine extract that had a comparable total phenolic content . Thus, bFurthermore, it is also to be noted that most of the studies testing isolated ACNs used the same commercially available supplement, made with ACNs isolated from bilberry and blackcurrant.Hibiscus sabdariffa (HS) extract powder providing 19 mg ACN on a group of 71 healthy and 51 MetS patients, using a preventive diet as control. No significant effect on blood pressure was found either with HS alone or with diet alone. However, in the group receiving both the HS powder and the preventive diet, a significant reduction of both SBP and DBP was observed [A synergistic effect with lifestyle and diet is also a likely relevant factor. Gurrola Diaz et al. tested the effect of 4-week consumption of a observed .Most interventions use fresh berries or berry extracts, which contain a mix of different compounds including different ACNs. This is undoubtedly the best approach in view of extrapolating the results to a real-life situation, in which whole foods are consumed and not isolated compounds, and the consumption of whole foods rather than supplements should be encouraged to promote health and prevent disease. However, this approach makes it more difficult to identify potential differential effects among different molecules, especially when trying to elucidate their mechanisms of action.Indeed, when studying single anthocyanins, Rechner & Kroner observed that the inhibitory effect on the redox-sensitive p38 MAPK and c-jun-N-terminal kinase pathways often reported for ACNs, was only caused by delphinidin and cyanidin, but not malvidin and peonidin, suggesting that the hydroxyl residue in position 3 of the B ring may play a key functional role . Thus, iThe different ACN profile of individual food sources is also a factor of variability. For example, blueberries contain predominantly delphinidin, malvidin, and petunidin; raspberries predominantly cyanidin and pelargonidin; and blackberries predominantly cyanidin and malvidin . It mustACN metabolism is complex and mostly unknown, and in order to fully understand their biological functions, it is necessary to better elucidate their metabolic fate . While mThus, it is not enough to study the biological effects of parent ACNs, but also the effects of their numerous catabolic products based on microbiota, physiology, and health of the GI in individuals. This likely explains most of the discrepancies between the mechanisms of action suggested in vitro and the actual in vivo outcomes.Increasing evidence links the composition of gut microbiota to key physiological effects related to the prevention of chronic disease, and this includes the contribution of gut bacteria to blood pressure regulation ,97. The Thus, interaction with gut microbiome is likely an important element of variability that could explain some of the different effects observed for ACN intake. To our knowledge, however, no study has directly investigated the relationship between gut microbiota and the effects of ACN intake on blood pressure regulation.A consistent number of studies documented a significant blood-pressure-lowering activity related to ACNs and ACN-rich berry consumption, suggesting that an effect indeed exists.The fact that many other studies failed to observe such an effect, indicates that the outcome is not generalized and likely depends on many other factors, and, in particular, the baseline characteristics of the population , ACN dose, duration of the intervention, differential effects of individual ACNs, and synergistic effects with other phenolics and bioactive phytochemicals in general. Additionally, ACN content and bioavailability from the food matrix , modified by the manufacturing process and storage conditions and duration, need to be taken into account. Finally, ACN absorption and metabolism, which is affected by the different microbiota enterotypes of each individual, his/her different genotype, the physiological condition of the gastrointestinal tract and its relative response to dietary bioactives, is also a factor to be considered. Further research will need to identify more precisely the clinical conditions and the characteristics of individuals for which an increased consumption of ACN-rich foods may be especially recommended and could potentially reduce the dose and/or the administration of antihypertensive medications.


To develop and test a beat-to-beat blood pressure monitoring device during coronary angiography, and compare it with invasive blood pressure monitoring. Twenty-eight patients with an indication for hemodynamic study were selected for this investigation, and kept in supine position. Before starting the coronary angiography, they were instructed about the use of the left radial bracelet for beat-to-beat blood pressure monitoring. There was a significant difference between the time required for the catheterization laboratory team to acquire the first invasive blood pressure reading and the time to obtain the first beat-to-beat reading . The intraclass correlation coefficients (95%CI) of systolic and diastolic blood pressures were 0.897 (0.780-0.952) and 0.876 (0.734-0.942), indicating good reproducibility. This study showed the process to develop a beat-to-beat blood pressure monitoring device. When compared to invasive blood pressure monitoring, there were no significant differences between the two methods. This technique may play a promising coadjuvant role when combined with invasive monitoring during coronary angiography procedures. Currently, there is a lot of interest around non-manual BP monitoring methods, since automating this process can contribute to optimizing staff time, and offer greater comfort to patients. In addition, BP readings acquired using automatic methods are comparable to manual readings.Blood pressure (BP) variations can occur in short time intervals, secondary to cardiopulmonary reflexes,1 neurOn the other hand, in some clinical situations, small variations in BP may occur suddenly and have great relevance, such as in vasovagal reflex, bleedings and cardiac arrhythmias, among others. Most automatic devices have been validated for focal measurements and, very often, there is a delay in the documentation of rapid BP variations. In Brazil, there are no devices for beat-to-beat peripheral arterial tonometry that have been tested and validated for clinical use; therefore, continuous BP monitoring can contribute to the follow-up of these patients.4Arterial tonometry is performed by a transducer positioned on the radial artery, detecting the pulse wave and calculating systolic and diastolic BP, updating values at every heart beat, continuously and non-invasively.5During coronary angiography procedures, invasive BP monitoring is mandatory for early detection of hemodynamic changes and complications of the procedure. Beat-to-beat BP monitoring devices with an accuracy comparable to that of invasive BP monitoring may contribute to hemodynamic monitoring during invasive and non-invasive procedures.To develop and validate a beat-to-beat blood pressure monitoring device to be used during coronary angiography, and compare its readings to those obtained by invasive blood pressure monitoring.2, history of thrombosis of the upper limbs (UL), previous amputation of the left upper limb (LUL), significant skin abnormalities, asymmetrical pulses, arrhythmias, emergency procedures, and those with hemodynamic instability were excluded.We selected 28 consecutive patients with ordered hemodynamic studies, coming from secondary care services, according to the capacity planning center of the Interventional Cardiology Department of a teaching hospital in the city of São Paulo (SP), in the period between February and September 2016. We enrolled patients of both sexes, aged over 18 years, with an indication for elective coronary angiography due to suspected coronary artery disease. Patients with body mass index (BMI) above 40kg/mHospital Israelita Albert Einstein , based on the principles of peripheral arterial tonometry adapted for the left radial artery. At this stage, the conceptual project of the bracelet was developed , we calibrated the peripheral arterial tonometry system.Continuous BP and heart rate monitoring was kept throughout the procedure, even during contrast injection. Blood pressure measurements were collected at six timepoints, during the coronary angiography, at regular intervals, and the data were compared with simultaneous measurements obtained by the invasive system.