Methods: A total of 44 patients presenting a skeletal Angle Class II malocclusion (ANB > 4°) due to mandibular retrusion and a cervical maturation stage between CS2 and CS3 were included in the study. Of these 44 patients, 22  were treated using the Herbst appliance, while 22  were followed for a 12-month observational period. A cephalometric tracing was performed at the beginning of treatment (T0) and after 12 months (T1). Results: In both groups there was a significant advancement of soft tissue pogonion , but the difference between the two groups was not significant (p = 0.172). On the contrary, both groups had a significant advancement of the mandibular sulcus  and a lower lip protrusion , but in both cases the HBT group showed a statistically significant greater increase in sulcus protrusion (p = 0.002) and lower lip protrusion (p = 0.029) than controls. There were no statistically significant effects on the upper jaw. Conclusions: The Herbst appliance advanced the lower jaw soft tissues.Background: To evaluate the profile changes following orthopedic/orthodontic treatment with the Herbst Miniscope Class II malocclusion is a very frequent orthodontic problem, affecting about 33% of the population , with a In order to influence growth of maxillary and mandibular bones, orthopedic-orthodontic treatments have been used by clinicians from years, but their efficacy has been widely debated ,8. In a There are several studies that have described appliances able to determine increases in mandibular growth, thanks to a mandibular propulsion ,11,12,13One possible treatment for Class II patients with mandibular retrusion is the Herbst appliance. Based on the “Bite Jumping” principle, this device acts by stimulating the condylar growth and remodeling of the glenoid cavity into a lower and forward position ,16. In tAlthough aesthetic improvement is the patient’s primary goal, few studies have investigated the perception of profile and soft tissue improvements resulting from functional therapy ,20. Only®). The null hypothesis was that the Herbst appliance did not change the soft tissue profile of the patients.Thus, the aim of this study is to evaluate profilometric changes in patients with skeletal Class II caused by mandibular retrusion, obtained with a simplified version of the Herbst appliance  on 19 December 2019.The sample comprised patients selected from Magna Græcia University’s dental clinic and orthodontic private practice. a full Class II molar relationship;ANB > 4°,Overjet > 6 mm,an age range of 9–15 years,good quality radiographs, andcervical vertebral maturation stage (CVMS)2 or >3 .The inclusion criteria of this study were the following: hyperdivergent subjects  ,tooth agenesis,previous orthodontic treatment, andperiodontal diseases.The exclusion criteria were the following: ® appliance. Transversal discrepancies and/or crossbites, if present, were treated with orthopedic or orthodontic expansion of the palate before functional treatment [a total of 22 patients  were treated with Herbst MiniScopereatment . The avereatment  and initreatment ;the CTR group comprised 22 patients . The CTR group followed the same inclusion and exclusion criteria as the treated group.The final sample consists of 44 patients :The cervical stage was assessed by one examiner on the T0 cephalogram according to the cervical vertebral maturation (CVM) method ,27.The cephalograms had a mean time interval T1-T0 of 12 months.The differences in the T1-T0 linear measurements were recorded according to Pancherz’s method ,28.One examiner trained in electronic cephalometric analysis performed all the cephalometric measurements using Dolphin Imaging 11.0 software . The measuring points, reference points, and lines were defined following Pancherz’s method. Where there was a double projection of two points, the midpoint was used. For all the linear measurements, the OL and the OLp of the initial radiograph were used as a reference grid. The grid was then transferred from the T0 to the T1 radiograph by superimposing it onto the N-T point line, with the T point as the registering point. All the linear measurements were made parallel to the OL.The profilometric changes obtained after the treatment period were evaluated by comparing the lateral teleradiography performed at the time T0, just before the start of treatment, with that at the time T1, 12 months after the start of treatment, when the functional appliance was removed. A cephalometric tracing of the CTR group was performed at the time T0 and after 12 months of observation (T1) without any orthodontic treatment. Once the cephalometric analyses were carried out, the traces were overlapped on/superimposed on the NSL plane (Nasion Sella line), the inclination of which does not change with age, to evaluate the changes in the profile in each patient . Soft tissue evaluation was performed by evaluating linear and angular measurements.According to Pancherz’s method  the occlAll the tracings were performed by one single blinded operator who trained in electronic cephalometric analysis and conducted all the cephalometric measurements using Dolphin Imaging 11.0 software .From the Pancherz cephalometric reference planes, normally used to evaluate skeletal and dental displacements, the distances of the soft tissue points examined were evaluated ,30.For each subject the Nasion (NA) and T points from the first head film tracing were transformed to the second tracing by using the structures of the anterior cranial base for orientation.The films were superimposed with great care so that the distance from the sella turcica was the same on both head film tracings. The reference lines used in the cephalometric analysis are shown in All measurements were done parallel to OL.NSL: (nasion-sella line) S to N line used in cephalometric orientationOL:  line that goes from U1 to the distobuccal cusp of the first permanent upper molar. Used as a reference line in the detection of cephalometric measurementsOLp:  perpendicular to OL passing through T point. It represents the line from which the distances to the measuring points were evaluated.For each patient, measurements were analyzed in the pre- and post-treatment periods (or after 12 months of observation) to evaluate profilometric changes:S: (sella) point located at the center of the sella turcicaT pointN: (nasion) earlier point of the nasofrontal sutureU1: (superior incision) lower point of the upper central incisorsPrn: , the most anterior point of the nasal apexANS: , most anterior point of maxillary boneA: (point A), posterior point of the anterior convexity of the maxillaA soft: (A soft point), maximum concavity of anterior lip superior pointSn: , the point of maximum concavity of the nasolabial curvatureULs: (upper lip), the most forward point of the upper lipU6: (upper first molar), distal point of upper first molarL1: (lower incision) upper point of the lower central incisorsLLi: (lower lip), most anterior point of the lower lipL6: (lower first molar), distal point of inferior first molarSub: , the posterior point of the inferior labial sulcusB: (B point), maximum concavity of anterior mandibular bonePo: (pogonion) anterior point of the mandibular symphysisPos: (soft tissue pogonion), most anterior point of the soft tissues of the lower jawThe measuring points are shown in SN: sella-nasion lineOLp-U1: line that evaluates the position of superior incisor compared to the perpendicular line to the occlusal lineOLp-Prn: line that evaluates the nasal prominence compared to the perpendicular line to the occlusal plane OLp-ANS: line that evaluates the anterior nasal spine point compared to the perpendicular line to the occlusal planeOLp-A: line that evaluates the maxillary’s position compared to the perpendicular line to the occlusal planeOLp-As: line that evaluates the position of A point of the soft tissue compared to the perpendicular line to the occlusal planeOLp-Sn: line that evaluates the position of the infranasal point compared to the perpendicular line to the occlusal plane (filtrum)OLp-ULs: line that evaluates the position of the upper lip compared to the perpendicular line to the occlusal planeOLp-U6: line that evaluates the position of upper first molar compared to the perpendicular line to the occlusal planeOLp-L1: line that evaluates the position of lower incisor compared to the perpendicular line to the occlusal planeOLp-LLi: line that evaluates the position of the lower lip compared to the perpendicular line to the occlusal planeOLp-L6: line that evaluates the position of the lower first molar compared to the perpendicular line to the occlusal planeOLp-B: line that evaluates the mandible’s position compared to the perpendicular line to the occlusal planeOLp-Sub: line that evaluates the position of the mandibular sulcus compared to the perpendicular line to the occlusal plane (concavity of the mandibular sulcus)OLp-Po: line that evaluates the position of the pogonion compared to the perpendicular line to the occlusal planeOLp-Pos: a line that evaluates the position of the soft tissue pogonion compared to the perpendicular line to the occlusal plane.Measurements were performed on lines parallel to the OL starting from the vertical reference line Olp and are shown in The sample size calculation showed that 19 patients per group were needed to detect an increase in mandibular length ≥2.0 to achieve 80% of power according to previously estimates changes in mandibular length (Pg/OLp) .Data were analysed by conventional descriptive statistics. A Shapiro-Wilk test was performed to evaluate wheter the samples were normally distributed.p < 0.05. All the analyses were performed with commercial software .Variables were analysed by means of paired t-test or within-group comparisons, while between-groups comparisons were performed by means of unpaired t-test. Absolute cephalometric changes were converted to relative changes over a 12-month period. The level of statistical significance was set at d2/2n where d is the difference between two measurements per pair and n is the number of double measurements. The methodological error does not exceed ±0.25 mm for each variable investigated. The values investigated were compared using the Student’s t-test. The mean and standard deviation (SD) were calculated for each variable, and the t-test was performed to compare the initial and final results of the period considered and to ascertain the differences between the groups. The magnitude of the methodological error for the linear measurements was calculated with the formula ± √ΣThe results are shown in p = 0.030of 2 mm, on mean average, of the lower lip (OLp-LLI), p = 0.002.of 4.3 mm, on mean average, of the sublabial sulcus , From the obtained data, a more anterior position from CTR group can be assessed:The aim of this article was to evaluate on cephalograms the sagittal changes of the profile in Herbst treatment. Cephalometric analysis helps the orthodontists evaluate their treatment results, taking into account profile changes. This evaluation is obviously limited to sagittal changes.It must be remembered that the patients selected presented a skeletal Angle Class II malocclusion with mandibular retrusion and favorable functional treatment response. The results of this study support the hypothesis that functional appliances positively influence the profile of patients with Class II malocclusion. This is consistent with the results of other studies that were carried out with other functional appliances ,33,34. ®. This confirms the findings of previous studies on Herbst appliance [According to the literature, there is a moderate increase in nasal prominence, in the position of the filtrum and the upper lip, most likely ascribed to the patient’s growth and not to the action of the appliance. A significant increase in the position of the lower lip and pogonion, albeit partly due to patient growth, is undoubtedly favored by the mandibular propulsion mechanism resulting from the therapy with Herbst Miniscopeppliance ,36. Although the influence of the functional treatment on mandibular growth appeared limited, and although the change observed in mandibular position could be ascribed mainly to normal growth, a significant improvement in the patient’s profilometric characteristics was observed.Above all, there was a noticeable advancement of the lower lip compared to the superior, limiting the gap existing before the therapy between the two structures. This advancement should be ascribed to a more protrusive position of the mandible determined by the Herbst appliance. The change in value of L1-LLi was due to a new muscle adaptation resulting from mandibular advancement. These results are similar to those of a recent study by Hourfar et al.  that retThe results are also in accordance with two studies ,37 that ® fixed appliance in subjects affected with class II malocclusion with mandibular retrusion were evaluated cephalometrically. The material consisted of 44 Class II subjects with mandibular retrusion, 22 treated with Herbst appliance and 22 in the control group. Lateral roentgenograms in centric occlusion were analyzed before and after treatment. The original occlusal line (OL) and the occlusal line perpendicular (OLp) through sella were used as reference.The profile changes following orthopedic/orthodontic treatment with Herbst MiniScopeIn conclusion, data from the study shows a significant improvement of the patient’s profilometric characteristics, resulting in an excellent correction of class II. It is advisable to carry out the correction of sagittal discrepancies as early as possible.