Patients with coexistent chronic heart failure (CHF) and diabetes mellitus (DM) demonstrate greater exercise limitation and worse prognosis compared with CHF patients without DM, even when corrected for cardiac dysfunction. Understanding the origins of symptoms in this subgroup may facilitate development of targeted treatments. We therefore characterized the skeletal muscle phenotype and its relationship to exercise limitation in patients with diabetic heart failure (D‐HF).pectoralis major biopsies were taken from age‐matched controls (n = 25), DM (n = 10), CHF (n = 52), and D‐HF (n = 28) patients. In situ mitochondrial function and reactive oxygen species, fibre morphology, capillarity, and gene expression analyses were performed and correlated to whole‐body exercise capacity.In one of the largest muscle sampling studies in a CHF population, P < 0.05). A unique mitochondrial complex I dysfunction was present in D‐HF patients only (P < 0.05), which strongly correlated to exercise capacity . Mitochondrial impairments in D‐HF corresponded to higher levels of mitochondrial reactive oxygen species (P < 0.05) and lower gene expression of anti‐oxidative enzyme superoxide dismutase 2 (P < 0.05) and complex I subunit NDUFS1 (P < 0.05). D‐HF was also associated with severe fibre atrophy (P < 0.05) and reduced local fibre capillarity (P < 0.05).Mitochondrial respiration, content, coupling efficiency, and intrinsic function were lower in D‐HF patients compared with other groups (Patients with D‐HF develop a specific skeletal muscle pathology, characterized by mitochondrial impairments, fibre atrophy, and derangements in the capillary network that are linked to exercise intolerance. These novel preliminary data support skeletal muscle as a potential therapeutic target for treating patients with D‐HF. Chronic heart failure (CHF) and type 2 diabetes mellitus (DM) remain two primary causes of mortality and morbidity.Patients with CHF develop significant skeletal muscle impairments, which impact exercise tolerance consequent to mitochondrial and metabolic derangements, fibre structural alterations, and impaired capillarity.The present study, therefore, performed skeletal muscle biopsy sampling in humans with the aim of characterizing key indices  between age‐matched controls (CON), CHF, DM, and D‐HF patients. We hypothesized that D‐HF would be associated with a distinctive muscle pathology that closely correlates to exercise limitation.Table−1, plasma glucose ≥11.1 mmol·L−1 2 h after the oral glucose tolerance test, and/or an HbA1c ≥6.5% (≥48 mmol·L−1). CHF patients had symptoms of stable CHF , and a LVEF <50% as confirmed by echocardiography [following current European Society of Cardiology (ESC) guidelines].2 and V̇CO2) and ventilation (V̇E).Clinical characteristics for all patients are presented in  ≥6.5% ≥4 mmol·L−1pectoralis major (~50 mg) were obtained from all participants during routine device implantation procedures. The biopsy was taken within 3 months following study recruitment and baseline clinical data collection. There were no complications or adverse events with this procedure. One piece of muscle sample was immediately placed in 1 mL of ice‐cold specialized preservation solution (BIOPS) for assessment of mitochondrial respiration,Skeletal muscle biopsies of in situ from saponin‐permeabilized skeletal muscle fibres using high‐resolution respirometry .c; (iv) succinate at 10 mM as a complex II substrate provided complex I + II OXPHOS; (v) 5‐μM carbonyl cyanide 4‐(trifluoromethoxy)‐phenylhydrazone (FCCP) for maximal uncoupled complex I + II respiration; (vi) complex I inhibitor rotenone at 0.25 μM provided uncoupled complex II respiration; and (vii) 2.5‐μM antimycin A as a complex III inhibitor for residual oxygen consumption (ROX) to calculate non‐mitochondrial (background) respiration, which was then used to normalize the data. As an index of total mitochondrial ROS production, the Amplex UltraRed assay was used to measure H2O2 production in each respiratory state as previously described.N,N,N',N'‐tetramethyl‐p‐phenylenediamine dihydrochloride (TMPD) as an artificial electron donor to complex IV in combination with 2‐mM ascorbate to maintain TMPD in a reduced state.Mitochondrial respiration was assessed Ulex europaeus agglutinin I . Slides were imaged via an optical microscope  attached to a digital camera  and analysed using digital image software . Fibre cross‐sectional area (FCSA), capillary‐to‐fibre ratio , capillary density , fibre‐type specific measures of local C:F (LCFR), and capillary density (LCD) were determined alongside heterogeneity of capillary distribution (i.e. logarithmic standard deviation of capillary domain area), using the automated software package DTect as described in extensive detail elsewhere.Immunohistochemistry methods have been described in detail previously.