®, for data analysis. The reproducibility between the two measurements was assessed by the intraclass correlation. To facilitate visualization of the two measurements, we plotted Bland-Altman charts. Additionally, we presented Pearson correlations to assess the linear association between the two results. Data were expressed as mean and standard deviation for quantitative variables. Categorical variables were presented as percentages. To compare the means of the two measurements, we used the Student’s t test for paired samples. Linear regression models were adjusted to verify the existence of any interaction of the systolic pressure measured with the device and BMI, diabetes or hypertension, with the systolic pressure measured by the invasive method. The same was done for diastolic BP. Both the Student’s t test and the linear regression assumed a normal distribution of the data, which was verified by the Kolmogorov-Smirnov test. The significance level was set at p<0.05.We used the software Statistical Package for the Social Science (SPSS), version 20.0, and StataUniversidade Federal de São Paulo (UNIFESP) under opinion 534.636, CAAE: 15481413.0.0000.5505, and all patients signed an Informed Consent Form.The study was approved by the Institutional Review Board of the The prototype development and bracelet enhancement stages are shown in versus 1.5±1.8 minutes; p<0.0001). During clinical tests, one patient (0.3%) asked for the bracelet to be removed due to pain on the left wrist. Continuous, beat-to-beat BP measurement was not lost in any of the patients during monitoring, even during contrast injection for coronary angiography.The mean age of patients was 61.5±9.9 years. Of the 28 subjects, 17 were males. The characteristics of the sample investigated are presented in versus 128.79mmHg±16.24mmHg; p=0.305). There was no statistical difference between mean diastolic BP values of the device, when compared with invasive monitoring . The intraclass correlation coefficients (95%CI) of systolic and diastolic BP were 0.897 (0.780-0.952) and 0.876 (0.734-0.942), indicating good reproducibility.There was no statistical difference between mean systolic BP values of the device when compared with invasive monitoring  for systolic and diastolic BP and diabetes were, respectively, 1.78 (-0.11- 0.97) and -0.44 (-0.75-0.44). The beta values of interaction (95%CI) for systolic and diastolic BP and hypertension were, respectively, 0.76 (0.24-1.25) and -1.25 (0.98-0.17). The beta values of interaction (95%CI) for systolic and diastolic BP and BMI were, respectively, -1.69 (-0.10-0.21) and -2.93 (-0.18-0.01).The main finding of this study was the development of a tool capable of monitoring BP beat-to-beat, with good correlation with invasive measurements. It seems to be an international consensus, and also advocated by the Multicenter Meeting on Hypertensive Crises that, once the emergency is confirmed, the situation always requires the use of injectable drugs through proper venous access, if possible using continuous infusion pumps and rigorous BP monitoring.6 which guided many clinical trials concerning technological development and validation protocols. Heusdens et al., investigated 25 consecutive patients undergoing endarterectomy and requiring BP monitoring, and compared non-invasive readings taken with a finger monitor with invasive BP readings, demonstrating a good clinical correlation. Hellman et al., looked into patients with Parkinson’s disease, with and without documented orthostatic hypotension, subjected to the Valsava maneuver using traditional methods and continuous, beat-to-beat BP monitoring. The authors demonstrated that continuous monitoring is more sensitive than traditional monitoring for diagnosis of postural hypotension in this population. Similar findings were reported by Langwieser et al., who studied the role of peripheral arterial tonometry in patients admitted to intensive care units, demonstrating that the technique has good accuracy when compared to invasive techniques, and can serve as an alternative for monitoring these patients. Our study, likewise, showed no significant differences between systolic and diastolic BP readings during coronary angiography.The validation of new devices for this purpose is no novelty. Since 1980, several protocols have been proposed, but it was only in 2010 that the European Society of Hypertension published a review with the international protocol for BP measurement in adults,7 whicOn the other hand, in a study conducted by Gupta et al., looking at continuous, beat-to-beat monitoring, with intermittent BP measurements during elective cesarean sections, it was demonstrated that patients monitored with the continuous technique had lower detection of BP drops and lower use of oxytocin when compared with the group on intermittent monitoring. The authors concluded that continuous monitoring can only be used as a support to conventional monitoring.11Furthermore, the concern with the safe use of devices is nationally reinforced in the Patient Safety Program, and actually is one of the program’s goals; for this reason, tolerance to the method was also an important factor investigated in this study, where only one (3.6%) of patients reported local pain with the use of the bracelet.12The total monitoring time may also be a determinant factor when assessing tolerance and, indeed, in our study, the beat-to-beat monitoring time was approximately one hour, which makes it impossible to compare with monitoring methods with different duration.versus 1.5±1.8 minutes; p<0.0001). This fact can be important in more urgent scenarios and is a promising finding for future clinical investigations. Another advantage is the fact that beat-to-beat BP monitoring remained unchanged during contrast injection, which can yield additional information during the procedure.The time of acquisition of the first BP reading by arterial tonometry was shorter when compared with invasive pressure monitoring (11.1±5.1 minutes  therefore, this control PA must be rigorous.Also, beat-to-beat BP control can be useful in post-cardiac arrest myocardial dysfunction and in the control of hypertensive crises, since the drop in ejection fraction and increased end-diastolic pressure of the left ventricle can take place hours later, with hypotension and low cardiac output and,13 theSome limitations are worth noting: the small number of patients and the exclusion of obese patients, patients with cardiac arrhythmias and hemodynamic instability, which warrants the need for new studies. Moreover, reproducing these results in other areas is essential for understanding their usability, once the population investigated in this study was quite specific.There was a correlation between the blood pressure readings using the invasive technique and the non-invasive, beat-to-beat blood pressure monitoring device. Also, greater agility was observed in obtaining the first blood pressure reading. Therefore, the device developed may become a promising tool for hemodynamic monitoring.