® equipment is definitely valid for improving the profile of patients with class II malocclusion caused by mandibular retrusion, favoring a progression of the lips and the chin. Further studies are needed to evaluate the profilometric changes in the long term determined by the appliance.The dentoalveolar compensation determined by the Herbst device in some subjects is able to determine an improvement of the profile even in absence of significant skeletal changes. Therefore, the new Herbst Miniscope


B-type natriuretic peptide (BNP) secretion is stimulated by cardiac dysfunction. However, it is unclear how finely myocardial ischaemia contributes to BNP secretion and whether increases in BNP secretion contribute to coronary vasodilation. This study investigated the direct interaction between plasma BNP levels and cardiac ischaemia using the baseline distal-to-aortic pressure ratio (Pd/Pa). We examined the baseline Pd/Pa and fractional flow reserve (FFR) in 167 patients with intermediate coronary stenosis. The plasma BNP level appeared to be associated with the baseline Pd/Pa in the study population, and this association appeared to become clear only in patients with an FFR ≤ 0.80. To examine the effect of the baseline Pd/Pa on the BNP level in these patients, structural equation modeling (SEM) was performed. The baseline Pd/Pa significantly affected the BNP level  and the left ventricular ejection fraction . To examine the role of BNP in coronary vasodilation, we proposed another path model using a novel value obtained by dividing the FFR by the baseline Pd/Pa (FFR/baseline Pd/Pa) as an index of the hyperaemic response. The BNP level significantly affected the FFR/baseline Pd/Pa . This study demonstrated that BNP finely responded to an exacerbation of cardiac ischaemia and that increases in BNP secretion effectively ameliorated coronary vasoconstriction. ANP and BNP have a wide range of biological effects; for instance, they induce vasodilation and natriuresis and inhibit the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system7. Plasma BNP is elevated in heart failure caused by various heart diseases, including ischaemic heart disease (IHD)10.B-type natriuretic peptide (BNP) is secreted mainly by the ventricles in heart failure, whereas normal atria secrete A-type natriuretic peptide (ANP) as well as BNP11. Moreover, the BNP level is elevated during early ischaemia, and an elevated BNP level is a significant risk factor for poor short-term and long-term prognoses12. Increases in the plasma BNP level are considered a compensatory response of the heart to ischaemia, because several reports have shown that BNP has a vasodilatory effect on the coronary artery system in humans14. However, it is still unclear how finely myocardial ischaemia itself contributes to BNP secretion and whether increases in BNP secretion actually induce vasodilation as a counter-adaptation. A precise analysis of the relationship between cardiac ischaemia and BNP secretion is the remaining action assignment.Previous reports have shown that myocardial hypoxia associated with a reduction in coronary blood flow increases cardiac BNP expression16. Pressure wires can be used to measure the fractional flow reserve (FFR), which requires the induction of maximal hyperaemia by drug administration, and the baseline distal-to-aortic pressure ratio (Pd/Pa), which does not require maximal hyperaemia17. The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study confirmed that FFR-guided percutaneous coronary intervention (PCI) was a safe long-term treatment for epicardial coronary stenosis;18 therefore, using the FFR to determine the need for PCI is acceptable. However, the baseline Pd/Pa is considered a more comprehensive index of coronary circulatory physiology than the FFR19. The coronary arterial tone is probably augmented in most patients with atherosclerosis. Therefore, we surmised that the baseline Pd/Pa would be a sensitive and useful index for evaluating coronary ischaemia.Coronary artery pressure wires are widely used in the clinic to assess the degree of coronary stenosis-induced myocardial ischaemiaHerein, we devised a new investigative method to examine the relationship between the BNP level and coronary ischaemia and performed simultaneous measurements of the plasma BNP level and the baseline Pd/Pa in patients with intermediate coronary artery stenosis.However, studies of this type are faced with another degree of intractableness. Many confounding factors can affect the plasma BNP level and baseline Pd/Pa. When confounders are present, the results do not reflect the actual relationship between the studied variables. Confounding variables are variables that are either positively or negatively correlated with both the dependent and independent variables, and bias caused by confounding variables can be difficult to prevent if multiple potential confounding variables are present or the study population lacks a sufficient size. SEM plays an important role in enabling researchers to understand how relationships between observed variables may develop. This analysis is useful for exploratory and explanatory factor analyses and can also be performed to assess relationships between variables in cases in which confounding bias may be present. In this study, we tried to propose a path model based on SEM to explain a complex phenomenon.The baseline characteristics, angiographic measurements and catheterization data for the study population are shown in Table Single regression analysis showed that the baseline Pd/Pa was clearly positively correlated with the FFR  in the study population. Nevertheless, the scatter plot appeared to spread as the baseline Pd/Pa and FFR decreased  (n = 1) and those receiving insulin therapy (n = 8) to reduce possible bias. The correlations between any two of these factors, which might have been confounders, were indicated by two-way arrows. The paths between variables were drawn from the independent variables to the dependent variables with directional arrows for every regression model . In this path model, the %DS was positioned on top of the other factors because the degree of organic stenosis could essentially affect every other parameter included in the model.To clarify the possible impact of the baseline Pd/Pa on the plasma BNP level, we conducted a path model analysis based on covariant structure analysis. The proposed theoretical path model is shown in Fig. The precise statistical analysis results are shown in Fig. To clarify the impact of the BNP level on the FFR/baseline Pd/Pa ratio, we conducted another path analysis. The proposed theoretical path model is shown in Fig. The statistical analysis results are shown in Fig. Single regression analysis showed that the LogBNP was significantly positively correlated with the FFR/baseline Pd/Pa ratio  in the FFR ≤ 0.8 group  cardiac ischaemia, as represented by the nonhyperaemic baseline Pd/Pa, had a causative impact on the plasma BNP level, suggesting the presence of a fine regulatory system of BNP by cardiac ischaemia; 2) BNP had a positive impact on the FFR/baseline Pd/Pa ratio, suggesting that a vasodilating action of BNP occurred in a compensatory manner; and 3) increasing BNP secretion was effective for palliation of the coronary arterial tonus, but the produced quantity of BNP was still inadequate for full coronary vasodilatation even in patients with high plasma BNP levels. A schematic illustration of our findings is shown in Fig. 18. This result indicated a possible direct relationship between cardiac ischaemia and BNP secretion. Then, we tried to determine a possible effect of cardiac ischaemia on the plasma BNP level using SEM. Since myocardial stretch or haemodynamic deterioration stimulates BNP secretion, many confounding factors exist with the plasma BNP level, such as LVEDP and LVEF. To account for possible confounding bias, we proposed a path model and revealed a possible effect of cardiac ischaemia on the plasma BNP level. Importantly, the contribution was fairly strong, because the standard regression coefficient was extremely high (β: −0.37), suggesting the presence of an exquisite BNP regulatory system driven by cardiac ischaemia.In the first phase of this study, we noted that the plasma BNP level appeared to be associated with the baseline Pd/Pa in the study population. This association appeared to become clear only in patients with coronary stenosis with an FFR of 0.80 or less, which is widely recognized as being suggestive of an ischaemic circumstance14. Thus, we investigated the possible direct effect of BNP on palliation of the arterial tonus. To quantify this effect, we introduced a novel measure (the FFR/baseline Pd/Pa ratio), which served as an index of the hyperaemic response. Then, another path model was proposed for this analysis, and we successfully found a potential effect of BNP on coronary vasodilation as a compensatory phenomenon.Previous reports suggested that BNP could affect coronary vasodilation at ischaemic sites in a compensative mannerTo reveal the power of secreted BNP for vasodilation, we examined the relationship between the BNP level and the FFR/baseline Pd/Pa ratio using regression analysis. The analysis showed a significant positive correlation between the BNP level and the FFR/baseline Pd/Pa ratio; importantly, as the BNP level increased, the FFR/baseline Pd/Pa ratio approached but still fell short of 1.0. This result suggested that the level of BNP secretion induced by ischaemia was insufficient to induce full coronary vasodilation even in patients with relatively high plasma BNP levels.13. Currently, we believe that BNP acts mainly on both the epicardial coronary arteries and the coronary microvessels.Speculation about the action sites of BNP in the coronary arteries is important because BNP can act at the levels of the epicardial coronary arteries and the coronary microvessels. If BNP acts on resistant coronary arteries, it may have promising flow-dependent coronary vasodilation-inducing properties. In our previous study, we reported that BNP had vasodilatory effects on the coronary artery system in humans and that the sensitivity of coronary resistance vessels to BNP was low compared with that of resistance vessels of the systemic circulation26. Furthermore, recent studies have noted a possible interaction of natriuretic peptides with NO activity. Interestingly, the natriuretic peptide system, including A- and C-type natriuretic peptides (ANP and CNP), has been reported to be involved in NO activity27. ANP restores the attenuated cardioprotective effects in diabetic hearts, possibly due to the increase in endothelial nitric oxide synthesis (eNOS) expression and subsequent