−1) were quantified and reverse transcribed to cDNA; mRNA expression was determined using real‐time quantitative PCR with SYBR® Green ROX™ qPCR Mastermix  and a qPCR system . Primers of key regulators of mitochondrial morphology were purchased from Qiagen including peroxisome proliferator‐activated receptor γ coactivator‐1α, superoxide dismutase 2 (SOD2), mitochondrial fission 1 (FIS1), optic atrophy 1 (OPA1), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), and NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3). Expression levels were normalized to an endogenous control, beta‐actin (ACTB), using the Δ‐Δ‐CT methodRNA was extracted and purified from snap‐frozen muscle tissue using the RNeasy® Fibrous Tissue Mini Kit . RNA concentrations  were compared using χ2 testing (or Fisher's exact test where appropriate). Pearson correlations examined relationships between continuous variables. Data are expressed as mean ± standard error of the mean unless otherwise stated. Statistical significance was accepted as P < 0.05.Outliers were identified and removed using the regression and outlier removal method, as previously described.TableTable2peak, or aetiology, drug/device therapies (except furosemide dose). Furthermore, no differences were present in terms of glycaemic measures between the DM and D‐HF patients (i.e. plasma glucose or HbAc1).The demographic and physical characteristics of the 115 included patients are presented in 2 flux for each mitochondrial respiratory state are presented in FigureP = 0.008; FigureP < 0.0001; FigureP < 0.0001 vs. CON; P = 0.007 vs. DM; P = 0.001 vs. CHF; FigureP = 0.003 vs. CON; P = 0.016 vs. DM; P = 0.004 vs. CHF; FigureP = 0.003) and DM  and DM (P = 0.175). The O2 flux measured at complex IV  is presented in Figure2 flux was 33% lower in D‐HF than in CON , where D‐HF was 43% and 36% lower than CON and CHF, respectively , H2O2 production was ~14‐fold, ~12‐fold, and ~4‐fold higher in D‐HF compared with CON (P < 0.0001), DM (P = 0.0001), and CHF (P = 0.0009), respectively  compared with CHF   and CHF (P = 0.044), respectively  and CHF (P = 0.001), respectively  and CHF (P = 0.014), respectively . No significant differences were found between D‐HF and DM groups, despite fibres in D‐HF showing a consistent trend to be smaller across all fibre types  and D‐HF (P = 0.035), respectively  in IIx fibres compared with CON. Additionally, the LCFR was lower in DM compared with CON for type IIx fibres  and CHF (P = 0.034), respectively  and 45% (P = 0.0174) higher in D‐HF compared with CHF for type IIa and type IIx fibres, respectively . In contrast, however, D‐HF patients still presented with lower complex I respiration (i.e. intrinsic dysfunction) compared with other groups, even after correcting for mitochondrial content. This was confirmed by the mitochondrial coupling efficiency ratio (i.e. the RCR) also being impaired in the D‐HF group only. Thus, while the lower values of mitochondrial oxygen flux fits with the common observation of reduced mitochondrial content in CHF2peak), linking the pathophysiology of whole‐body exercise intolerance to skeletal muscle mitochondrial dysfunction in D‐HF and suggesting this could be a potential therapeutic target. Of note, these indices were more strongly correlated in patients with D‐HF compared with CHF alone  driving the mitochondrial complex I dysfunction in D‐HF remains unclear. However, our data implicate a potential role for mitochondrial‐derived ROS. Mitochondrial ROS production was substantially elevated and proportionally greater at complex I in patients with D‐HF compared with other groups, while the gene expression of the mitochondrial antioxidant SOD2 was lower which may have compromised ROS clearance. Regarding the latter, recent data have shown levels of SOD2 are able to modulate mitochondrial ROS and dysfunction alongside atrophy in an animal model of mechanical ventilation.Loss of muscle mass is common in many diseases and limits both exercise tolerance and quality of life.2 delivery limitations in D‐HF, the current study also quantified skeletal muscle capillarity, using both global and local measures of capillarity, which allowed us to gain greater insight compared with the standard approach.2 delivery. In contrast, when we applied the scale‐independent measure of local C:F (i.e. LCFR),2/substrate supply from capillaries surrounding both type IIa and IIx fibres to be greatest in D‐HF patients. It is interesting to note that these differences were not evident when the global measure of C:F was quantified, highlighting the increased sensitivity of the LCFR method when muscle atrophy is present.2 transport (indicated by our capillary measures) in addition to O2 utilization  may combine with a reduced muscle mass to exacerbate whole‐body exercise intolerance in patients with D‐HF. Of note, our data indicate that fibre atrophy was proportionally greater than the capillary rarefaction in patients with D‐HF , which seems to further reinforce greater impairments in the maintenance of muscle mass  occur in the combination of both CHF and DM.To assess potential O2peak) in CON and DM groups to evaluate their current levels of aerobic fitness, while we cannot comment on whether current levels of physical activity may have influenced our results.pectoralis major which is likely not impacted to the same degree as the lower limbs by detraining. However, a further study comparing upper vs. lower limbs muscle alterations  in the current patient groups would be worthy of future investigation.This study was limited by the observational design, which allowed characterization of variables and their relationships rather than prove causality. Further mechanistic studies are therefore warranted. All patients were referred for device implantation and whether our findings apply to the wider population is unknown. We also did not have a measure of exercise intolerance (i.e. V̇OThis study provides novel evidence that patients with D‐HF suffer severe skeletal muscle mitochondrial dysfunction, fibre atrophy, and capillary remodelling when compared with CHF or DM patients. The mitochondrial dysfunction is the result of both qualitative and quantitative alterations at complex I, which was well correlated to exercise intolerance and was paralleled by elevated mitochondrial‐derived ROS and impaired mitochondrial gene transcription. Targeting the skeletal muscle may therefore represent a novel therapy for the treatment of exercise intolerance in patients with D‐HF.None declared.