The drop in blood pressure during pregnancy may persist postpartum, but the impact of pregnancy on blood pressure across the life course is not known. In this study we examined blood pressure trajectories for women in the years preceding and following pregnancy and compared life course trajectories of blood pressure for parous and nulliparous women. We linked information on all women who participated in the population-based, longitudinal HUNT Study, Norway with pregnancy information from the Medical Birth Registry of Norway. A total of 23,438 women were included with up to 3 blood pressure measurements per woman. Blood pressure trajectories were compared using a mixed effects linear spline model. Before first pregnancy, women who later gave birth had similar mean blood pressure to women who never gave birth. Women who delivered experienced a drop after their first birth of − 3.32 mmHg  and − 1.98 mmHg  in systolic and diastolic blood pressure, respectively. Subsequent pregnancies were associated with smaller reductions. These pregnancy-related reductions in blood pressure led to persistent differences in mean blood pressure, and at age 50, parous women still had lower systolic  and diastolic  blood pressure compared to nulliparous women. The findings suggest that the first pregnancy and, to a lesser extent, successive pregnancies are associated with lasting and clinically relevant reductions in systolic and diastolic blood pressure.The online version of this article (10.1007/s10654-018-0358-z) contains supplementary material, which is available to authorized users. Longitudinal studies have shown that blood pressure increases during a woman’s life –3. In thUsing data from the population-based Nord-Trøndelag Health Study (the HUNT Study) linked with the Medical Birth Registry of Norway (MBRN) we examined blood pressure trajectories for women in the years preceding and following pregnancy and compared life course trajectories of blood pressure for parous and nulliparous women.The HUNT Study is an ongoing longitudinal study in which all people aged 20 and above in Nord-Trøndelag county, Norway are invited to undergo an extensive health assessment, including clinical measurements and questionnaires . So far HUNT data were linked with the MBRN to retrieve information on births using the unique personal identification numbers assigned to Norwegians at birth or immigration. All births in Norway since 1967 have been recorded in the MBRN , and datIn each HUNT survey, blood pressure was measured by trained staff after the person had rested. In HUNT1  blood pr2) was measured at each HUNT examination. The HUNT questionnaires included information on smoking and anti-hypertensive medication , use of oral contraceptives and breastfeeding duration (HUNT2 and HUNT3), and highest obtained educational level (HUNT1 and HUNT2); lower secondary (up to 9 years), upper secondary (10–12 years) and tertiary education (college or university). Information on work titles (HUNT3) was obtained from a structured interview. Due to lack of educational information for women who participated only in HUNT3, we derived educational status from work titles for 4041 women based on recommendations from Statistics Norway [Body mass index  was retrieved from the MBRN, which records these disorders from standardized forms filled in at the birth clinics and returned shortly after delivery. Validation studies within the HUNT population have shown that 88% of preeclampsia cases in the MBRN were confirmed by evidence in hospital records , and 74%We used a linear spline mixed effects model  to estimIn analyses restricted to parous women, we examined whether the effect of pregnancy on blood pressure varied by age at first pregnancy. To confirm that the average blood pressure trajectories drawn using data from all examinations among all women were representative of within-woman changes in blood pressure across time, we performed a sensitivity analysis excluding women who had only one blood pressure measurement. Further to confirm that the trajectories represented the actual within-woman change in blood pressure due to pregnancy, we studied the difference in blood pressure change for women who had their pregnancy between HUNT2 and HUNT3 to women who remained nulliparous throughout the same interval and were 43 years or younger at HUNT2, the maximum age at HUNT2 of those who went on to have their first birth. To examine the extent of confounding by oral contraceptive use and BMI, the analysis of change in blood pressure between HUNT2 and HUNT3 was adjusted for change in BMI and oral contraceptive use between the HUNT surveys. Also, in order to investigate the potential mediating effect of breastfeeding upon the association between pregnancy and a drop in blood pressure, we also categorized women who delivered according to breastfeeding duration after first pregnancy. Lastly, we estimated the blood pressure trajectories for women with a hypertensive disorder and normotension in first pregnancy. All statistical analyses were carried out using Stata IC 13  and MLwiN  version Characteristics of the 21,513 parous and 1925 nulliparous women included in the analysis are given in Table Figure It took parous women roughly a decade to reach their mean pre-pregnancy blood pressure levels. From age 30 to 40 years, parous women had a faster rise in blood pressure compared with nulliparous women . Yet, the lower blood pressure in parous compared with nulliparous women lasted beyond 50 years of age .We examined whether the effect of pregnancy on blood pressure varied by age at first pregnancy. The blood pressure decline from pre to post first pregnancy was only slightly smaller  for systolic and slightly larger  for diastolic for each 1-year higher age at first pregnancy. When restricting our analysis to the 15,233 women with repeated (2 or 3) blood pressure measurements we observed similar trajectories as in our main analysis , confirming that our main results were representative of within-woman changes in blood pressure. As a sensitivity analysis, we examined how the amendment for the effect of antihypertensive medication influenced our results and found that the shape of the trajectories remained essentially unchanged when we used the original, unamended blood pressure values in the analysis .Our analysis of within-woman change in blood pressure comparing the 621 women who gave birth to their first child between HUNT2 and HUNT3 to the 427 who remained nulliparous confirmed that pregnancy was associated with reductions in systolic and diastolic blood pressure similar to those observed in the main analysis ; the estimated mean drop after pregnancy was − 3.99 mmHg  for systolic and − 3.04 mmHg  for diastolic blood pressure. Additional adjustment for oral contraceptive use and BMI did not substantially attenuate the estimated association between pregnancy and blood pressure change . The blood pressure change was broadly similar across categories of breastfeeding duration; however, 79% of women with first birth between HUNT2 and HUNT3 breastfed for > 6 months after their first pregnancy, and the low number of women with no or short breastfeeding duration prevented precise estimates for those groups .interaction = 0.195 for systolic and 0.007 for diastolic blood pressure). In women with normotension in first pregnancy, the mean adjusted changes from pre to post first pregnancy were − 3.43 mmHg  in systolic and − 2.15 mmHg  in diastolic blood pressure. In women with a hypertensive disorder in first pregnancy, the corresponding changes were − 2.02 mmHg  systolic, but only 0.01 mmHg  diastolic. Women with a hypertensive disorder in first pregnancy had higher mean blood pressure throughout the age span, compared with both nulliparous women and women with a normotensive first pregnancy .Among 21,513 parous women, 20,038 had normotension and 1475 had a hypertensive disorder in first pregnancy . There was some evidence that the blood pressure drop from pre to post first pregnancy differed between the two groups Below is the link to the electronic supplementary material.


Hypertension control remains a major global challenge. The behavioral approaches recommended for blood pressure reduction are stress reduction, increased exercise and healthy dietary habits. Some study findings suggest that yoga has a beneficial effect in reducing blood pressure. However, the role of yoga on blood pressure has received little attention in existing health care practices in developing countries. This study will be conducted in primary health care facilities in Nepal to assess the effectiveness of a pragmatic yoga intervention to complement standard practice in further reducing blood pressure.This will be multicentric, two arms, randomized, nonblinded, pragmatic trial. It will be conducted in seven District Ayurveda Health Centers (DAHCs) in Nepal between July 2017 and June 2018. The study participants will consist of hypertensive patients with or without antihypertensive medication attending to the outpatient department (OPD). One hundred and forty participants will be randomized to treatment or control groups by using a stratified block randomization. At the study site, the treatment arm participants will receive an intervention consisting of five days of structured yoga training and practice of the same package at home with a recommendation of five days a week for the following 90 days. Both the intervention and control groups will receive two hours of health education on lifestyle modifications. The primary outcome of this trial will be the change in systolic blood pressure and it will be assessed after 90 days of the intervention.This study will establish the extent to which a yoga intervention package can help reduce blood pressure in hypertensive patients. If proven effective, study findings may be used to recommend the governing bodies and other stakeholders for the integration of yoga in the national healthcare system for the treatment and control of hypertension.CTRI/2017/02/007822. Registered on 10/02/2017.Clinical Trial Registry- India (CTRI); CTRI Reg. No-  Hypertension is a major public health issue worldwide. Globally, 874 million