increase in NO activity27. Moreover, CNP induces vascular relaxation by endothelium-dependent and endothelium-independent mechanisms29. Although more precise human studies are required, the interaction of natriuretic peptides and NO activity should be closely linked; natriuretic peptides would support the impaired NO activity in diseased vessels and the attenuated vascular tonus.Natriuretic peptides exert direct vasodilatory effects by increasing the level of cyclic GMP, which acts as a second messenger31. Additionally, chronic ANP treatment has been reported to ameliorate hypertension and end-organ damage in the kidney by reducing oxidative stress, increasing systemic NO activity levels, and diminishing the collagen content and apoptosis in both sexes32. Moreover, angiotensin receptor-neprilysin inhibitor (ARNi) is expected to contribute to these outcomes33. However, a matter of paramount importance is controlling obesity through diet and exercise because the plasma natriuretic peptide levels are comparatively low in patients with obesity, and their influence increases as the degree of obesity becomes more severe34. Importantly, we also reported that the plasma BNP levels were relatively low in patients with chronic IHD compared with those of non-IHD patients35 and that the low reactivity of BNP could play a causative role in IHD36. We believe that treatment of obesity will be beneficial for preventing IHD in part by increasing endogenous natriuretic peptide levels.The results of this study suggest that the plasma BNP level increases in response to cardiac ischaemia and that increases in the plasma BNP level attenuate the coronary arterial tonus; however, the level at which BNP is secreted is insufficient to induce full coronary vasodilation. These results indicate that natriuretic peptides may be useful as a therapy for IHD in the future. Infusions of synthetic ANP (carperitide) and BNP (nesiritide) would be effective in inducing coronary vasodilation. Indeed, we previously reported that ANP and BNP were effective in suppressing coronary artery spasm during hyperventilation tests19, variables such as diabetes mellitus, hypertension, dyslipidaemia and the smoking status could affect the measurement. We also performed a multiple regression analysis of factors to determine the baseline Pd/Pa using the variables BNP, diabetes mellitus, hypertension, dyslipidaemia, and smoking status in patients with an FFR ≤ 0.80. As a result, the BNP levels inversely correlated with the baseline Pd/Pa (p = 0.026) (data not shown).Most of the stenotic coronary arterial lesions encountered herein were single moderate stenotic lesions, but multi-vessel coronary artery disease was infrequently encountered. BNP secretion may be affected by the presence of other stenotic vessels. However, we performed the same analyses for patients with single moderate stenotic lesions (n = 42); the results were similar, and the baseline Pd/Pa had the same impact on the BNP level in the single-vessel group (p = 0.002) (data not shown). Additionally, the %DS was included in path models A and B; however, we surmised that a simpler path model might be sufficient to satisfy the objectives of the current study. Thus, we performed additional analyses using path models in which the %DS was not included. The results of these analyses were similar to those of the analyses performed using the path models in which the %DS was included (data not shown). Moreover, because the baseline Pd/Pa might be influenced by micro-circulatory functionIn this study, we examined the relationship between endogenous plasma BNP and the actual ischaemic heart. However, confirming the relationship between plasma BNP and the ischaemic heart may require inducing ischaemia and then observing changes in plasma BNP. In addition, synthetic BNP may need to be administered exogenously to test for coronary artery dilatation. These experiments must be planned using animal models.An FFR value of 0.8 is a widely accepted cut-off. In this study, however, we examined the validity of this cut-off using BNP values. In Supplementary Figure SEM is an effective analysis method for confirming hypotheses, but the analysts need to examine a sufficient number of hypotheses before and after model construction. By making full use of the analyst’s knowledge, the hypotheses approach the right model. In other words, trial and error is necessary. However, this is also a good aspect of SEM.The next problem concerns cause and effect. For confounding variables (the third variable that affects both the cause and effect variables), the causal relationship of the target must be examined. To further refine the cause and effect, detailed confounding variables need to be considered. Furthermore, to be causal, strictly speaking, priorities must be discussed before the event occurs in terms of the temporal priority at which the causal event occurs. Care must be taken to conclude that there is an exact causal relationship without such a consideration. Therefore, this paper does not necessarily indicate cause and effect. A directed acyclic graph may be effective as an alternative method for strictly discussing causality.SEM is a convenient analytical method and can be used to easily estimate parameters, so it is used in a wide range of academic fields. However, the following points should be noted:The present study was associated with some limitations. First, we measured only circulating BNP levels in this study. Ideally, plasma BNP levels in the coronary sinus may be required to clarify more precisely the interaction between the BNP level and cardiac ischaemia. Blood sampling was performed almost immediately before coronary pressure measurement in almost all cases. Therefore, although we do not think that a time lag exists between blood sampling and haemodynamic measurement, the effect of some time lag cannot be completely denied. Second, we used different types of drugs during cardiac catheterization for treatment of IHD. Thus, we could not exclude the possibility that these drugs affected the current results. Third, the ischaemic myocardial area subtended by the stenosis might influence BNP, but we did not consider the myocardial area or lesion locations in our analyses. Ideally, cardiac ischaemia might be measured as oxygen tension, which is the physiological stimulus for cardiomyocytes. However, we did not measure the myocardial oxygen tension in this study. Fourth, the path analysis makes many assumptions. For example, linearity is assumed for a very large number of relationships. Therefore, we may need to build other path models and perform additional analysis.In this study, in which we simultaneously measured the baseline Pd/Pa and plasma BNP levels, we demonstrated that BNP secretion finely responded to and was increased by cardiac ischaemia. The increase in BNP secretion was effective for palliation of coronary vasoconstriction. However, the level of BNP secretion induced by ischaemia was still inadequate for full coronary dilatation.37. We routinely examined both values to accurately determine each patient’s need for further catheter-based interventions. We excluded patients who required emergent treatment  and patients with severe valve diseases because their haemodynamic statuses and biomarker levels were highly variable and did not reflect the values under stable conditions. The study population of 167 patients was divided into two groups according to their FFR values. The FFR ≤ 0.8 group consisted of patients whose FFR was ≤ 0.8, and the FFR > 0.8 group consisted of patients whose FFR was > 0.8. The ethics committee of the Jikei University School of Medicine approved the study protocol (24–355[7121]), and we complied with the routine ethical regulations of our institution. Informed consent was obtained from each patient, and all clinical investigations were conducted in accordance with the principles expressed in the Declaration of Helsinki. We also posted a notice about the study design and contact information at a public location in our institution.The study population initially consisted of 1930 patients with IHD who were consecutively admitted to our institutions from March 2014 to July 2016. We performed cardiac catheterization on all patients and completed the required baseline Pd/Pa and FFR measurements in 167 patientsWhole blood (5 ml) was collected in tubes containing potassium EDTA (1 mg/ml of blood), and the plasma BNP levels were determined by enzyme-linked immunosorbent assay (non-extracted) using an antibody against human BNP . Blood sampling was performed almost immediately before coronary pressure measurement in almost all cases.38 as described in further detail below. The nonhyperaemic baseline Pd/Pa and FFR were calculated as a ratio of Pd to Pa at rest and during hyperaemia and reported as the average of ratios measured during 5 cardiac cycles. Adenosine  or papaverine  was used to induce hyperaemia in this study. Adenosine was administered through a peripheral vein at a dose of 150 μg/kg/min, and papaverine was administered via the left coronary artery at a dose of 12 mg and via the right coronary artery at a dose of 8 mg, which induced maximal dilatation within 15 s. Intracoronary isosorbide dinitrate (at least 0.5 mg) was administered before coronary angiography in all patients. In this study, we propose the value obtained by dividing the FFR by the baseline Pd/Pa (FFR/baseline Pd/Pa) as an index of vasodilation. A value of 1 indicated that the coronary arteries were fully dilated even at the basal condition.Coronary angiography was performed via a radial, brachial or femoral artery approach in standard multiple views by experienced operators using 5–7 French guiding catheters without side holes. All patients received a bolus of heparin (at least 2000|IU) before the procedure. A 0.014-inch pressure-monitoring guidewire  was externally calibrated and advanced through the guiding catheter to its tip before being placed at a location distal to the stenosis. Subsequently, the Pd and Pa were measured at rest and during drug-induced hyperaemiaQuantitative coronary angiography was performed by an independent analyser blinded to the FFR data. Using a guiding catheter for calibration and an edge detection system , the analyser measured the reference vessel diameter and minimum lumen diameter and calculated the %DS.34. The obtained structural equation models were tested and confirmed at the P < 0.05 significance level. Briefly, the model defines some hierarchical regression models that determine the Pd/Pa. Paths between variables were drawn from the independent variable to the dependent variables with directional arrows for every regression model (arrowheads on one end only). The presence of a two-way arrow between two variables was indicative of a correlation between these two variables. For every regression, the total variance in the dependent variable was theorized to be affected either by variables that were independent of the model or by extraneous variables. Each path had a standardized coefficient of the regressing independent variable on the dependent variable for the relevant path. The indirect effects were determined by multiplying the path coefficients of these intervening variables.Continuous variables are expressed as the means ± standard deviations (SDs) or as medians [interquartile range]. To achieve a normal distribution, we log-transformed the BNP levels prior to the analysis. Correlations between two factors were investigated by single regression analysis and expressed as Pearson correlation coefficients. Multiple logistic regression analysis was performed as needed. All statistical analyses were performed using IBM SPSS Statistics version 23.0 . P values < 0.05 were considered statistically significant. Path analysis based on SEM was used to investigate the relationships among clinical factors in this study population, specifically to survey probable causal effects for the baseline Pd/Pa. The path analysis was performed with IBM SPSS AMOS version 23 . This analysis compares the power among multiple independent variables that confound each otherSupplementary information.