Introduction: There is paucity of data about the possible role of ABO antigen in response to pharmacologic reperfusion therapy in ST-segment elevation myocardial infarction (STEMI) and its relationship with ST segment recovery; thus, we aimed to evaluate the association of ABO antigen with ST-segment resolution in STEMI patients treated with thrombolysis.Methods: This prospective and observational study was conducted between March 2016 and September 2017 on patients with first acute STEMI within the first 12 hours after onset of symptoms treated with thrombolysis. Myocardial reperfusion success was determined by single-lead ST-segment recovery in 12-lead ECG. Patients were considered as responders if ST-segment resolved ≥50% or were assigned as non-responders if ST-segment resolution was <50%. Univariable and multivariable analyses were performed to examine the contribution of "A" and "B" blood group antigens to ST-segment resolution and the occurrence of major adverse cardiovascular or cerebrovascular event (MACCE). Odds ratio (OR) with 95% confidence interval (CI) were reported for each variable.Results: In this study 303 patients  with a mean age of 56.6 ± 16.8 (ranging from 39 to 87 years) were enrolled. 184 patients (60.7%) were responders and 119 patients (39.2%) were non-responders. The presence of either A (4.5 folds increase) or B (5.4 folds increase) antigen was associated with a higher likelihood of a response to thrombolytic therapy, while had not effect on the occurrence of MACCE.Conclusion: We conclude that the presence of A or B blood group antigens is associated with a better response to thrombolytic therapy in patients with acute STEMI. This finding may imply a higher likelihood for thrombotic occlusion of coronary arteries in patients who have either A or B antigen in their blood. More specifically, we hypothesized that the presence of A or B antigens modify the therapeutic effect of thrombolysis through their effects on coagulation.This study included a prospective cross-sectional comparison of ST-segment resolution response in patients who were admitted to a university-affiliated heart center with evidence of acute STEMI between March 2016 and September 2017 and received thrombolysis. The study design, protocols, and informed consent forms were reviewed and approved by the institutional review board for its merit and ethics in human subject research. All patients signed a partial waiver form for Health Insurance Portability and Accountability Act to allow the investigating team to screen their medical records for study eligibility. Following the screening process, all patients who met the inclusion criteria were asked to sign consent for the study prior to initiation of thrombolysis.All admitted patients to the medical center with first acute STEMI, who were experiencing symptoms no longer than 12 hours were screened for possible inclusion. Patients deemed eligible for primary PCI underwent primary PCI and were not included in this study. Those who could not undergo primary PCI and for various reasons mainly unavailability of catheterization lab, and received thrombolysis at the discretion of consultant cardiologist were screened for inclusion. Patients with any contraindication to the use of thrombolytic medications, such as aortic dissection, systolic blood pressure (SBP) >180 mm Hg, history of head trauma or any surgical procedure within past 90 days, and history of cerebrovascular accident within the past 90 days did not receive thrombolysis and were not included. Patients who had known hypersensitivity reaction to reteplase, previous history of myocardial infarction, left bundle branch block (LBBB) pattern in ECG, cardiogenic shock at admission, and patients who refused to participate were also excluded. Electrocardiographic measurements were performed first on presentation, immediately before thrombolytic therapy, and then, 90 minutes after fibrinolysis. All patients received acetyl salicylic acid (325 mg), clopidogrel (300 mg in patients younger than 75 and 75 mg in patients above 75 years old), unfractionated or low molecular weight heparin, and statins on admission in the emergency department. All qualifying patients received the standard thrombolysis regimen at the institute consisting of two intravenous bolus doses of 10 units of reteplase  administered 30 minutes apart.Patient clinical and demographic characteristics including age, smoking history, medication use and history of hypertension, diabetes mellitus, hyperlipidemia, chronic kidney disease, cerebrovascular disease, as well as family history of CADs, systolic and diastolic blood pressures at admission were recorded. Peripheral blood samples for each participant were collected in citrate tubes at admission time, which were stored until they were analyzed within 24-hours of collection. Biochemical measurements including serial and peak creatine kinase (CK) with MB fraction, cardiac troponin-I, serum glucose and creatinine, and full lipid profile including total cholesterol, high-density lipoproteins, low-density lipoproteins and triglycerides concentrations were performed. Blood typing for ABO and Rh antigen and complete blood cell count were collected from the patient clinical records. Blood group antigen was the main predictor variable of interest in this study which was test against all potential confounders, as above.12 The magnitude of ST segment elevations were assessed in all involved leads . Myocardial reperfusion was the primary outcome variable of this study as determined by ≥50% resolution in single-lead ST-segment elevation within 90 minutes after thrombolysis when it was compared to its baseline value. Patients were considered as responders if ST-segment resolved ≥% 50, otherwise were considered as non-responders.13 The occurrence of a composite major adverse cardiovascular and cerebrovascular events (MACCE) was considered a secondary outcome variable to this study. This variable refereed to any single or combined occurrence of myocardial re-infarction, stroke, acute heart failure (cardiogenic shock/pulmonary edema), and/or death.STEMI was defined according to the criteria published by the American College of Cardiology as clinical symptoms suggestive of acute myocardial ischemia with increased cardiac biomarkers above the 99th percentile upper reference limit accompanied by new ST-elevation defined by ≥1 mm at the J-point in two contiguous leads in all leads other than leads V2–V3 and ≥2 mm in men ≥40 years; ≥2.5 mm in men <40 years, or ≥1.5 mm in women in leads V2-V3.Family history of atherosclerotic cardiovascular disease in at least one first-degree male relative before 55 years or before 65 years of age in a first-degree female relative was considered as a family history of premature cardiovascular disease. Hypertension was defined as either SBP of ≥140 mm Hg, diastolic blood pressure (DBP) ≥90 mm Hg (measured at least two times) or current use of any anti-hypertensive medications in combination with a self-report of hypertension. The diagnosis of diabetes was defined as meeting at least one of the following criteria: fasting blood glucose (FBG) ≥126 mg/dL, 2-hour post prandial glucose (2h-PPG) ≥200 mg/dL, or taking anti-diabetic medications. Hyperlipidemia was defined as total cholesterol of >200 mg/dL or taking lipid-lowering agents.15 A 20% difference in the prevalence was clinically considered as significant. A total of 97 patients were required in each group to detect this difference. Additionally, based on our previous work using a patient population from similar demographic and geographic distribution, the prevalence of patients with either A and/or B blood group antigens were 68% while those patients lacking the either antigen (O Blood group) was 32%.16 Therefore, a total of 303 patients were enrolled to meet the minimum of 97 patients with O blood group. With a sample of this size the power of the study was 0.80 with 95% confidence interval.Power analysis and sample size determination was performed using G*Power statistical tool and online calculator provided to the public by the website of the University of British Columbia. The frequency of ST-segment resolution (≥50%), the primary outcome variable, was used for calculating the sample size. In our previous work, significant ST-segment resolution occurred in 57.3% of the STEMI patients receiving thrombolysis.P values less than 0.05 were considered statistically significant. All analyses were performed