adults had systolic blood pressure (SBP) of 140 mmHg or higher in 2015 . Risk ofPrevention and management of hypertension is a global public health challenge. Apart from antihypertensive medicines, lifestyle modifications have been recommended as an equal first line approach for controlling hypertension , 5. Healp < 0.00001)  among the mild to moderate essential hypertensives [p = 0.018, and DBP: 98 mmHg Vs 88 mmHg; p = 0.018) among the essential hypertensive participants [Use of complementary and alternative medicine (CAM) for treating high blood pressure is becoming increasingly popular . A trialicipants . In a Coicipants . Howevericipants . A definicipants –14. Moreicipants –14.This study aims to assess the effectiveness of structured yoga program in reducing blood pressure level in hypertensive patients attending DAHCs in Nepal. The study will be conducted in real-world clinical practice settings, with typical patients and by government health workers, who are not the professional yoga instructors. If the study finding is significant, yoga may be integrated as a complementary therapy for hypertension management in public health facilities in Nepal.The primary objective of the study is to assess the effect of structured yoga practice on blood pressure reduction among people with hypertension attending the primary healthcare facilities. This study will determine whether practicing yoga leads to a clinically relevant reduction in blood pressure. Both clinic management and follow-on home-based yoga practice among hypertensive participants will be in the prescribed program. The outcome will be the change in systolic blood pressure at 90 days. We will also record the change in diastolic blood pressure. The secondary aim of the study is to assess the effect of yoga in reducing body mass index among the same participants.This study will be conducted among 140 hypertensive participants in seven District Ayurveda Health Centers in Nepal. It will be a randomized, two-armed, non-blinded, pragmatic trial.This study will be conducted in seven purposively selected DAHCs in Nepal. Currently, two centrals, 14 Zonal and 61 District Ayurveda Health Centers are catering preventive, promotive & curative primary healthcare services throughout Nepal under Department of Ayurveda (DoA), Ministry of Health, Nepal. Recently, DoA has initiated Training of Trainers (ToT) of yoga to capacitate its technical staffs (Ayurveda doctors and paramedics working at DAHC) to educate the patients and community on basic yoga skill. The main objective of ToT is to integrate and promote yoga within Ayurveda health system for health promotion and disease prevention. This study will orient and mobilize the trained DAHC human resources to deliver yoga interventions for the hypertensive participants those attending primary healthcare centers.This study has purposively selected seven DAHCs from the following districts: Ramechhap, Dhading, Nuwakot, Kaski, Rupandehi, Surkhet and Rolpa- based on ecological belt and development region Fig. .Fig. 1LoStudy participants will include hypertensive patients with or without anti-hypertensive medications attending DAHCs. Inclusion criteria include a SBP between 130 and 159 mmHg and/or DBP between 85 and 99 mmHg. Following are the sample selection criteria in detail.Age between18 years and 70 yearsBP criteria: SBP of 130 to 159 mmHg or DBP of 85 to 99 mmHg3 months or more of prescribed antihypertensive medication or without previously prescribed anti-hypertensive medicationsAttending to DAHCsPerson having diabetes (self-reported) and mental diseasesPregnant womenKnown secondary cause of hypertension (self-reported)Hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg)Practicing yoga more than one month in the previous 6 monthsThe intervention consists of three components: a) five days of yoga training (two hours per day); b) two hours health education session on healthy lifestyles; and c) home based self-practice of yoga daily for 90 days (with daily session lasting for 30 min). The treatment arm participants will receive all the intervention components whereas the control group will only be given the two-hour health education program and standard clinic care. Before the intervention, District Ayurveda Health Center staff (one from each center) will be orientated on yoga intervention packages and health education for high blood pressure prevention.Structured yoga program contains yoga postures, breathing exercise and meditation Table . StudiesHealth education group counseling session (a single 2-h workshop) will be organized for both intervention and control groups. The course curriculum and contents have been adopted from the health education materials endorsed by National Health Education Information and Communication Center (NHEICC), Ministry of Health, Nepal. It contains behavioral and lifestyle modification education designed to reduce an exposure to the risk factors of hypertension like alcohol consumption, smoking, physical inactivity, and fat and salt reduction in diet  at outpatient clinical settings with an aneroid sphygmomanometer (BP set). The secondary outcome will be the body mass index (BMI) and heart rate (HR). Both will be assessed at baseline and after the intervention.Sample size calculations are based on continuous outcome superiority trial; assuming 7 mmHg of mean difference in systolic blood pressure between control and experimental groups . This stBoth the DAHC research staff and clinicians will be trained on the protocols and procedures of the study. They will screen the hypertensive patients attending DAHCs for the eligibility criteria; obtain written consent; enroll the eligible participants for the study; and send the participants’ name for centrally generated stratified blocks for randomization Fig. . That isBaseline and post-intervention data on primary and secondary outcomes will be collected during a face to face interview. Additionally, anthropometric measurements and clinical examination data will also be collected. This study will also collect pre-intervention information on tobacco use, alcohol consumption, dietary patterns and physical activity.The interview questionnaire will cover participant’s demographics and health behavior. The health behavior questions are designed to assess tobacco use, alcohol consumption, fruit and vegetable consumption and physical activity. Tobacco, alcohol and diet related questions will obtain information on frequency and pattern of use or intake. These questions are particularly adopted from STEPs survey questionnaire tool . For meaTo assess the change in BMI, height and weight will be measured using portable stadiometer and digital scales .Blood pressure will be measured with an aneroid sphygmomanometer (BP set) in outpatient settings. Before taking the measurements, participants will be requested to rest for 15 min with legs uncrossed. Three readings of the systolic and diastolic blood pressure will be recorded in each five-minute interval. The average of second and third readings will be used for analysis.Data will be complied, edited, processed and analyzed using Epidata 3.1 and Stata 14.0. Analyses will be performed based on the intention-to-treat (ITT) principle. In the case of missing data and lost to follow-up, the last data obtained from a participant will be used for analysis. Similarly, for the participants who will start new medication or change the dose of existing medication during the study period, data will be replaced via the last observation carried forward method. Sensitivity analyses will be performed to test whether the findings from the available-case analysis are consistent and will lead to similar conclusions as in the primary analysis. A per-protocol (PP) analysis will also be carried out for only those patients who will complete the treatment as allocated.p < 0.05 will be considered statistically significant.Baseline characteristics will be presented in tables with frequency, proportions and mean ± standard deviation; frequency comparisons will be made using Chi-squared tests, and independent sample t-tests for mean differences. Primary and secondary outcomes will be analyzed with mixed-effects linear regression models where each health center will allow to have a random intercept. Potential confounding variables including smoking, alcohol consumption and physical activity will be treated as fixed factors. Both models will include baseline assessments as covariates. All tests will be two-tailed and To ensure the data safety, a data monitoring and quality assurance team will review the procedures for maintaining the confidentiality of data, and the quality of data collection, management and analyses. They will assess the missing information and errors in the dataset. They will also closely monitor recruitment, participation status, treatment compliance, regular follow-up and overall quality of research, and provide necessary feedback to the study team.The central and district research team will review participants’ data regularly to ensure safety of the trial. Research Investigators, mostly DAHC clinicians, located in each district will be responsible for reporting serious adverse events and unanticipated problems to the Principal Investigator, who will inform Ethical Review Board (ERB) within 48 h of the events. The district research team will also quickly follow up, assess and treat or refer the participants as required.Hypertension is emerging as one of the major public health concerns in Nepal. Risk factors survey of the non-communicable disease (NCD) reported that 25.7% of all study population had hypertension . SimilarGlobal action plan for the prevention and control of non-communicable diseases envisages for a 25% relative reduction in the prevalence of raised blood pressure in the next 10 years. Nepal has a well formed contextualized plan . InteresThis study is not designed to determine which components of the yoga intervention will have an effect on blood pressure. To minimize errors in blood pressure measurement, data enumerators  will be uniformly trained in blood pressure measurement including proper timing and positioning of the cuff and the patient.