Many asthmatic children suffer from uncontrolled asthma with frequent exacerbations, despite an optimal treatment plan using inhalation medication. Studies have shown that therapy adherence and inhalation technique are often suboptimal in asthmatic children, but these have traditionally been hard to measure. A novel device functioning as an add-on to the inhaler has been developed to measure both aspects by recording vibration patterns during inhalation. This data can be converted to smart feedback and provided to patients immediately via a mobile application. The aim of this study is to improve asthma control in children between 6 and 18 years old by providing immediate smart feedback on the intake of inhalation medication. Asthma control will be measured by forced expiratory volume in 1 s, (Childhood) Asthma Control Test ((c-)ACT) score, and lung function variability and reversibility.The study will be performed in Medisch Spectrum Twente . The goal is to include 68 uncontrolled moderate to severe asthmatic children between 6 and 18 years old who receive controller inhalation medication through the Nexthaler®, Ellipta®, or Spiromax®. The study consists of three phases. Phase 1 is observational and will last 4 weeks to observe the baseline adherence and inhalation technique as monitored by the add-on device. A randomised controlled trial lasting 6 weeks will be performed in phase 2. Patients in the intervention group will receive immediate smart feedback about the performed inhalations via a mobile application. In the control group, adherence and inhalation technique will be monitored, but patients will not receive feedback. In phase 3, also lasting 6 weeks, the feedback will be ceased for all children and revision of current therapy may occur, depending on the findings in phase 2. Asthma control can be assessed by means of spirometry  and (c-)ACT questionnaires.Immediate smart feedback may improve therapy adherence and inhalation technique, and thus asthma control in children and prevent unnecessary switches to targeted biologics. Performing this study in children is desired, since they are known to react differently to feedback and medication than adults.NL7705. Registered on 29 April 2019Dutch Trial Register  Asthma is a common chronic condition in children, characterised by airflow limitation . Based oRecent developments in asthma treatment have paved the way for the use of targeted biologics in children with uncontrolled asthma despite optimal treatment . In asthSo far, no reliable real-time techniques for monitoring therapy adherence and inhalation technique have been established . MultiplCurrently, AMIKO  has developed a new add-on device, Respiro™, which assesses adherence and inhalation technique by recording vibration patterns associated with inhaler use. Analysis of these vibration patterns allows critical technique errors to be identified, in particular, failing to reach sufficient inspiratory peak flow and insufficient inhalation duration as well as other non-critical errors. The vibration features can precisely assess the amount of medication that is inhaled by the user. In addition to providing an assessment of the proficiency of use, analysis of the recorded files provides information on the time of use per inhalation and the interval between doses. Through the Respiro™ mobile application, immediate smart feedback on inhalation technique and therapy adherence, in detail on the orientation of inhaler, time and date of inhalation, peak flow, duration of inhalation, and inhalation volume can be provided to the user by a mobile application.This study could greatly contribute to the optimal treatment of asthma, since no previous study in children has been performed with the use of immediate smart feedback on the intake of inhalation medication with regard to both inhalation technique and therapy adherence. An earlier performed study in which therapy adherence and inhalation technique were measured has been performed in adults with stage 3 to 5 asthma according to GINA , and thiThe hypothesis of this study is that at the end of phase 2, more patients in the intervention group have improved clinically than in the control group.Children suffering from uncontrolled moderate to severe asthma will be asked to participate in this study, and they either performed spirometry including a spirometry test at most 6 months prior to the study or they are scheduled for one. Asthma is considered uncontrolled when the (Childhood) Asthma Control Test ((c-)ACT) score is lower than 20 and/or the lung function reversibility in response to a short-acting bronchodilator is ≥ 12%.All subjects are required to suffer from uncontrolled moderate to severe asthma, are between 6 and 18 years old, and should be all outpatients in either Medisch Spectrum Twente (MST) in Enschede (The Netherlands) or in Ziekenhuisgroep Twente (ZGT) in Hengelo or Almelo (The Netherlands), both large teaching hospitals. Furthermore, they need to have a (c-)ACT score of lower than 20 and/or a lung function reversibility in response to inhalation medication of ≥ 12%. Children are unable to participate in the study if their controller inhalation medication cannot be distributed by either the Nexthaler®, Ellipta®, or Spiromax®, because the Respiro™ add-on is only compatible with these inhalers thus far. Switching between dose aerosol and dry powder inhaler device is allowed, if medication remains the same. Patients should use this device at least a month before entering the study. Moreover, children will be excluded if they, or parents of children below 12 years old, are unable to speak or understand Dutch or if children suffer from pulmonary chronic conditions other than asthma, which can present with asthma, mimic asthma, or potentially influence lung function, such as cystic fibrosis, bronchopulmonary dysplasia, or primary ciliary dyskinesia.Recruitment will take place from 1 October 2019 to 1 September 2021 in both MST and ZGT. However, the study will be entirely performed in MST meaning patients from ZGT need to travel to the MST for study-related activities. All subjects and parents of children under 16 will be informed about the study prior to inclusion by a brochure. Furthermore, a short overview of the study will be given during (regular) appointments by the paediatrician or researchers, and patients are provided with extra information on paper to read at home. If patients are interested in participation, a physical appointment will be scheduled for the inclusion. During this inclusion visit, the patient will be provided with the devices for the study and with instructions to use them. Written informed consent (IC) forms will be signed and collected by the researchers before inclusion. If subjects are under 12 years of age, both parents or their guardian(s) need to sign the IC. In case subjects are between 12 and 16 years old, both the children and both parents or guardian(s) need to sign the IC. If children are older than 16, they are allowed to sign themselves. Data of patients will be encoded in the order of inclusion. Subjects and/or parents can always withdraw their permission during the study, and their data collection will be terminated. Data collected before the withdrawal of permission can be used in analyses as stated in the patient information letter.1), lung function variability (LFV), and (c-)ACT. An overview of the study phases including parameter measurements is shown in Fig. To assess the effect of feedback on therapy adherence and inhalation technique on asthma control, a multi-phase study is set up in which phases 1 and 3 are considered observational and phase 2 pertains to a randomised controlled trial (RCT). The randomisation groups of phase 2 will persist in phase 3, but no new randomisation will be performed. The parameters which will be measured during the study include forced expiratory volume in 1 s  during the first appointment on which subjects will be instructed to perform spirometry at home twice per week at a fixed time during the entire study. Additionally, subjects will receive an add-on device (Respiro™ from AMIKO) that will be attached to their inhaler. This add-on device will monitor therapy adherence and inhalation technique during all three phases. After the first observational period (phase 1), patients will be randomised into one of two groups at the start of phase 2. In the intervention group, the add-on device will provide the asthmatic child with immediate smart feedback about performed inhalations, whilst retaining its monitoring function for researcher observations. Immediate smart feedback can be described as feedback which can be provided to patients via a mobile application immediately after intake of inhalation medication and based on whether  errors were made. The control group will not receive any feedback, and the add-on device will only fulfil a monitoring function. Besides feedback, both groups will receive treatment according to standard care.After phase 2, an observational follow-up period of 6 weeks (phase 3) will be initiated to determine any differences in therapy adherence and inhalation technique between the intervention and control groups. Treatment during phase 3 is depending on previous therapy adherence and asthma control, as shown in Fig. All subjects will be instructed to keep using both the spirometer and add-on device in phase 3 for monitoring purposes. When the asthma control of any subject deteriorates rapidly in a short amount of time, the standard care will be followed with regard to treatment. Continuing participation in the study will then be evaluated by the paediatrician and the subject, including his or her parents/guardians in the process. Adherence and inhalation technique data from the control group are available for patients and parents after the termination of the study procedures, during the exit