using SPSS version 25.0 .Data were expressed as value and percentage for categorical variables. All numeric variables were tested using Kolmogorov–Smirnov test for the presence of a normal distribution and mean and standard deviation (SD) were used to express numerical variables with a normal distribution. Since all continuous variables had normal distribution, they were tested with independent t-test. Categorical data were also analyzed using chi-square test and Fisher exact test, as appropriate. Pearson analyses were used to correlate ABO blood group antigens and other clinical variables with favorable response to thrombolysis (ST segment resolution) and incident MACCE as the dependent outcome variables. Odds ratio (OR) with 95% confidence interval (CI) were reported for each variable, both after univariate and multivariate analysis. A total of 352 patients were screened; from which, 315 fulfilled the inclusion criteria. After excluding patients with incomplete laboratory data, 303 patients  with a mean age of 56.6 ± 16.8 (ranging from 39 to 87 years) were enrolled in this study.P = 0.092). Diabetes mellitus was found to be the only independent predictor of MACCE in our study population [OR: 3.262 (1.502-7.083)]. On the contrary, antiplatelet use, neutrophil/lymphocyte ratio (NLR), A and B antigens did not independently predict MACCE. Neither presence of A nor B antigen associated with the occurrence of MACCE in multivariate analysis ].19 Furthermore, Ketch et al in a cohort study on 1198 patients who underwent PCI for acute myocardial infarction, showed higher prevalence of atherosclerosis and prior history of PCI among patients with O blood type, despite of no difference in procedural success, in-hospital blood transfusion, and incident MACE after 1 year follow-up.20 On the other hand, in a study by Carpeggiani et al in Italy, it has been reported that non-O blood group is associated with increased risk for cardiac death and mortality.7 Zhou et al in another study among 2708 patients, suggested that A blood group was an independent risk factor for the presence and severity of CAD.21 According to the findings of a meta-analysis study, non-O blood group increased risk of myocardial infarction by 25% (95% CI: 1.14–1.36); however, by focusing only on the results of prospective studies, this association was not confirmed .22 Recently, Lin et al demonstrated that blood type O is associated with spontaneous reperfusion of the occluded coronary artery in acute myocardial infarction patients23; which was in contrast to our findings. However, Askin et al reported no association between the ABO blood type and thrombus burden in STEMI patients.24 Another study in the Netherlands did not find any correlation between ABO blood groups and cardiovascular complications or long-term mortality during four years of follow-up after vascular surgery.25 Likewise, Ketch et al showed that the rate of recurrent thrombotic events including myocardial infarction, stent thrombosis, and target vessel revascularization was similar in patients with non-O and O blood types.20 It has been well accepted that the distribution of ABO blood groups are distinct in different ethnic population.26 Thus, the possible reason for these discrepancies might be due to the diversity of population and ethnic differences of these studies.Several previous studies revealed the relation between ABO blood groups and risk of CAD.27 ABO blood groups are suggested to associate with atherosclerotic cardiovascular diseases, through the effects of soluble intercellular adhesion molecule-1 (sICAM-1), soluble P-selectin (sP-selectin), and soluble E-selectin (sE-selectin).29 Many studies reported the association of ABO antigens with serum cholesterol and low-density lipoprotein cholesterol levels.31 Ketch et al also reported the higher prevalence of hypercholesterolemia among those with O blood type.20 Taken together, poor response to thrombolytic therapy in patients with O blood type may be attributable to the higher burden of atherosclerosis and hypercholesterolemia in these patients, which may lead to a less favorable response to fibrinolysis. Of course, in the present study angiographic assessment of coronary artery involvement was not performed, so this possible mechanism is only hypothesis generating and needs detailed coronary angiographic data.Regarding dyslipidemia as an independent risk factor for incident IHD,33 It is well-known that inflammation may increase the presence and progression of cardiovascular diseases, probably through mediating C-reactive protein, interleukin-6 and tumor necrosis factors.34The mechanisms through how ABO antigens may participate in the pathogenesis of CAD and myocardial infarction remain unproved. Most of the familial CAD might be linked to heritable risk factors, and the inheritance of ABO antigens could have important roles in this condition. The effects of blood group antigens on the level of inflammatory proteins and their central role for inflammation in all phases of the atherosclerotic process have been previously identified.35 The less frequent causes of ACS may include spasm of coronary arteries and embolization of calcium or vegetations. The response to thrombolytic therapy depends on the nature of the occluding lesion and burden of thrombus. Lesions with higher thrombus burden are more likely to respond to the administration of thrombolysis. The presence of A or B antigens in peripheral blood are considered a risk factor to hypercoagulability. Topcu et al investigated thrombus burden in patients with STEMI undergoing primary PCI.36 Non-O blood group associated with high angiographic thrombus burden that may explain the higher response rate to thrombolysis among patients with Blood groups of A, B and AB. On the other hand in patients with O blood group the presence of smaller thrombus burden as the main occluding lesion correlates with a less favorable response to thrombolysis in patients with this blood group.Moreover, the etiology of an acute coronary syndrome (ACS) varies from embolization of a fractured atheroma to a sudden occlusion of the coronary artery by a fresh clot on the thrombogenic surface of chronic atheromatous lesion.37 It has been shown that this factor participates in platelet aggregation along with fibrinogen37; thus, the observed increased risk of non-O blood group for CAD in the literature could be attributable to higher vWF levels in these patients, which has been reported to be approximately 25% higher in non-O vs. O-blood groups in several studies.38 Furthermore, a relationship between Factor VIII (FVIII) plasma concentrations and ABO blood groups has been seen, which is suggested to be mediated via VWF.39On the other hand, Von Will brand factor (vWF) plays an important role in hemostasis and thrombosis by mediating platelet adhesion to the vascular wall, especially under high shear stress action.Some limitations may exist in the current study. First, the study is subject to the limitations inherent to its cross-sectional, small sample size and single center non-randomized design. Second, we exclude patients who underwent primary angioplasty; thus, angiographic measures like number of involved vessels, coronary thrombolysis in myocardial infarction flow and myocardial blush grade remains unknown in the present study, and we relied on ST resolution as the only surrogate for myocardial reperfusion after thrombolysis. In addition, we did not measure vWF level, which may have prognostic value independent of ABO blood groups. So, larger well-powered studies are needed to confirm the results of the present study.We concluded that the presence of A or B blood group antigens is associated with a better response to thrombolytic therapy in patients with acute STEMI. This finding may imply a higher thrombotic component of coronary artery occlusion in these patients.No conflict of interest has been declared by the authors.The study design, protocols, and informed consent forms were reviewed and approved by the institutional review board for its merit and ethics in human subject research. All patients signed a partial waiver form for Health Insurance Portability and Accountability Act to allow the investigating team to screen their medical records for study eligibility. Following the screening process, all patients who met the inclusion criteria were asked to sign consent for the study prior to initiation of thrombolysis.No funding has been requested for this study.