In this paper, we present a new model based on modular neural networks (MNN) to classify a patient's blood pressure level (systolic and diastolic pressure and pulse). Tests are performed with the Levenberg-Marquardt (trainlm) and scaled conjugate gradient backpropagation (traincsg) training methods. The modular neural network architecture is formed by three modules. In the first module we consider the diastolic pressure data; in the second module we use details of the systolic pressure; in the third module, pulse data is used and the response integration is performed with the average method. The goal is to design the best MNN architecture for achieving an accurate classification. The results of the model show that MNN presents an excellent classification for blood pressure. The contribution of this work is related to helping the cardiologist in providing a good diagnosis and patient treatment and allows the analysis of the behavior of blood pressure in relation to the corresponding diagnosis, in order to prevent heart disease. The learning ability of neural networks and their pattern classification characteristics are the reasons why these models can be of great importance for medical applications. Nowadays there are many approaches in intelligent computing, such as evolutionary computing, fuzzy systems –7 and neHypertension that threatens to be present in most of the people of the world is a dangerous disease and leads to fatal consequences such as death and is a risk factor for people who suffer from it: obesity, diabetes mellitus, etc.Hypertension is a global problem as it affects more than a billion people and causes more than ten million (avoidable) deaths each year. The only way to know if a person suffers from this disease is to constantly check the blood pressure and effectively diagnose and prevent this disease , 24.Currently, there are several computer techniques that have been applied in medicine, such as neural networks and fuzzy systems to diagnose hypertension; by using these methods we can provide information about the factors and risks the patient may have.The main contribution of this work is the proposed Arterial Hypertension Classification and Diagnosis model based on modular neural networks for disease prevention. In this way, the cardiologist with the help of the model may prescribe the necessary treatment to the patient since hypertension is a disease that can evolve without showing any symptoms; this is the reason it is also known as “the silent killer”.In this work, an MNN model is used to classify the patient's hypertension level, tests are also performed with the Levenberg-Marquardt (trainlm) and scaled conjugate gradient backpropagation (traincsg) training methods, and this neural network consists of three modules. In the first module we consider the diastolic pressure data; in the second module we use details of the systolic pressure; in the third module, pulse data is used. Therefore, we obtain the patient's blood pressure through ambulatory blood pressure monitoring (ABPM); so far we have 300 records.Artificial neural networks with the back propagation learning algorithm to obtain the hypertension diagnosis were presented by Sumathi B. et al. . The metHuang S. et al.  presenteVilkov V.G. et al. , 27 presBarman M. et al.  presentePatil P. et al.  designedMorsi I. et al.  presenteHussein S.  analyzedTouyz M. R. et al.  presenteNeural networks are integrated by many interrelated components. A neural network can have a structure of multiple inputs and outputs; these systems operate similarly to the human brain. A neural network learns from input values, and this helps us learn about the human being –35.In Mexico, a large number of professional studies have been made with the idea of determining the prevalence of hypertension, defined as the frequency of the disease at a given time in a particular place. The most important studies use different methodological criteria, which make them difficult to compare. In these studies, different blood pressure levels are used to define this disease. They even propose an adequate standardization to measure it, which usually leads to overdiagnosis. The number of measurements made at the time of the survey, be it on the same day or on different days, impacts significantly the prevalence of the disease. Another study that was decided to be included on the findings reported is the study of heart diseases of San Antonio (ECSA), which includes Mexican-American population and has a branch in Mexico City: the study of diabetes in Mexico City (EDCM). In these studies, the prevalence and incidence of hypertension and other cardiovascular factors are also reported.Hypertension may be essential  or secondary (with demonstrable cause) and can also be isolated or as metabolic syndrome; this disease is incapacitating and deadly due to the damage caused to important organs: blood vessels, heart, kidney, and eyes. Normal levels of blood pressure are those below 139/89 mmHg; secondary hypertension can be suspected in young people younger than 35 years of age or when there is no hypertension history in the family or in the absence of a family. Treatment of hypertension helps reducing damage to organs or even reverses it if possible; this treatment may be a drug with antidepressant use or nonpharmacological treatment, which includes changes in hygienic-dietetic habits .The risk of cardiovascular complications begins, apparently with blood pressure values of 115mmHg for systolic and 75 mmHg for diastolic. In the clinical area, several subtypes of hypertension determined by isolated elevations of systolic and diastolic, or the combination of both are used. These subgroups have their own natural history and present a different cardiovascular risk.Isolated systolic hypertension (ISH) is common after 50 years of age, affecting nearly 50% of people between 50 and 59 years of age, reaching 90% in those over 80 years old. This subtype of hypertension reflects the increase in the stiffness of the aorta and great vessels without an increase in arteriolar resistance.When there is an increase in arteriolar resistance combined with a lack of increased arterial stiffness, the isolated diastolic pressure subtype (IDP) occurs; this subtype predominates in people younger than 40, comprising almost 60% of the population .Hypertension includes calculating pulse pressure (PP), which is done by subtracting the diastolic pressure and systolic quantities , 38. In Previously, the pulse was measured when the examiner or physician would sit comfortably on the right side to support the patient's elbow and, with his right thumb, explore the antecubital fosse, where the brachial artery is. The patient's arm reflex should be activated. When the thumb or finger of the examiner is correctly in place, he or she can raise or lower the patient's forearm by varying the pressure applied to the artery, feeling the maximum pulse. The right thumb of the examiner can feel the patient's carotid artery similarly, which he or she may feel by gently grasping the patient's fingertips with theirs. The digital pulse can be counted exactly by simultaneously palpating the radial artery while the examiner supports the patient's wrist. The femoral pulse of a child of tender age should be sought only while the leg is relaxed voluntarily.The arteries pulsations provide information about heart rhythms and speed, arterial pulse differential , thrills (shudders), and waveform. , 40.Bradycardia. The bradycardia term simply means slower rate. Bradycardia athletes: the heart of an athlete is much more powerful than a normal person, which allows their heart force a greater volume of blood with each beat, a large proportion of blood driven into the arterial tree with each beat probably produces sufficient circulatory reflexes to begin causing bradycardia.Tachycardia. Tachycardia means rapid heart rate. The three causes of tachycardia are increased body temperature and heart stimulation by the sympathetic and toxic states of the heart. Increased heart rate of about 10 beats per minute for each degree Celsius increases body temperature, up to 41°C; at this temperature, the heart rate may actually decrease by increasing muscle wasting as a result of fever. Tachycardia causes hyperthermia and increases the frequency of the heart rhythm [t rhythm .Nowadays modern laboratory methods often require outpatient-monitoring equipment to measure a variety of the indicators for blood pressure (BP), for 24 hours continuously. The biological rhythms are physiological functions and pathological alterations. The BP with an average heart rate of 72 beats per minute and 103.680 pulse waves is produced with corresponding changes in BP . While aThis section presents the proposed method for blood pressure classification, which consists of designing of modular neural networks (MNN) and the integration of responses of MNN with an average method. The main goals are to implement and find the best MNN architecture; the MNN consists of three modules; the first module is for the systolic pressure, the next module is the diastolic pressure, and in the last module we have pulse, this way we classify the arterial hypertension of a person.In The proposed method to classify the blood pressure of a patient was validated with tests performed on 16 patients and positive results were obtained for the MNN.The results of the best MNN architecture are shown in The results of the best MNN architecture are shown in In In this section a hypothesis test is made based on the errors obtained with the architecture of the modular network using the Levenberg-Marquardt learning method (trainlm) to obtain the trend of the systolic pressure. In addition, the results are compared with linear regression models based on the obtained errors.X . The general equation corresponding to a linear regression model is as follows:β represents a parameter that establishes the linear relationship between variables. ϵ represents the random error terms. X represents the real data. y is the variable for classification. The model used to perform the statistical comparison was the well-known linear regression. This model describes the relationship between a dependent variable and  as a function of one or more independent variables βo and β1 are the following (for each of the modules): The formulas to estimate the beta parameter values are given byModule 1βo =0.101663348532528 β1= 1.028385618868264 Module 2βo = 0.04938271 β1= 1.024901397932274 Module 3βo =0.565544448530641 β1= 1.104635529315485  μ1 − μ2) is the expected difference.  and Levenberg-Marquardt (trainlm), and we achieved good results with the second method (trainlm). Good results were also obtained in the diastolic, systolic, and pulse models, since the trend was good with respect to the records used to perform the tests. In addition, we have made a comparison between the neural network model and the regression equations, showing that the MNN model statistically outperforms the regression model. In this paper we conclude that this classification method is effective and could help the cardiologist to detect and prevent a patient's blood pressure.