visit for evaluation with their paediatrician.1 of ≥ 10%, compared to baseline measured at the start of phase 1 [1 will be measured and is compared to the baseline measurement at the start of phase 1. These are absolute measurements in litres, whereas relative improvement is also displayed in percentages (%); (2) absolute increase in (c-)ACT score of ≥ 3 points compared to baseline (c-)ACT score measured at the start of phase 1 [The primary outcome of this study, measured at the end of phase 2, is asthma control. If one or more of the following seven criteria are fulfilled, the patient will be deemed to have clinically improved in asthma control. An overview can be seen in Fig.  phase 1 . The FEV phase 1 ; (3) absSecondary outcomes include therapy adherence and inhalation technique. Subjects are considered to be adherent if they take as many inhalations during the day as prescribed. Therefore, adherence can be calculated by actual medication intake divided by the prescribed intake per day. The sum of all percentages will be taken and divided by the number of days adherence is assessed. Besides the often used cut-off of 75% for good adherence, therapy adherence will also be studied in more detail. Next to the dichotomous way of measuring adherence, patients will also be classified as underusers (< 50%), suboptimal users (50 to < 75%), optimal users 75–125%), and overusers (> 125%) based on adherence rates %, and ov and inhaAt the start of phase 1, demographics and use of nasal corticosteroids will be retrieved from the electronic health record or they will be asked during the first meeting. Moreover, reversibility in response to inhalation medication will be determined by spirometry. In case reversibility was already determined in the 6 months prior to the start, no new measurement will be performed and this value will be used as the baseline. Moreover, the (c-)ACT score will be determined for each subject at the start of phase 1. These are regarded as the baseline measurements to determine asthma control at the start.1 will be assessed over the entire study, and the LFV will be determined according to Eq. After the initial measurements, participants will be provided with the Respiro™ add-on device and the Air Next spirometer. The Air Next spirometer is used both in the hospital and at home to perform spirometry. The Respiro™ add-on will be attached to the inhaler of the subject until the end of the study and will measure the peak inspiratory flow, duration of the inhalation, orientation, opening and loading of the inhaler, and the date and time of the inhalation. Participants are instructed to perform spirometry at home twice a week at a fixed time. The data including the FEV1 and this value will be compared to baseline. After the initial measurement, salbutamol is administered, and after waiting for 5 min, another spirometry will be performed to determine the reversibility. Participants, and parent(s) or guardian(s) of participants between 6 and 11 years old, will also be asked to complete the (c-)ACT questionnaire to determine their ACT score. Finally, data collected by the add-on will be used to determine adherence and inhalation technique over an entire phase.At the end of each phase, spirometry will be performed in the hospital to assess FEVAn overview of the moments of measurement for all parameters is presented in Table Before phase 2, a 1:1 blocked, stratified randomisation  will be Because of the nature of the intervention, blinding of patients and staff to the classification of groups will not be possible. The statistician and the investigator that will analyse the data will be blinded.Z test was used as a test statistic. The proportion of patients with improvement of asthma control is expected to be 10% in the control group and 40% in the intervention group. Since these proportions are just rough estimates, due to missing literature on the effect of feedback on asthma control to base these estimates on, an interim analysis according to the O’brien-Fleming approach [P < 0.0054 according to O’brien and Fleming), inclusion should be stopped. Patients who are already included in the study will continue the study until they went through all phases. Furthermore, the power is set to 80%. This sample size analysis was performed with PASS  and showed the requirement of a minimum of 62 subjects to obtain significant results. To compensate for potential dropouts, a small buffer of 10% was created and therefore the aim is to recruit 68 patients for this study. The buffer is relatively low based on historical dropout rates.The number of subjects required for this study was determined by performing a two-independent proportion power calculation, and the two-sided approach  will be Baseline characteristics will be displayed as means with standard deviations (SD) or medians with interquartile range (IQR) for continuous variables depending on the distribution of the variable; categorical variables will be displayed as counts with corresponding percentages.1 and (c-)ACT-scores changing over the 3 phases, will be analysed via a mixed model repeated measurements analysis (MMRMA). The advantage of this method is that incidental missing data can be estimated by patterns of other participants [P values of ≤ 0.0492 are deemed statistically significant for the primary outcome. P values of ≤ 0.05 are deemed statistically significant for secondary outcomes. The randomised part of the study has an intention-to-treat design; all randomised patients will be analysed.For the between-group comparison of the number of patients who clinically improved in asthma control, the chi-square test will be used . Continuicipants . MoreoveZ test and this interim analysis allows the opportunity to perform slight modifications in population size or design, or termination due to effectiveness or futility, if the effect does not correlate with the original estimations [One interim analysis will be performed after half of the required patients finished phase 2. The power in the power analysis was adjusted for this single interim analysis. The interim analysis will be performed to assess the effect of feedback on the inhalation of medication in an early stage. This is desired, since the effect is estimated in the two-sided imations .The option to provide immediate smart feedback to patients about inhalation technique and therapy adherence could be a great addition to the current asthma care in children, since inhalation technique and therapy adherence both appear to be poor in the current asthmatic children –15. ImmeBesides, the GINA guidelines  emphasisHence, the aim of this study should be clear, but several decisions made in this research protocol deserve further elaboration. To start off, the intervention time is only 6 weeks. Therapy adherence and inhalation technique have the tendency to decline over time . This woBased on both the combination of therapy adherence and inhalation technique, and asthma control at the end of phase 2, the feedback will cease for all children, and revision of medication may occur. When the combination of therapy adherence and inhalation technique  results in less than 75% of the medication being properly inhaled and asthma control is not improving, this will be a cue to schedule another consult with the paediatrician. However, in daily practice, inhalation medication can also be overused by patients (more than twice a day), and overuse is considered a form of suboptimal use of medication as well. For the transition between phases 2 and 3, they will, however, be considered as therapy adherent. This can be explained as overusers are likely to be in need of more relief of symptoms. Treatment evaluation for step-up therapy should therefore be considered in these patients as asthma control is still lacking despite prescribed intake of medication. Nonetheless, the percentage of overusers in both randomisation groups will be determined to assess whether feedback on inhalation technique and therapy adherence will either encourage or discourage overuse. Another point of debate is the two critical errors regarding inhalation technique defined in this study, because no general consensus is reached on what errors are considered critical . In pracAn interim analysis will be performed after half of the subjects finished phase 2. As mentioned previously, the true (short-term) effectiveness of feedback on inhalation technique and therapy adherence is yet unknown. This interim analysis gives more insight into the effect of feedback, and small adjustments to the study design or population could be made if necessary. If the effect turns out to differ greatly from the expected effect, the study can be terminated for futility or inclusions can be stopped for effectiveness, to prevent unnecessary burdens to future participants.1, lung function reversibility after intake of medication, and LFV, are included.The (c-)ACT questionnaire is the current validated gold standard in modern Dutch healthcare to assess the severity of asthma in children. However, this questionnaire is a subjective measure which needs to be filled in by the patients (and parents/guardian) resulting in a score that determines asthma severity. Therefore, the (c-)ACT comes with a number of drawbacks . Asthma RCTs characteristically have high internal validity, but low external validity . This mePrevious research  has showFinally, this study is specifically focussed on improving asthma control in children, because children tend to react differently to behavioural interventions than adults would . TherefoThe favourable approval for this trial was obtained for The Netherlands for protocol NL69291.044.19/version 5, 09 October 2019.The first patient was enrolled on 08 October 2019, with 6 patients so far recruited. The expected total duration of recruitment is 2 years and is scheduled to finish on 01 October 2021.