Hypoxia is common during daily nursing procedures (DNPs) routinely performed on mechanically ventilated patients. The impact of automated ventilation on the incidence and severity of blood oxygen desaturation during DNPs remains unknown.2) during DNPs performed on patients mechanically ventilated in automated and conventional ventilation modes . All patients with FiO2 ≤ 60% and without prone positioning or neuromuscular blocking agents were included. Patients underwent two DNPs on the same day using AV (INTELLiVENT-ASV®) and CV  in a randomized order. The primary outcome was the percentage of time spent with SpO2 in the acceptable range of 90–95% during the DNP.A prospective randomized controlled crossover trial was carried out in a French intensive care unit to compare blood oxygen pulse saturation (SpOp <  0.001). The percentage of time spent with SpO2 in the acceptable range during DNPs was longer in the AV period than in the CV period . After adjustment, AV was associated with a higher number of DNPs carried out with SpO2 in the acceptable range  and a lower incidence of blood oxygen desaturation ≤ 85% .Of the 265 included patients, 93% had been admitted for a medical pathology, the majority for acute respiratory failure (52%). There was no difference between the two periods in terms of DNP duration, sedation requirements, or ventilation parameters, but patients had more spontaneous breaths and lower peak airway pressures during the AV period (AV appears to reduce the incidence and severity of blood oxygen desaturation during daily nursing procedures (DNPs) in comparison to CV.NCT03176329) in June 2017.This study was registered in clinical-trial.gov ( The safety, feasibility, and efficacy of this mode have been demonstrated with promising results that show a reduction in both the number of manual interventions needed and the incidence of blood oxygen desaturation for various patient conditions, including acute respiratory failure, post-cardiac surgery, and weaning from MV [Daily nursing procedures (DNPs) are routinely performed several times per day in the intensive care unit (ICU) and are crucial for patients’ hygiene and rehabilitation, and to prevent/treat complications due to immobilization –4. Howevlinician . Briefly from MV –20. To o2) ≤ 60% were included. Exclusion criteria were prone positioning, use of neuromuscular blocking agents, age < 18 years old, pregnant women, patients with a contraindication to AV , and patients with a low-quality measurement for SpO2. The study was initiated and supported by the Groupe Hospitalier Sud Ile de France . The study protocol was approved on the 13th of September 2016 by the ethical committee (Comité de Protection des Personnes Ile de France VI) and registered in ClinicalTrials.gov (NCT03176329). Patients or their next-of-kin gave their informed consent before randomization.This single-center randomized controlled crossover study was conducted from September 2016 to March 2018 in a 22-bed, mixed ICU of a French tertiary center. All patients of both sexes mechanically ventilated for at least 48 h with a fraction of inspired oxygen  connected to the patient’s monitor . After randomization, each patient underwent two DNPs on the same day, with 6 h between the two. One was performed in CV and the other in AV in a randomized order defined at inclusion. DNPs were performed by two nurses and included a bundle of care covering patient hygiene , mobilization (repositioning), ventilator-associated pneumonia prevention , and pressure ulcer prevention and treatment (massage of back and pressure points). All the patient’s monitoring and ventilation parameters, including heart rate, mean arterial pressure, SpO2, FiO2, expiratory tidal volume, total and spontaneous respiratory rate, positive end-expiratory pressure (PEEP), and inspiratory and mean airway pressure, were automatically recorded every minute during the DNP using Evolucare Intensive 6.4® . Arterial blood gas samples were performed 5 min before each DNP to determine the PaO2/FiO2 ratio. All events that occurred during the DNPs, such as blood oxygen desaturation, change of ventilation mode, accidental disconnection of the ventilator, the need for manual ventilation, activation of an oxygen bypass, or endotracheal suctioning, were also reported by the nurse in charge.All included patients were ventilated using a HAMILTON-S1 ventilator  and SpOVT) was set below 7 mL/kg predicted body weight (PBW) for acute respiratory distress syndrome, below 9 mL/kg PBW for subjects with normal lungs, and below 11 mL/kg PBW for subjects with chronic obstructive pulmonary disease. In BIPAP and PSV, inspiratory pressure and pressure support were set according to the same VT limits as in VC. Plateau pressure was limited to 30 cmH2O, while positive end-expiratory pressure (PEEP) and FiO2 were set to maintain SpO2 before the DNPs at between 94 and 98% [2 within an acceptable range of 90–95% by adjusting the FiO2 setting. The basic principles of INTELLiVENT-ASV® are detailed as previously described [2 and PEEP controllers were set by the attending physician with a lower limit for SpO2 at 90% and a PEEP limited to 5–15 cmH2O. The high limit for airway pressure was set at a maximum of 30 cmH2O. For both DNPs, alarm limits were set by the clinicians. In the case of major blood oxygen desaturation , biphasic positive airway pressure (BIPAP), or pressure-support ventilation (PSV). In VC mode, the tidal volume . Secondary outcomes were as follows: Incidence of SpO2 in the acceptable range during the DNP; mean, minimum, and maximum SpO2 during the DNP ; incidence and time spent with SpO2 lower than 90%; incidence and time spent with SpO2 lower than 85%; and time spent with FiO2 at 100%. The safety outcome parameters were the occurrence of major adverse events  during the DNP. Two interim analyses for primary and safety outcome parameters were planned after 90 and 180 patients were enrolled.The primary outcome was the time spent with SpO2 between 90 and 95%. We calculated a sample size of 267 patients by group to detect a 15% increase in the primary outcome for DNPs performed in AV as compared to CV . Continuous variables are expressed by mean ± standard deviation and nominal variables as n (%). Continuous variables were compared using the non-parametric Wilcoxon test and nominal variables were compared using Fisher’s exact test. After a univariate analysis to assess all risk factors for primary and secondary outcomes, a multivariate analysis was performed including all univariate factors with p <  0.15. Differences were considered significant where p <  0.05. All calculations were performed using SPSS Statistics V20® .Based on previous studies on DNPs , 10 and There were no safety issues that required premature interruption. Among the 465 patients assessed for eligibility, 185 were excluded, leaving 280 for inclusion , whereas PaO2/FiO2 and SpO2/FiO2 were similar . DNP duration