Heart transplantation causes denervation of the donor heart, but the consequences for cardiovascular homeostasis remain to be fully understood. The present study investigated cardiovascular autonomic control at supine rest, during orthostatic challenge and during isometric exercise in heart transplant recipients (HTxR).A total of 50 HTxRs were investigated 7–12 weeks after transplant surgery and compared with 50 healthy control subjects. Continuous, noninvasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 60° head-up tilt and during 1 min of 30% of maximal voluntary handgrip. Plasma and urine catecholamines were assayed, and symptoms were charted.At supine rest, heart rate, blood pressures and total peripheral resistance were higher, and stroke volume and end diastolic volume were lower in the HTxR group. During tilt, heart rate, blood pressures and total peripheral resistance increased less, and stroke volume and end diastolic volume decreased less. During handgrip, heart rate and cardiac output increased less, and stroke volume and end diastolic volume decreased less. Orthostatic symptoms were similar across the groups, but the HTxRs complained more of pale and cold hands.HTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest as well as attenuated blood pressures and total peripheral resistance responses during orthostatic challenge, possibly caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences. Heart transplantation (HTx) remains the treatment of choice for end-stage heart failure, offering improved survival and quality of life for the recipients  and an isometric exercise test (handgrip) might be beneficial, as this combined setup might differentiate between effects of afferent and efferent cardiac denervation. Orthostatic responses are presumably affected by both afferent denervation of low-pressure cardiopulmonary baroreceptors and efferent denervation of the sinoatrial node and myocardium, whereas isometric exercise responses are affected by efferent denervation only. To the best of our knowledge, no previous study of HTxRs has applied a similar experimental approach. In addition, previous reports of orthostatic responses , which addresses autonomic denervation and reinnervation in a population-based prospective cohort of HTxRs. The present study reports results from the first encounter (baseline) only, compared with a group of healthy controls. AccHEART has been approved by the Norwegian National Committee for Ethics in Medical research. Participation was based upon informed consent.All patients at the Department of Cardiology, Oslo University Hospital receiving a heart transplant between January 2013 and December 2015 were screened for eligibility. To be included, we required the age of the recipient to be between 16 and 70 years and the transplant surgery to have been performed during the last 7–12 weeks  on both antecubital areas 1 h before arriving.All participants attended a 3-day investigational program at the Oslo University Hospital, Norway. The program was executed between 7.30 and 11.00 a.m. and was carried out in a fixed sequence. It included a clinical examination, autonomic cardiovascular control assessment, blood, and urine sampling, and questionnaire charting. All participants were instructed to abstain from tobacco products and caffeine 48 h prior to attendance, and to fast overnight. They were maintained on immunosuppressive medications, while all other drugs were paused on the morning of testing. They brought morning spot urine in a sterile container, and were instructed to apply a local anesthetic ointment  is a combined hardware and software device for noninvasive continuous recording of cardiovascular variables , to avoid syncope and other manifestations of failing cardiovascular homeostasis. Prior to initiation of the autonomic tests, participants were asked to perform maximum left-sided handgrip for 10 s, using an electronic device that provides a continuous display of the force . Based on the maximum value, the 30% level was calculated, and the participants used a couple of minutes to familiarize with this force.Z/dt)  was obtained from the electrocardiogram. Continuous arterial blood pressure was measured noninvasively beat-to-beat by finger plethysmography 0.51456.All primary cardiovascular variables (beat-to-beat recordings) were manually inspected and artifacts (such as non-sine node beats) were removed. Thereafter, beat-to-beat stroke volume (SV) was calculated from the impedance signal. Cardiac output (CO) was calculated as SV times HR, and total peripheral resistance (TPR) was calculated as mean blood pressure divided by CO. Flow-dependent variables were indexed according to body surface area (BSA), estimated from the formula BSA = 0.0235 × height (cm)For each individual, the median values of all cardiovascular variables were computed in the following epochs: (1) from 30 to 270 s. after start of supine rest; (2) from 30 to 270 s. after 60° head-up tilt; and (3) from 57 to 60 s. After initiation of each handgrip procedure, the mean value across the two most representative series of cardiovascular recordings  were used in subsequent analyses.The epochs were defined in accordance with previously established routines at our laboratory . Finally, mean values across all individuals in each group  were computed.Blood samples for catecholamine analysis were obtained from venous puncture in vacutainer tubes treated with ethylene glycol tetra acetic acid and glutathione from Sigma-Aldrich . They were immediately put on ice and centrifuged  within 15 min. Both plasma epinephrine and norepinephrine were analyzed by high-performance liquid chromography (HPLC)  with a reversed-phase C-18 column  and electrochemical detector  using a commercial kit from Chromsystem. The intra- and inter-assay coefficients of variation (CV) were 3.9% and 10.8%, respectively. Urine samples for catecholamine analysis were acidified to pH ~ 2.5 after collections, and thereafter analyzed by the same HPLC system as for plasma catecholamines. The intra- and inter-assay CVs were 3.9 and 5.2%, respectively. N-terminal pro-brain natriuretic peptide (NT-pBNP) in plasma was assayed at the accredited laboratory at Oslo University Hospital, Norway using routine procedures.The autonomic symptom profile (ASP) is a validated inventory for assessing autonomic symptoms  was charted using the activPAL accelerometer device  for 7 consecutive days  . Results are presented with mean (standard deviation) or median (interquartile range) for continuous data, depending on distribution. Categorical data are reported with frequencies. Statistical tests of differences between HTxRs and healthy controls were performed applying Student t test, Mann–Whitney U test, Chi square test or Fisher’s exact test as appropriate. Relationships between selected variables within the HTxR group were explored by Pearson correlation analyses. A p value ≤ 0.05 was considered statistical significant, and all tests were carried out two-sided. As several variables are strongly intercorrelated, p values were not adjusted for test multiplicity.Statistical analyses were carried out using SPSS statistical software . Previously, studies with identical experimental setup have been conducted at our institution; in the present study, power estimation suggested that a total of 50 participants in each group would support a power of about 80% to detect a medium effect size (Cohen’s n = 20) were comparable to the study participants regarding demographics and pre- and postoperative characteristics  time of 2.5 (0.4) months after HTx surgery  or re-transplantation (n = 4). The bicaval surgical technique with a small left atrial cuff and cavoatrial anastomoses was applied to all cases. They were maintained on immunosuppressive therapy, consisting of cyclosporine A (CsA) and mycophenolate mofetil in the majority of male recipients and tacrolimus and mycophenolate mofetil in the majority of female recipients. In patients with renal dysfunction (n = 13), a combination of low-dose CsA and the mTOR inhibitor everolimus was initiated. In addition, corticosteroids and statins were given to all HTxRs, and a total of 15 patients were on beta-blocking agents. Routine surveillance myocardial biopsies (each week during the first 8 weeks and then after 10 and 12 weeks) revealed an episode of acute rejection in a total of 14 HTxRs prior to inclusion in the AccHEART study. At the time of inclusion, acute rejection was revealed in five of the recipients (2R in 3 patients and 1R in 2 patients); all without symptoms and with normal heart function.The included HTxRs underwent either primary single-organ orthotopic HT . Orthostatic symptom score was identical