Raised intracranial pressure (ICP) is a prominent cause of morbidity and mortality after severe traumatic brain injury (TBI). However, in the clinical setting, little is known about the cerebral physiological response to severe and prolonged increases in ICP.BTO2) monitoring  were selected for retrospective review. Secondary parameters reflecting autoregulation , cerebrospinal compensatory reserve (RAP), and ICP pulse amplitude were calculated.Thirty-three severe TBI patients from a single center who developed severe refractory intracranial hypertension (ICP > 40 mm Hg for longer than 1 h) with ICP, arterial blood pressure, and brain tissue oxygenation (Pp < 0.0001) at high levels of ICP (> 50 mm Hg). In 4 cases, PRx was impaired (> 0.25 a.u.) before ICP was raised above 25 mm Hg. Concurrently, PBTO2 decreased from 27.3 ± 7.32 mm Hg at baseline ICP to 12.68 ± 7.09 mm Hg at high levels of ICP (p < 0.001). The pulse amplitude of the ICP waveform increased with increasing ICP but showed an ‘upper breakpoint’—whereby further increases in ICP lead to decreases in pulse amplitude—in 6 out of the 33 patients.PRx deteriorated from 0.06 ± 0.26 a.u. at baseline levels of ICP to 0.57 ± 0.24 a.u. (Severe intracranial hypertension after TBI leads to decreased brain oxygenation, impaired pressure reactivity, and changes in the pulse amplitude of ICP. Impaired pressure reactivity may denote increased risk of developing refractory intracranial hypertension in some patients. Raised intracranial pressure (ICP) can occur due to an expanding mass lesion or due to increases in volume of any of the vascular, cerebrosipinal fluid (CSF) or parenchymal compartments within brain . The detSurprisingly, the cerebral physiological sequelae of raised ICP secondary to traumatic brain injury (TBI) are unclear. As previously shown, increased ICP decreases CPP, which with dysfunctional autoregulation, causes a decrease in cerebral blood flow, raises arterial blood pressure (ABP), and modifies the ICP pulse waveform . HoweverIn this study, we sought to describe the cerebral oxygenation, cerebrovascular pressure reactivity, and ICP pulse amplitude response to severe and sustained intracranial hypertension after severe TBI.This study was conducted as a retrospective analysis of a prospectively maintained database cohort (1992–2017), in which high-frequency physiological monitoring data had been archived. Monitoring of brain modalities was conducted as a part of standard patient care and archived in an anonymized database of physiological monitoring. Data on age, injury severity, and clinical status were recorded at the time of monitoring on this database, and no attempt was made to re-access clinical records for additional information. Since all data were extracted from the hospital records and fully anonymized, no data on patient identifiers were available, and therefore, formal patient or proxy consent and institutional ethics approval were not required.n = 24) or brain oxygenation monitoring (n = 9). This is because PRx monitoring only began in 1996 and brain oxygenation monitoring in 2004.TBI patients with a clinical need for ICP monitoring and computerized signal recordings were included for analysis. A total of 1146 head-injured patients admitted to the Addenbrooke’s Hospital Neurocritical Care Unit between 1992 and 2017 were included for the initial database. As described previously, this is likely to represent approximately 25% of all TBI admissions and 50% of all TBI admissions with ICP monitors [ICP was monitored with an intraparenchymal sensor . ABP  at the level of the right atrium (1992–2015) and at the foramen of Monro (2015–2017—one patient). Brain tissue oxygenation was monitored using a Licox probe via a cranial access device . Probes were positioned at a constant depth in the white matter, pericontusional in focal injuries or in the non-dominant frontal lobe in diffuse injuries. Probe positioning was verified by means of a head computed tomography (CT) scan.http://www.neurosurg.cam.ac.uk/icmplus after 2002). Heart rate was determined as the fundamental frequency of the ABP signal over a 10 s window within the cardiac (40–180 cycles/min) frequency band. Amplitude of the cardiac pulse in ICP and ABP was determined as the fundamental amplitude in the cardiac frequency band (40–180 cycles/min). ABP and ICP signals were averaged (mean) over a 10-s window; then PRx was calculated as the moving Pearson correlation of 30 consecutive ABP and ICP, updated every minute. Cerebrospinal compensatory reserve (RAP) was calculated similarly as the moving correlation between mean ICP and the pulse amplitude of ICP. AMP was divided by aABP (giving AMP/aABP ratio) to get an indication of the transmission of the cardiac pulse from the blood pressure to the ICP.All data were sampled at least 50 Hz with proprietary data acquisition and analysis software . The number of segments (3) was chosen a priori to allow for 3 different portions of the ICP, AMP relationship .t test. No adjustments for multiple comparisons were made in this exploratory analysis. To test whether early PRx was different between those who developed refractory high ICP and TBI patients who did not, we first identified controls for the 24 cases who had simultaneous ICP and PRx data with 24 controls (selected from the 1146 patients) who were matched for sex, initial GCS and age. Then we performed a Wilcox test for the ICP values between the two groups. Because the primary aim of this study was descriptive, we used all available cases in the database rather than performing a priori sample size calculations. We used the R language and software environment for statistical computation , the means of each variable from each patient were calculated in 10 mm Hg wide intervals of ICP and CPP and then local regression smoothing (LOWESS) was applied. This binning procedure, prior to LOWESS fitting was to ensure that patients with longer recordings did not contribute disproportionately to parts of the smooth. Pairwise comparisons between physiological variables at the different ICP levels were performed using Student’s n 2.12.1 ) using tn 2.12.1 , ggplot2Admission characteristics are displayed in Table BTO2 followed the decrease in CPP almost linearly to reach oxygen pressures of less than 5 mm Hg. In addition, a dissociation between the rise in mean ICP and pulse amplitude of ICP can be seen near the end of the recording, such that with increasing ICP, pulse amplitude remained constant. This failure for ICP pulse amplitude to increase despite increases in mean ICP has been postulated to be due to critical cerebrovascular collapse.Two patient examples illustrating the heterogeneous nature of the response to intracranial hypertension are depicted in Fig. Across all patients, PRx Fig.  showed aBTO2 responses are viewed together .When compared to 24 controls , initial mean PRx in the first five hours of monitoring was higher Fig.  in the cGrouping each of the patients’ data into three ICP groups . This highlights the potential utility of continuous assessments of cerebral autoregulation in predicting raised ICP events. Encouragingly, a previous investigation found that a feature similar to PRx -ICP correlation from low-frequency data) can help predict periods of raised ICP 30 min before they occur [Perhaps most striking though, is that PRx was disturbed before the onset of intracranial hypertension in a selection of the patients. This has been observed previously in a cohort of brain-injured patients of mixed pathologies , but has not been statistically assessed . After mey occur . IdentifReasons why impaired cerebral pressure reactivity may be a harbinger of raised ICP in some patients but not others deserves further discussion as it perhaps reflects different pathophysiological profiles of intracranial hypertension. Intracranial hypertension is a result of changes in compartmental volumes within the brain: increases in volume of the brain tissue , the cerebral spinal fluid, or the blood . Disturbed autoregulation preceding an increase in ICP may indicate a primary vascular dysfunction that, over time, causes raised ICP. In these cases, a vascular dysfunction as manifest in impaired PRx could lead to vasogenic edema, which over hours could lead to progressive increases in ICP. Cases where ICP and PRx are disturbed simultaneously indicate that either the impaired vascular function is a consequence of the raised ICP, or the underlying pathophysiological mechanism is occurring rapidly. Simultaneous perturbations in PRx and ICP could conceivably occur with obstruction in CSF flow, a rapidly expanding lesion or during a sudden increase in blood volume.In addition, we found a consistent increase in MAP at elevated levels of ICP , metabolic rate of the nearby cerebral tissues, and any diffusion barriers [In this sample of patients with extreme increases in ICP, Pased ICP . Howeverbarriers –22. Therbarriers –25. The barriers . Furtherbarriers .BTO2 to after PBTO2-targeted therapy, found that keeping PBTO2 above 20 mm Hg was associated with decreased mortality [Nevertheless, monitoring of brain oxygenation, sometimes in combination with cerebral microdialysis has increased in popularity over last decade with some promising initial results. In a retrospective analysis comparing before Portality . In addiortality –30.The increase in pulsatility of ICP with increasing levels of mean ICP has been interpreted as a loss of cerebral compensatory reserve. In this scenario, when the intracranial system is on the steep ascending portion of the pressure–volume curve, a pulsatile injection of blood volume from the cardiac cycle would be expected to produce a large increase in pulsatile pressure. However, at extreme levels of ICP (approaching diastolic blood pressure) it has been demonstrated in animal models that ICP pulsations may in fact decrease . This han = 24). Furthermore, time points besides the first 5 h for the ability of PRx to predict intracranial hypertension should be investigated. In addition, the current study does not address the pragmatic issue of how multimodality monitoring data can be integrated into clinical care without causing a detrimental information overload. While ongoing data collection with the increasing availability of multimodality monitoring will likely shed light on this area in the near future, controlled experimental studies that mimic the increase in ICP observed after human TBI need to also play a role as they can effectively isolate the effects of the disease from that of treatment.Due to the small sample size, these analyses must be considered as preliminary descriptions. While it was possible to include more patients by relaxing the definition of refractory intracranial hypertension, we wished to describe the physiological response across the widest range of ICPs and therefore opted to only include patients with severe intracranial hypertension. Further, because intracranial physiology will depend heavily on concurrent therapies, detailed clinical annotations to the monitoring data would aid interpretation and increase the generalizability of the study. Stratification of physiological responses to intracranial hypertension by ICP treatment modality (for example decompression or barbiturates) may yield useful information describing early indicators of a beneficial versus a pathological physiological response. The association between early PRx and later development of intracranial hypertension needs to be treated with caution as the case–control analysis was only carried out in a small subset of patients with concurrent PRx monitoring (Severe intracranial hypertension after TBI leads to decreased brain oxygenation, impaired pressure reactivity, and a characteristic ICP pulsatility response.