varied from 2 to 55 min in the overall cohort. As detailed in Table p <  0.001). Patients had a lower peak airway pressure  and mean airway pressure  during the AV period than during the CV period.Baseline characteristics of the overall cohort are detailed in Table 2 range during the AV period . In 160 patients (60%), SpO2 was in the acceptable range during the AV period as compared to 123 patients (46%) during the CV period (p = 0.001). After adjustment for confounding factors, AV was associated with a greater number of DNPs performed with SpO2 in the acceptable range . In the overall cohort, blood oxygen desaturation to levels < 90% and ≤ 85% occurred in 161 (30%) and 80 (15%) patients, respectively. Incidences of blood oxygen desaturation to lower than 90% were less frequent during the AV period than during the CV period  and were also shorter . Incidences of major blood oxygen desaturation (≤ 85%) were less frequent during the AV period than during the CV period  and were also shorter . After adjustment for confounding factors, AV was associated with a lower incidence of blood oxygen desaturation ≤ 85% during DNPs . As shown in Fig. 2min in the optimal range during the AV period (p = 0.02), while more patients had the SpO2min ≤ 85% during the CV period (p = 0.002). There was no difference between the two periods for the other secondary endpoints (Table Data for the primary and secondary endpoints are provided in Table p = 0.004) and less endotracheal suctioning per DNP . PEEP was manually increased in two patients (1%) during the CV period and automatically increased by the ventilator in 53 patients (20%) during the AV period. With the exception of one episode of bradycardia (< 40 bpm) in one patient during the AV period, no major adverse events occurred during DNPs in either period. Accidental disconnection of the ventilator occurred in 18 (7%) and 16 (6%) patients during the AV and CV periods, respectively (p = 0.9).All the unplanned interventions performed by a nurse or physician during DNPs are detailed in the Online supplement content 5. A change of ventilation mode occurred in only one patient in each period, and two patients required manual ventilation in the CV period. Patients required fewer manual activations of an oxygen bypass during the AV period than during the CV period  was superior to CV with respect to maintaining SpO2 within an acceptable range and reducing the incidence and severity of oxygen desaturation.Although ICU nurses and physicians frequently observe blood oxygen desaturation relating to DNPs in their daily practice, these respiratory events remain poorly documented. In a cohort of 53 ICU patients (including 45% under MV), De Jong et al. observed blood oxygen desaturation ≤ 90% and ventilatory distress  in 10 and 13%, respectively, of the 184 DNPs performed [Various physiological changes may be implicated by the occurrence of blood oxygen desaturation during DNPs. Patient mobilization is one of the most important, and in particular lateralization, which can induce a decrease in lung compliance, alveolar derecruitment, mobilization of respiratory-tract secretions, airway irritations and coughing, ventilator-patient asynchrony , 23–26, The impact on patient outcomes of DNPs and their related adverse events remains unclear. Previous studies have suggested that early mobilization of the patient would be associated with a greater chance of achieving rehabilitation objectives in the ICU setting –4. De Jo2 values and the incidence and severity of blood oxygen desaturation during DNPs. A prospective randomized controlled study of 60 post-cardiac surgery patients showed that in comparison to CV, INTELLiVENT-ASV® significantly reduces the percentage of time, as well as the total duration and number of episodes per patient of ventilation parameters  being within a “not acceptable” zone [2/FiO2 ratio compared to PSV [2 in an optimal range defined by the authors as between 92 and 96% [Our study suggests AV may have a protective effect when compared to CV in terms of SpOle” zone . During d to PSV . In acco and 96% .2 when SpO2 decreases, but also by automatically decreasing PEEP and FiO2 when SpO2 is supranormal. In contrast, nurses and physicians are not able to adjust FiO2 every time while they are providing care, especially during mobilization of a patient. As suggested by our results, the need for endotracheal suctioning during DNPs seems less frequent in AV, which could be interpreted as the cause or the consequence of a lower incidence of blood oxygen desaturation.The positive results of AV on the incidence of blood oxygen desaturation may be explained by many factors: INTELLiVENT-ASV® continuously and quickly adapts oxygenation, increasing PEEP and FiO2 set at 100% by default. Third, we should have systematically assessed and prevented pain related to patient’s care. Indeed, the incidence of respiratory events decrease significantly with the application of an analgesic protocol before and during DNP, as previously described by De Jong et Al. Future studies on DNP should take pain prevention and treatment into account [2 measurements remains controversial, particularly in ICU patients with acute organ failure, as previously observed [2 represents the only parameters to assess oxygenation at bedside during this procedure. Finally, although we found a significant difference in the primary outcome in favor of AV during DNPs, the clinical impact remains unknown. Further studies are warranted to confirm our results and to assess the real impact on patient outcomes and management.Several factors may limit the interpretation of our data. First, this was a single-center study in a single-blinded design, carried out in an ICU staffed by nurses and physicians considered as advanced users of AV. However, previous studies have consistently reported on the efficacy and safety advantages of using AV over CV –20. Seco account . Moreove account . Fourth,observed . However2 within an acceptable range and reducing the incidence and severity of desaturation, with more spontaneous breathing and lower peak and mean airway pressure.AV used during DNPs routinely performed on ICU patients undergoing MV appears to be superior to CV in maintaining SpOAdditional file 1: Online supplemental content 1. Basic principles of INTELLiVENT-ASV®. Supplemental content 2. Protocol for nurses in case of major blood oxygen desaturation (SpO2 ≤ 85%) during the daily nursing procedure (DNP). Supplemental content 3. Multivariate logistic regression test for SpO2 in the acceptable range (between 90% and 95%) during the daily nursing procedure (DNP). Supplemental content 4. Multivariate logistic regression test of risk factors for occurrence of at least one major oxygen desaturation (SpO2 ≤ 85%) during the daily nursing procedure (DNP). Supplemental content 5. Nurse/physician interventions during the daily nursing procedure (DNP) according to ventilation mode .