across groups, whereas HTxRs complained more of pale and cold hands.Systolic blood pressure (measured supine using standard oscillometric technique) was slightly, but significantly increased in the HTxR group, whereas diastolic blood pressure was identical, as were left ventricular ejection fraction Table . Levels At supine rest during the autonomic experiments, heart rate, blood pressures and total peripheral resistance index were significantly higher, and stroke index and end diastolic volume index were significantly lower in the HTxR group compared with healthy controls Table . CardiacWithin the HTxR group, total peripheral resistance index during supine rest showed a strong negative correlation to body weight and to dosage of prednisolone; in partial correlation analyses controlling for body weight, the associations between prednisolone and TPRI became negligible and non-significant Table . In addiThe most important results of this study are: (1) at supine rest, HTxRs have higher blood pressures and total peripheral resistance than healthy controls. (2) During orthostatic challenge, HTxRs have attenuated blood pressure and total peripheral resistance responses. (3) During isometric exercise, HTxRs have preserved blood pressure and total peripheral resistance responses, but an attenuated cardiac output response.The tendencies towards hypertension and peripheral vasoconstriction in HTxRs are well known , suggesting that usage of diuretics and thereby reduced diastolic filling might contribute to lower cardiac output response. The functional impact of this particular homeostatic aberration remains to be fully characterized, but reduced exercise capacity is a logical assumption. This hypothesis deserves further investigations; interestingly, handgrip strength is a marker of frailty in heart failure patients  was chosen to avoid interference from compensatory responses related to the surgical procedure per se, and at the same time avoid any reinnervation processes to have taken place. While the data suggest that the latter presumption holds, we cannot completely rule out that long-lasting effects from the surgical procedure and subsequent intensive care might have influenced the results. Cardiac transplantation is an effective treatment against chronic heart failure; as the patient group was investigated 7–12 weeks after transplant surgery, we find it likely that previous autonomic abnormalities related to a failing heart would have normalized prior to inclusion. However, it is possible that “hangover” effects from the patients’ previous health condition or another underlying disease process might have biased the results.p values were not adjusted for test multiplicity; however, the computed confidence intervals support the conclusions drawn from the statistical tests .Missing data were not imputed; however, the numbers of missing data points were few and considered negligible. HTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest, as well as attenuated blood pressure and total peripheral resistance responses during orthostatic challenge; both these effects might be caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences in HTxRs.


This secondary analysis of the Systolic Blood Pressure Intervention Trial uses a random forest–based analysis to assess whether clinically important heterogeneity exists in the risk of harm associated with intensive blood pressure treatment among adults with hypertension who smoke. Does clinically important heterogeneity exist in the risk of harm from intensive blood pressure control in adults with hypertension who smoke?In this ad hoc secondary analysis of the randomized Systolic Blood Pressure Intervention Trial (SPRINT), potential heterogeneous treatment effects were identified via a random forest–based analysis using half of the trial data and tested by applying Cox proportional hazards regression models to the remaining data. Smokers with systolic blood pressure greater than 144 mm Hg were associated with a significant increase in cardiovascular events from lower blood pressure targets despite overall positive trial findings.Adults with hypertension who smoke may have a higher rate of cardiovascular events associated with intensive blood pressure control. The randomized Systolic Blood Pressure Intervention Trial (SPRINT) showed that lowering systolic blood pressure targets for adults with hypertension reduces cardiovascular morbidity and mortality in general. However, whether the overall benefit from intensive blood pressure control masks important heterogeneity in risk is unknown.To test the hypothesis that the overall benefit observed in SPRINT masked important heterogeneity in risk from intensive blood pressure control.In this exploratory, hypothesis-generating, ad hoc, secondary analysis of data obtained from 9361 participants in SPRINT, a random forest–based analysis was used to identify potential heterogeneous treatment effects using half of the trial data. Cox proportional hazards regression models were applied to test potential heterogeneous treatment effects on the remaining data. The original trial was conducted at 102 sites in the United States between November 2010 and March 2013. This analysis was conducted between November 2016 and August 2017.Participants were assigned a systolic blood pressure target of less than 120 mm Hg (intervention treatment) or of less than 140 mm Hg (standard treatment).The primary composite cardiovascular outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.P = .03). This subgroup was also associated with a higher likelihood to experience acute kidney injury under intensive blood pressure control .Of 9361 participants in SPRINT, 466 participants (5.0%) were current smokers with systolic blood pressure greater than 144 mm Hg at baseline, with 230 participants (49.4%) randomized to the training data set and 236 participants (50.6%) randomized to the testing data set; 286 participants (61.4%) were male, and the mean (SD) age was 60.7 (7.2) years. Combinations of 2 covariates  distinguished participants who were differentially affected by the intervention. In the testing data, Cox proportional hazards models for the primary outcome revealed a number needed to harm of 43.7 to cause 1 event across 3.3 years among participants who, at baseline, were current smokers with systolic blood pressure greater than 144 mm Hg (10.9% [12 of 110] of primary outcome events for intervention treatment vs 4.8% [6 of 126] for standard treatment; hazard ratio, 10.6; 95% CI, 1.3-86.1; In this secondary analysis of SPRINT data, current smokers with a baseline systolic blood pressure greater than 144 mm Hg had a higher rate of cardiovascular events in the intensive treatment group vs the standard treatment group. Further research is needed to evaluate the potential tradeoffs of intensive blood pressure control in hypertensive smokers. Traditional subgroup analyses typically fail to identify these heterogeneous treatment effects (HTEs) because the analyses are limited by multiple testing concerns, estimation bias, and prespecified univariate covariate testing,10 The method adapts the machine learning technique random forest analysis to predict subgroup treatment associations over a rich set of variables and functional forms. Here, we construct a random forest in half of the trial data (training data) to identify patient subgroups that may have been harmed by intensive blood pressure control and then validate these hypotheses using Cox proportional hazards regression models in the remaining half of the data (testing data). We test the hypothesis that the overall benefit in the trial masked important heterogeneity in risk from intensive blood pressure control.In the present study, we use a machine learning method to investigate potential heterogeneity in the cardiovascular morbidity and mortality effects of intensive blood pressure control reported in SPRINT.TRIPOD) reporting guideline, a standardized, evidence-based set of recommendations for reporting prediction modeling studies.12 The Icahn School of Medicine at Mount Sinai Institutional Review Board deemed this analysis exempt from review and waived the need for obtaining informed patient consent because the data were deidentified.This is an exploratory, hypothesis-generating, ad hoc, secondary analysis of data obtained from 9361 participants in SPRINT. Study design and reporting were based on the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis . Patients with diabetes or prior stroke were excluded. After randomization, participant’s antihypertensive regimens were adjusted on the basis of the treatment assignment to achieve the appropriate systolic blood pressure (SBP) target. Demographic