Supplemental Digital Content is available in the text. P=1×10−11; diastolic blood pressure: OR, 1.25 ; P=3×10−8; pulse pressure: OR, 1.1 ; P=0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers  and β-blockers  decreased the risk of AF. Blood pressure–increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or β-blockade could reduce the risk of AF.Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 ;  In population studies such as the Framingham Heart Study and Atherosclerosis Risk in Communities Study, up to 20% of AF cases are attributed to preexisting hypertension.Preventative studies on a population scale are difficult to accomplish in a randomized and adequately powered fashion with sufficient duration. To overcome this limitation, this study used a population genetics–based approach within a Mendelian randomization (MR) framework to better understand the causal role of blood pressure on the risk of AF. This technique takes advantage of the random allocation of blood pressure–associated genetic variants that occurs at conception. This random assortment minimizes the chance of environmental confounding, enabling investigation into the causal relationship between blood pressure and AF. We subsequently evaluated genetic proxies for the pathways targeted by antihypertensive medications to better understand potential class effects of antihypertensive medications on AF.Data Supplement.The authors declare that all supporting data are available within the article and its 19 Blood pressure data were obtained from the 2018 Evangelou et al International Consortium for Blood Pressure+UK Biobank GWAS meta-analysis, which included systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) measurements in up to 757 601 individuals. Summary statistics for blood pressure are publicly available and were downloaded from the National Heart, Lung, and Blood Institute Genome-Wide Repository of Associations Between SNPs and Phenotypes catalog (https://grasp.nhlbi.nih.gov/FullResults.aspx). AF data  were obtained from the 2018 Roselli et al AF GWAS meta-analysis from the AFGen  consortium study, including 65 446 AF cases and 522 744 controls. Summary statistics for AF were contributed by the AFGen consortium (http://afgen.org), are publicly available, and may be downloaded from the Variant to Function Knowledge Portal (http://www.kp4cd.org/datasets/v2f). Because both the blood pressure exposure and AF outcome studies included participants from the UK Biobank (458 577 for BP and 351 017 for AF), bias due to sample overlap was estimated using a previously described tool, available at https://sb452.shinyapps.io/overlap.20 Across all ranges of sample overlap (0%–100%), there was no substantial inflation in type I error rate or bias .For the primary analysis, summary-level data for genome-wide association studies (GWAS) of hypertension and AF were used.Data Supplement.18 For each BP trait, genetic variants associated with SBP, DBP, and PP at genome-wide significance (P<5×10−8) were identified and linkage disequilibrium pruned using the default settings of the clump_data function of the TwoSampleMR package  using the 1000 Genomes European ancestry reference panel to identify independent variants. Because the Evangelou et al21 study adjusted effect estimates for body mass index potentially leading to introduction of collider bias as body mass index is causal for both elevated blood pressure and AF, a sensitivity analysis was performed using systolic (n=436 419) and diastolic (n=436 424) blood pressure GWAS summary statistics from European UK Biobank participants adjusted for genotyping array, age, sex, and population structure.21The 2018 Evangelou et al International Consortium for Blood Pressure+UK Biobank discovery meta-analysis GWAS included up to 757 601 participants. This analysis included up to 299 024 European participants from 77 independent studies genotyped with various arrays and imputed to either the 1000 Genomes Reference Panel or the HRC platforms and 458 577 participants from the UK Biobank. Blood pressure ascertainment varied among cohorts, and study-specific details are presented in the The AFGen consortium identified participants from >50 studies , including participants from the UK Biobank, Biobank Japan, other international biobanks, and international cardiovascular cohort studies . AF ascertainment was study specific, including diagnostic codes, electronic health record information, and self-report.22The primary analysis estimated the effect of blood pressure on the risk of AF using 2-sample MR with an inverse-variance weighted model with random effects. The MR-Egger bias intercept test was used to identify the presence of bias from directional pleiotropy. Sensitivity analysis was performed using weighted median MR and Egger intercept tests, which are more robust to the presence of invalid genetic instruments.24 We used 2 approaches to estimate the effect of blood pressure–lowering medication on risk of AF:Recent work has demonstrated that genetic proxies can be used to estimate the effect of individual antihypertensive drug classes on clinical outcomes using an MR framework.23 Single-nucleotide polymorphisms (SNPs) were identified within corresponding genes, promoter regions, or enhancers that were associated with SBP in the 2018 UK Biobank and International Consortium of Blood Pressure GWAS meta-analysis at genome-wide significance (P<5×10−8) and clumped to a linkage disequilibrium threshold of r2<0.1 using the 1000 Genomes European reference panel. These genetic variants were used as instruments to model the effect of lower SBP mediated by individual antihypertensive drug classes. The SNPs were then utilized to estimate the effect of the individual antihypertensive drug classes on the risk of AF using 2-sample inverse-variance weighted and median weighted MR as above.Genes encoding the targets of antihypertensive medications  were identified using DrugBank and the GeneHancer database in the GeneCards platform (v4.7).24 Twelve antihypertensive drug classes were considered: adrenergic neuron blocking drugs; α-adrenoceptor blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, β-adrenoceptor blockers, CCBs, centrally acting antihypertensive drugs, loop diuretics; potassium-sparing diuretics and aldosterone antagonists, renin inhibitors, thiazides and related diuretics, and vasodilator antihypertensives. SNPs were identified for the protein targets of each drug class using the Genotype-Tissue Expression project data , which contain expression quantitative trait loci analyses of 48 tissues in 620 donors.25 SNPs defined by Genotype-Tissue Expression as the variant with the smallest nominal P for a variant-gene pair were selected for analysis and validated as instruments by estimating their effect on SBP using 2-sample MR. Expression quantitative trait loci with evidence of a significant effect on SBP by gene expression MR (P<0.05) were used for the analysis.Expression quantitative trait loci for protein targets of antihypertensive medications were used as a proxy for the action of a drug on its target .https://github.com/MRCIEU/TwoSampleMR).26 Variants associated with each blood pressure exposure at genome-wide significance (P<5×10−8) were harmonized with the variants from the AF GWAS19 and linkage disequilibrium clumped  using the 1000 Genomes European ancestry reference panel, identifying a final set of independent SNPs to use as a genetic instrument for blood pressure. The exposure-outcome association was calculated for each variant independently; inverse-variance weighted 2-sample MR with random effects was used as the primary analysis with a weighted median analysis performed as a sensitivity analysis.27 For each variant included in the genetic instruments, the proportion of variance (R2) in the phenotype explained was calculated using the formula  .28 F statistics were then calculated for each variant using the formula  to assess the strength of the selected instruments.29 Changes in blood pressure were expressed in terms of a 10-mm Hg increment as it was viewed as a clinically relatable target for blood pressure modification. All statistical analyses were performed using R, version 3.6.2.31.Two-sample MR was performed using the TwoSampleMR package in R (Data Supplement). For the SBP instrument, the mean F statistic was 75 . For the DBP instrument, the mean F statistic was 79.9 . For the PP instrument, the mean F statistic was 76.4 . Bias due to sample overlap from the UK Biobank participants included in both the blood pressure exposure GWAS and AF outcome GWAS was estimated to be negligible across a range of observational effect sizes: for example, at 100% sample overlap, bias was estimated to be 0.0003 for an observational OR of 1.3 and 0.00069 for an observational OR of 1.6 (Table S4).We identified a set of independent variants to serve as instruments for SBP (n=399) and DBP (n=398) and PP (n=347), which accounted for 4.0%, 4.2%, and 3.6% of the measured variability in these exposures, respectively . When using these genetic proxies to estimate the effect of each 10-mm Hg decrease in SBP by each antihypertensive drug class, genetically predicted protein targets of CCBs and BBs were associated with lower risk of AF .24 Using this technique, antihypertensive medication proxies reduced the risk of AF . There was no strong evidence of effect of other antihypertensive medication classes on AF risk (Table S7).To estimate the effect of blood pressure reduction by different classes of antihypertensive medications, we identified common genetic variants located within genes of protein targets of CCBs and BBs, as described previously.This study utilized MR to leverage population-level genetic information to explore the causal relationship between blood pressure and AF. The genetic determinants of elevated SBP and DBP were found to strongly associate with the risk of AF—an association that persisted in statistical sensitivity analyses more robust to the inclusion of pleiotropic variants. Previously validated genetic proxies for the therapeutic effects of antihypertensive drug classes were used to estimate the impact of individual antihypertensive drug classes on incident AF, suggesting a potential role for antihypertensive medications in prevention.5 These findings, however, were limited in demonstrating a causal role for hypertension in the development of AF due to the potential of residual confounding and reverse causation.14 This study sought to mitigate this risk of confounding by using genetic instruments randomly assorted in the population to proxy the effect of increased blood pressure traits on the risk of AF. In doing so, we found that genetically proxied increases in SBP and DBP were associated with increased risk of AF. These elevated blood pressure effects are directionally similar to those identified in observational studies.30 In this analysis, PP was not as strongly associated with the risk of AF as SBP and DBP changes. As PP is dependent upon systolic and diastolic pressure, our data would suggest that the relative magnitude of each independent blood pressure parameter is more predictive than the relationship between the two. There are 2 prior studies looking at blood pressure genetics and AF; both of which are complimentary to the current study. The first was an MR analysis using an SBP polygenic risk score derived from an older blood pressure GWAS.31 The second used a less exhaustive set of blood pressure–related SNPS to demonstrate that SBP and DBP mediate ischemic stroke risk, in part, through AF.32A relationship between hypertension and AF has previously been established in observational analyses.35 This scaring and fibrosis is thought to create altered patterns of conduction and functional slowing, allowing for the development and perpetuation of AF triggers.36 Concordantly, hypertensive animals have greater heterogeneity of atrial activation with increased susceptibility to AF induction.34 Other manifestations of left atrial remodeling such as increased left atrial size have been associated with hypertension and elevated SBP in particular.37 It should be noted, however, that the impact of hypertension on AF risk persists after adjustment for left atrial size and mass.30A variety of mechanisms have been proposed to explain how hypertension contributes to the risk of AF. Animal models of hypertension have demonstrated the presence of left atrial scaring and inflammation.38Beyond mechanism, this study explores the question of whether pharmacological intervention may meaningfully impact a patient’s risk of AF. While it would be ethically difficult to fully withhold antihypertensive therapy in a randomized trial, we leveraged genetic proxies to explore the impact of individual antihypertensive drug classes. Our study suggests that both CCBs and BBs can significantly mitigate a patient’s risk of developing AF. While it is tempting to compare the results of our genetic study with human pharmacological studies, there are inherent differences in these two approaches. Our analysis used genetic proxies to model antihypertensive class effects and reflects a lifetime of genetic exposure. By contrast, antihypertensive drug trials estimate the effect of only a limited duration of antihypertensive therapy initiated later in a patient’s life. It should be noted that while other drug classes like angiotensin receptor blockers did not demonstrate a significant AF-reducing effect in our study, we may have been underpowered to detect a relationship between the two due to a lack of robust genetic instruments. While it is possible that certain antihypertensive drug classes have more of an AF-reducing effect than others, our analysis is not able to fully tease out this question. It should be further noted that clinical trials and case-control analyses have not found BBs and CCBs to be consistently superior to other drug classes including angiotensin receptor blockers and angiotensin-converting enzyme inhibitors when examining impact on AF burden.A final point should be made that while the effect size of a blood pressure increase on AF was smaller in magnitude than the effect size of CCB and BB drug therapy on AF, this discrepancy may be partially explained by a nonlinear or heterogenous relationship between blood pressure reductions and blood pressure increases. The difference in effect size may also be due to the pleiotropic effects of these particular antihypertensive medications as β-receptor signaling and calcium handling have both been implicated in AF initiation and arrhythmogenesis independent of blood pressure.First, while the GWAS of AF was multiethnic, the study was enriched with individuals of European ancestry as was the GWAS of blood pressure traits. This may have skewed the risk estimates in our findings, and as such, the analysis should be repeated in other populations before being generalized across ethnic groups. Second, this analysis estimates the lifelong effects of genetically predicted blood pressure reduction on AF risk and does not directly investigate the effects of shorter term alterations in blood pressure such as through pharmacological treatment in adulthood. Third, it should be noted that the risk reduction of CCBs and BBs was quantified in terms of 10-mm Hg blood pressure increments, which assumes a linear relationship. However, this study cannot answer the question of what level of blood pressure reduction maximizes AF risk reduction.Blood pressure–increasing genetic variants were associated with an increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction through pharmacological intervention and specifically calcium channel blockade or β-blockade could reduce the risk of AF.From a public health perspective, early interventions to limit lifetime exposure to elevations in SBP and DBP could have tremendous impact on the prevalence of AF. Furthermore, initiatives targeting known AF risk factors like hypertension and obesity may be key to reducing AF at a population level.M.C. Hyman and F.E. Marchlinski are supported by the Winkelman Family Fund in Cardiovascular Innovation. D. Gill is supported by the Wellcome Trust 4i Programme (203928/Z/16/Z) and British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London. V.M. Walker is supported by the Medical Research Council Integrative Epidemiology Unit. The unit is supported by the UK Medical Research Council and University of Bristol (MC_UU_00011/4 and MC_UU_00011/1). N.M.D was supported by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756-09 S.M. Damrauer is supported by the Department of Veterans Affairs (IK2-CX001780). This publication does not represent the views of the Department of Veterans Affairs or the US Government.All authors have completed and submitted the International Committee of Medical Journal Editors Form for disclosure of potential conflicts of interest. D. Gill is employed part-time by Novo Nordisk outside of the submitted work. S.M. Damrauer receives research support to his institution from RenalytixAI and personal consulting fees from Calico Labs, both outside the current work. The other authors report no conflicts.