Pathophysiology of hypertension and bronchial asthma (BA) shares many similarities, especially those related to the metabolic syndrome (MS).In this study, the indicators of the MS were evaluated in normoglycemic normotensive asthmatic patients to clarify if the components of the MS can still interact to increase the risk of BA, provided that blood pressure and glucose level are kept within the normal physiological ranges.Body mass index (BMI), waist circumference (WC), mean arterial blood pressure (MABP), fasting blood glucose (FBG) and fasting blood insulin (FBI) levels, the quantitative insulin sensitivity check index (QUICKI), serum lipid profile, and spirometric measurements were all compared between 120 asthmatic patients and 59 non-asthmatic subjects. Cigarette smoking, pregnancy, age below 20 years or above 40 years, diabetes mellitus and hypertension, and other chronic diseases were excluded from all studied groups.th-75th interquartile]=88.50 [78.00-101.75], FBI [19.98 (11.12-40.14)], and triglyceride (TG) level [109.5 (76.50-134.0)]) compared with non-asthmatic subjects . QUICKI and MABP were lower in asthmatic patients (0.310 [0.283-0.338] and 86.66 [83.33-93.33]) compared with non-asthmatic subjects (0.320 [0.297-0.353] and 93.33 [83.33-93.33]), (P<0.05). BMI, FBG, low-density lipoprotein, high-density lipoprotein, and total cholesterol levels were comparable in the studied groups.Asthmatic patients demonstrated higher WC (median [25The present finding gives further evidence for higher WC, FBI, TG level, and insulin resistance in normotensive, normoglycemic asthmatic patients compared to healthy controls.The findings of this study suggested that abdominal obesity, hypertriglyceridemia, hyperinsulinemia, and insulin resistance may still be interacting and hence increase the risk of BA in normotensive, normoglycemic subjects. The metabolic syndrome (MS) refers to the co-existence of several recognized cardiovascular risk factors, namely, impaired glucose tolerance, obesity, dyslipidemia, and hypertension ,2. TheseSeveral evidences suggest epidemiological and etiological links between MS and BA ,4. HyperThe pathophysiology of hypertension and BA shares many similarities . The broThe link between adiposity and BA appears to extend beyond the negative impact of obesity on pulmonary ventilation. The close relationship between BA and high body mass index (BMI) is certainly present -27, espeAs described earlier, the pathophysiological mechanisms of hypertension and BA are not that different, especially those related to the MS. In this study, BMI, waist circumference (WC), blood pressure, fasting blood glucose (FBG) level, fasting blood insulin (FBI) level, the quantitative insulin sensitivity check index (QUICKI), and serum lipid profile were all evaluated in normoglycemic normotensive asthmatic patients. We believe that the findings of the present study will clarify if the components of MS can still interact to increase the risk of BA provided that blood pressure and glucose level are kept within the normal physiological ranges.The ethical clearance of this study was approved by the Ethical Review Committee -Al-Neelain University Board, Khartoum, Sudan. All the studied volunteers enrolled in this study signed informed consent before being recruited for this study.The test group consisted of 120 asthmatic patients who were recruited from Chest Clinics – Military Hospital, Khartoum, Sudan, during the period June 2016-January 2017. The control group involved 59 non-asthmatic subjects, who were co-patients, University students, and employees. The asthmatic patients were defined as self-reported, physician-diagnosed BA cases  for at least 2 consecutive years. Cigarette smokers, pregnant women, and individuals age below 20 years or above 40 years and patients with chronic diseases such as diabetes mellitus and hypertension were all excluded from the studied groups.Asthmatic patients were classified into controlled and uncontrolled based asthma control test (ACT) . Patient2) ) and diastolic blood pressure (DBP) . The exa2) . The exae (PEFR) .FBG was determined by the glucose oxidase/peroxidase method (BioSystem S.A-Spain) . FBI levet al. as follows: LDL = Total cholesterol – HDL – TG/5 [Evaluation of lipid profile in the studied groups involved measurement of total cholesterol level using cholesterol oxidase/peroxidase enzymatic colorimetric method (BioSystem kit-BioSystem S.A-Costa Brava-Spain) , triglycL – TG/5 .th-75th interquartile (Q1-Q3). Unpaired T-test was used to assess the statistical difference of the mean for normally distributed variables. Alternatively, significant statistical differences of abnormally distributed variables were assessed by comparing median (Q1-Q3) and giving the P value of the Mann-Whitney U test. The association between IR and the different studied groups was determined by Chi-square test, odds ratios (OR), and 95% confidence interval (CI). P<0.05 was considered significant for all statistical tests used.Statistical evaluation was performed using SPSS  and OpenEpi (www.OpenEpi.com). Normal distribution of variables was examined using Shapiro-Wilk test. The normally distributed variables were described with the mean and the standard deviation (SD). Studied variables with abnormal distribution were described with the median and the 25Distribution of age and gender were comparable in the studied groups, The characteristics of the studied asthmatic patients are summarized in WC was higher in asthmatic patients, Insulin and TG levels were higher in asthmatic patients (compared to the non-asthmatic subjects), IR was higher among asthmatic patients compared to the control group . IR was comparably higher in controlled  and uncontrolled asthmatic patients  compared to non-asthmatic subjects, The discussion of the present findings includes the pattern of change in the well-documented indicators of MS among the studied asthmatic patients.Although BMI was higher in the studied asthmatic patients compared to non-asthmatic subjects, the difference in the mean did not reach statistical significance. WC was higher in asthmatic patients compared to the control group. These findings are not biased by the distribution of age and gender, which were comparable among the studied groups.Previous studies repeatedly showed a close relationship between BA and high BMI -27. At tet al., the prevalence of BA in men is likely to increase if BMI <22 kg/met al. were further supported by a Chinese study that proved the association between airway hyperresponsiveness and extremes of BMI range, both in men and women [According to Luder nd women . The samnd women . The hignd women ,29. Actund women . AccordiAlthough several studies suggested the association between BA and hypertension ,48, otheIt seems evident that hypertension and BA share some similarities in their pathophysiology . Smooth The findings of the present study showed significantly lower systolic, diastolic, and MABP among asthmatic patients compared to the control group. This finding should be interpreted bearing in mind that hypertension was among the exclusion criteria upon the selection of the volunteers in the present study. Based on the literature review, the relatively lower readings of the blood pressures in the studied asthmatic patients may be explained by the adverse effects of beta-2 agonist used for BA treatment ,50 as weet al. investigated blood pressure in patients treated with continuous albuterol inhalation because of status asthmaticus [et al. findings were further supported by another study that evaluated two patient cohorts: The first included patients with respiratory distress who received at least 10 mg of albuterol, and the second involved patients who had continuous albuterol nebulization because of status asthmaticus [et al. finding, diastolic hypotension linearly correlated with albuterol dose in both cohorts [Wisecup hmaticus . Their rhmaticus . The res cohorts .