data were collected at baseline; clinical and laboratory data were obtained at baseline and every 3 months thereafter, with participants queried about medical events and hospitalizations every 6 months; and medical records and electrocardiograms were obtained for documentation of events, including serious adverse events. Full details of the original study methods and detailed inclusion and exclusion criteria are available elsewhere.14The study sample consisted of all participants in SPRINT, a randomized, controlled, open-label trial assigning an SBP target of less than 120 mm Hg (intervention group) or assigning a target of less than 140 mm Hg (control group) to persons with an SBP of 130 mm Hg or higher and an increased cardiovascular risk. The study was conducted at 102 clinical sites in the United States between November 2010 and March 2013.In this post hoc secondary analysis, we used the SPRINT primary outcome as the trial’s primary composite cardiovascular outcome, which included myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Details on the 27 baseline factors we analyzed are provided in eTable 1 in the 15In the present ad hoc analysis of the SPRINT cohort, the data of 9361 participants were randomly divided into 2 equal and independent subsets: a training set for machine learning–based hypothesis generation and a testing set for statistical inference–based hypothesis testing. We ensured that the distributions of covariates and outcomes in the training data were reflective of the whole data set using entropy weight minimization . The other 50% of the training data are used to estimate the association between the treatment and outcome in these subgroups, ensuring an “honest” estimate and reducing the possibility of overfitting  was estimated by calculating the proportion of the permuted interaction coefficients that were greater than the true interaction coefficient. A subgroup hypothesis was considered validated  only if (1) the HR for the interaction between the treatment and the subgroup was greater than 1 and statistically significant (2-tailed P < .05 and the FDR < 0.05) and (2) the HR for the subgroup was greater than 1 and statistically significant (2-tailed P < .05).In the testing data, these subgroup hypotheses were examined using Cox proportional hazards regressions to estimate hazard ratios (HRs) for the primary outcome, with stratification according to clinic site. Following standardized protocols for detection of HTEs, the Cox proportional hazards regression models contain terms for study group assignment, a subgroup dummy variable, and their interaction.In addition to examining subgroup differences in the study’s primary composite cardiovascular outcome, we also tested whether the treatment was positively associated with adverse events that may have contributed to increased rates of the primary outcome within a subgroup, again using Cox proportional hazards regression models. All adverse outcomes available in the SPRINT data that were categorized as serious adverse events or resulted in emergency department visits were included in the analysis because these outcomes are interpretable and well documented.To explore mechanisms through which the intervention may have contributed adversely to the study’s primary composite cardiovascular outcome, we analyzed blood pressure changes in the standard and intensive intervention groups during the course of the study. Differences between treatment groups were calculated for the means of the mean arterial pressure ]), diastolic pressure, and systolic pressure within the identified subgroup and among the rest of the cohort.17 All analyses were performed between November 2016 and August 2017 using R, version 3.2.2  and Stata, version 14 (StataCorp). The statistical code for the random forest analysis is available online.18Data from SPRINT were obtained from the National Heart, Lung, and Blood Institute’s Biologic Specimen and Data Repository Information Coordinating Center.Of 9361 participants in SPRINT, 466 participants (5.0%) were current smokers with SBP greater than 144 mm Hg at baseline, with 230 participants (49.4%) randomized to the training data set and 236 participants (50.6%) randomized to the testing data set; 286 participants (61.4%) were male, and the mean (SD) age was 60.7 (7.2) years. In the present ad hoc analysis, the SPRINT data set was randomly divided into a training set (n = 4681) and testing set (n = 4680). This training set was used for model development, while the testing data set was preserved for internal validation of hypotheses . The traUsing the training data, the random forest algorithm identified subgroups with high likelihood of differential benefit or harm from the intensive blood pressure intervention. There were a total of 5250 leaves in the 1000 trees tested in the random forest. In the majority of leaves (4911 [94%]), the estimated association between treatment and the primary outcome indicated variable benefit from the intervention, but the remaining 339 leaves (6%) indicated potential harm. Relative to all other covariates, those associated with kidney function  and cardiovascular disease risk factors  most frequently defined membership in the 6% of subgroups with a higher likelihood of being adversely affected by treatment , our analysis validated that 1 subgroup  had a significantly greater frequency of primary events in the treatment group (10.9% [12 of 110]) than in the control group (4.8% [6 of 126]), with an HR of 10.6  (P = .02) and remained significant when accounting for multiple comparisons (FDR < 0.05)   . The numP = .04; for all remaining participants: HR, 1.6; 95% CI, 1.2-2.2; P = .005) (eTable 4 in the P = .007).Further analyses indicated that acute kidney injury, a treatment-associated serious adverse event, was significantly more prevalent in current smokers with a baseline SBP greater than 144 mm Hg. This subgroup of participants was more likely to experience acute kidney injury under intensive blood pressure control (10.0% [11 of 110]) compared with usual care (3.2% [4 of 126]) , driven by a far more sustained and pronounced reduction in diastolic blood pressure (approximately 2-fold) than SBP  had an HR greater than 1 with P < .10 (eTable 5 in the 16 Similarly, estimating an FDR is a challenge given covariate dependencies in hypothesized subgroups. Nested FDR approaches may be one way to recover some power when testing multiple hypotheses, but more formal study is required to identify optimal ways to minimize multiple hypothesis testing error when searching a multicovariate space for heterogeneous treatment effects. Another potential concern is that censoring was slightly greater among the hypertensive smoker subgroup members than among the remaining participants. It is important to note that the random forest–based algorithm we used does not account for censoring when identifying subgroup hypotheses in the training data. This limitation was addressed by using Cox proportional hazards regression models in the testing data, but the covariate partitioning algorithm can be improved by including censoring explicitly in the construction of each tree.A second related limitation is that, by splitting the data, we significantly reduced our power to detect meaningful differences in the hazards of the primary outcome in the testing data. The modest statistical power may have partly contributed to the wide CIs we observed. It is also likely that bona fide subgroups could be missed by this method. Besides the subgroup of hypertensive smokers, no other subgroup analyzed had an HR greater than 1 with This post hoc secondary analysis of SPRINT data demonstrates that a machine learning method for HTE prediction can reveal unexpected and previously unappreciated HTEs within an existing randomized clinical trial to identify potential hypotheses to test in future research. Understanding heterogeneity in treatment effects is critically important so that clinicians can target an intervention to patients most likely to benefit and can avoid unnecessary harm to hidden high-risk groups. Further prospective study is required to determine how different blood pressure targets may harm high-risk subgroups, such as hypertensive smokers. Greater mechanistic evidence for the role of current smoking status on aggressive SBP lowering and careful investigation of reliable indicators of risk, including diastolic blood pressure, are also warranted. Our findings suggest that randomized clinical trials with beneficial effects can still have unwanted effects in population subgroups. Estimating HTEs with data-driven methods can be an important step in safely and rationally applying scientific insight to clinical practice.