The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure.We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA  trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization.Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10 mmHg lower SBP 1.05 (95% CI 0.99–1.12) P = 0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13 (95% CI 1.04–1.22) P = 0.002) in 2325 patients with additional CVD . In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10 mmHg lower SBP 0.95 (0.86–1.04) P = 0.26; P for interaction 0.005).The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration.Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010 Elevated blood pressure is considered an important additive risk factor in patients with type 2 diabetes, augmenting the already heightened risk for morbidity and mortality in these patients . However2, coronary artery by-pass graft surgery for the qualifying event, percutaneous coronary intervention within 15 days prior to the screening visit, planned coronary revascularization within 90 days after the screening visit, or inability to provide written informed consent. There were no exclusion criteria related to blood pressure levels. The median follow-up time was 25 months. Lixisenatide (or volume-matched placebo) was administered as sub-cutaneous injections, with a maximal daily dose of 20 µg/day. For the purpose of this secondary analysis, 216 patients were excluded due to missing baseline data  have been published previously , 16. In Baseline blood pressure was assessed as the mean of screening and randomization blood pressures. The median number of days between the screening and randomization visits was seven (interquartile range [IQR] 7–8 days). The study instructions stated that blood pressure measurements should be performed with the patient in the supine position, after the patient had rested comfortably for at least 5 min. Pulse pressure (PP) was calculated as systolic blood pressure (SBP) minus diastolic blood pressure (DBP). Throughout the trial, the antihypertensive medications could be adjusted according to local practice guidelines, as deemed appropriate by the patient´s treating physicians. When available, left ventricular ejection fraction (LVEF) was reported by the enrolling sites on an electronic case report form, as described previously .Descriptive data are presented as mean ± standard deviation (SD) and/or as median [IQR] for continuous variables. Between-group differences were tested for statistical significance with Student’s t-test, Wilcoxon rank sum test, analysis of variance or Kruskal–Wallis test for continuous variables, and with Chi square test for categorical variables. The incidence of death was plotted against SBP, DBP, and PP, using restricted cubic spline curves with three knots. The associations were tested for overall statistical significance and for evidence of statistically significant non-linearity based on the Poisson distributions of the incidence rates. A proportional hazards Cox regression model was used to calculate the hazard ratio (HR) for death with 95% confidence intervals (CI) associated with a blood pressure difference of 10 mmHg. For significant associations that also exhibited evidence of significant non-linearity, piecewise Cox regression was used to determine hazard ratios separately for the lower and the upper parts of the spline curves. All spline curves and Cox regressions were adjusted for randomization group and for history of coronary revascularization prior to randomization and for the following potential baseline confounders, that were selected from a previously published risk prediction model : age, seOverall, the mean age was 60.3 ± 9.7 years and 1779 patients (30.4%) were women. The median number of days between the index ACS and the first blood pressure measurement was 52 [IQR: 30–86 days]. Baseline SBP was less than 140 mmHg in 4256 patients (72.7%) and baseline DBP was less than 90 mmHg in 5273 patients (90.1%). There were 2325 patients (39.7%) who prior to randomization had a history of additional CVD  and/or stroke (n = 314) and/or heart failure (n = 1317)). Baseline patient characteristics are presented in Table Overall, there were 421 deaths among the 5852 patients in this analysis (3.3 deaths per 100 patient-years). There were more deaths among the 2325 patients with additional CVD  than among the 3527 patients with index ACS only  P < 0.001. The number of deaths did not differ significantly between tertiles of SBP  P = 0.66.Out of the 421 deaths, 307 were cardiovascular deaths (2.4 cardiovascular deaths per 100 patient-years). Overall, there was no significant association between SBP and mortality . There were 77 deaths in the group with additional CVD (3.5 deaths per 100 patient-years) and 163 deaths in the group with index ACS only (2.1 deaths per 100 patient-years) P < 0.001. As in the original cohort, there was no significant overall association between SBP and mortality  and 1605/2325 in patients with additional CVD (69%), P = 0.06). The baseline distributions of LVEF are shown graphically in Additional file The main finding of this study was that in ELIXA participants with type 2 diabetes and a recent acute coronary event, there were no overall significant relationships between SBP or PP and mortality, but there was a non-linear relationship between DBP and mortality, such that lower DBP was associated with higher mortality for DBP levels lower than 80 mmHg and no significant relationship was observed for DBP values of 80 mmHg and higher. However, a greater burden of CVD, as defined by prior CVD in addition to the index event, modified the relationship between blood pressure and risk of death. Independently of several known predictors of death, lower baseline SBP or lower baseline DBP were significantly associated with higher mortality in patients with a history of additional CVD, but not in patients without additional prior CVD. A greater burden of CVD modified the relationship between blood pressure and risk of death also in a sensitivity analysis in which patients with heart failure were excluded, and in a sensitivity analysis of patients for whom additional adjustment for LVEF was made. Compared with patients with additional CVD, patients without additional CVD had lower systolic blood pressure and a more favorable risk factor profile: they were, on average, younger, had lower BMI, higher eGFR, shorter duration of diabetes, and were less often treated with insulin despite having similar HbA1c, and more often treated with a statin. These differences may have contributed to the lower event rates in the group without additional CVD and may explain why patients with additional CVD appeared to be more vulnerable to the detrimental effects of low blood pressure.Coronary perfusion occurs mainly during diastole, and lower diastolic blood pressure has been associated with higher odds for angina in patients with coronary artery disease . DiabeteIn patients with diabetes, randomized trials that compared different blood pressure treatment targets have not shown a clear benefit of lower treatment targets on survival –24. BeneIn a secondary analysis of high risk patients with both type 2 diabetes, hypertension and coronary artery disease who participated in the HIJ-CREATE  trial, achievement of strict systolic blood pressure control was not associated with cardiovascular risk . Other oThe most important study limitation is the observational study design, which implies that the described associations do not necessarily represent causal relationships. Although the associations between lower SBP or lower DBP with higher mortality were independent of several known predictors of death, this study did not address potential pathophysiological mechanisms that might explain the relationship between blood pressure and mortality. It is possible that patients with lower blood pressure had other concomitant risk factors that influenced their prognosis. For instance, poor general health, falls and increased arterial stiffness may have contributed but were not measured in the ELIXA trial. Therefore, the present analysis should not be mistaken for a randomized trial of appropriate blood pressure targets, and the results should be interpreted in the context of individualized risk stratification rather than in the context of determining optimal blood pressure treatment targets. Another limitation of the present study was that information regarding coronary anatomy or measurements of coronary artery disease severity were not collected. Inter-arm blood pressure differences are known to be associated with coronary artery disease severity  and to pIn this analysis of ELIXA participants with type 2 diabetes and a recent coronary event, a history of additional CVD modified the relationships between SBP or DBP and mortality. Independently of known predictors of death, lower SBP or lower DBP were significantly associated with higher mortality in patients with a history of additional CVD, but not in patients without additional CVD. These findings suggest that patients with a history of multiple cardiovascular events may be more vulnerable to detrimental effects of low blood pressure. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration.Additional file 1. Additional tables and figure.