+/Ca++ exchanger protein-1 (NCX1) expression in vascular smooth muscles [++ level in arterial smooth muscles during periods of vasoconstriction [Noteworthy, it is difficult to hypothesize that adverse effects of beta-2 agonist used for BA treatment can explain as much as 10 mmHg difference in blood pressure between asthmatic and non-asthmatic, as shown earlier in the results. This marked difference in blood pressure should motivate researchers for further investigation; however, IgE-induced reaction in patients suffering from atopic BA is likely to be among the explanations. Recent studies suggested that IgE induces downregulation of Na muscles . NCX1 istriction . The roltriction .Although blood glucose level was higher in the studied asthmatic patients compared to non-asthmatic subjects, the difference in the mean did not reach statistical difference. This finding is expected since diabetes mellitus was among the exclusion criteria upon selection of the volunteers of the present study. In spite of the statistically comparable blood glucose levels in the studied groups, the insulin level was significantly higher in the asthmatic patients compared to the control subjects, which suggested increased susceptibility of IR in the first group. This hypothesis is further supported by the significantly lower values of QUICKI in the studied asthmatic patients compared to the non-asthmatic subjects. According to the present results, the odds of having IR are doubled in asthmatic patients compared to the control subjects, regardless of the degree of asthma control. Alternatively, the odds of having IR increased with the increase in the intensity of BA treatment received.In a previous Sudanese study on the hyperglycemic effect of BA, Lutfi and Sukkar compared the readings of random blood glucose (RBG) levels of 41 apparently healthy subjects to a group of 72 patients with BA, after being classified according to ACT and anti-asthma treatments . SimilarThe association between IR and BA is supported by a recent cross-sectional study performed on adolescents aged 12-17 years from National Health and Nutrition Examination Survey . AdjustePrevious efforts toward the use of inhaled insulin formulations for the treatment of diabetes mellitus gave insights on the possible direct effects of insulin on the respiratory airways . ClinicaIn spite of the aforementioned studies on the pro-inflammatory effects of insulin and the possible contribution of hyperinsulinemia in the pathogenesis of BA, other reports demonstrated anti-inflammatory effect of insulin -65. InsuAlthough the researches that uncovered the pro-and anti-inflammatory effects of insulin appeared contradictory, these reports do not oppose the findings of the present study. Hyperinsulinemia and IR were both obvious in the studied asthmatic patients compared to the control group. In the studied asthmatic patients, the pro-inflammatory effects secondary to hyperinsulinemia seemed to be augmented by the lack of anti-inflammatory effects due to IR. However, further researches are desirable to clarify this hypothesis and to postulate the possible synergistic effects of hyperinsulinemia and IR on the pathogenesis of BA.et al., who demonstrated increased serum TG levels, but comparable LDL and total cholesterol levels in asthma patients with high BMI compared to healthy controls in the same BMI-range [The present results showed significantly higher TG levels in asthmatic patients compared to the control subjects. In contrast, LDL, HDL, and total cholesterol levels were comparable in the studied groups. These findings are comparable with van Zelst MI-range . AnalysiMI-range . AlternaMI-range . The totMI-range . Their fMI-range . A recenMI-range .Although the association between dyslipidemia and BA was reproduced by several previous reports, the exact mechanism for this association is unclear and remained for further investigations. Dyslipidemia is a known indicator of IR, which is common among patients with BA, as described earlier -15,57,58Although the present results showed significantly higher TG levels in the asthmatic patients compared to the control subjects, LDL, HDL, and total cholesterol levels were comparable in the studied groups. This finding should be interpreted bearing in mind that major associations with hypercholesterolemia such as hypertension and diabetes mellitus were among the exclusion criteria upon the selection of the volunteers in the present study. Such exclusion criteria might have acted as cofounders that precluded the marked differences in cholesterol levels between the study groups.The asthmatic patients examined in the present study were limited to otherwise healthy, 20-40 years of age, non-smokers so as to control for possible risk factors of hypertension and IR. However, the modulatory effects of smoking, age, and comorbidities related to obesity should be considered in further studies intended to evaluate indicators of MS in normoglycemic normotensive asthmatic patients.The present study did not assess the presence of atopy among the studied groups. Evaluation of IgE levels and skin-prick test, if considered, could have clarified whether the indicators of MS are linked to atopy. Likewise, the study did not measure the level of important cytokines and other chemical mediators involved in the pathogenesis of BA, Th-2/Th-1 ratio, differential count of eosinophils, and other inflammatory cells. Assessment of these markers in future researches will definitively give better insights about the possible links between MS, IR, and BA. Follow-up of the currently examined indicators of MS in the same studied groups in a prospective cohort will be beneficial to identify the risk of diabetes mellitus and hypertension in the asthmatic patients involved in this study.The current finding suggests that abdominal obesity, hypertriglyceridemia, hyperinsulinemia, and IR may still interact in normotensive, normoglycemic subjects to increase the risk of BA. In contrast, BMI and serum cholesterol level failed to show the usual trend of MS in the studied asthmatic patients. Although the blood pressure was within the normal physiological range, it was relatively lower in asthmatic patients as compared to the control group. This is probably because of the adverse effects of beta-2 agonist used for BA treatment or IgE-induced reaction in atopic asthma patients. The implications of this study remain open for further investigations to explain their molecular and cellular basis.The study received ethical approval from the Ethical Review Committee -Al-Neelain University Board, Khartoum, Sudan. All studied subjects signed informed consent before being enrolled in the study.Not applicable.The data supporting the present findings are contained within the manuscript.None to declare.None to declare.MFL designed the study. HAAS and ABMA carried out experimental protocols. MFL and HAAS analyzed the data. MFL and RFE prepared the manuscript draft. All authors read and approved the final manuscript.


Determining subclinical Brain stroke (BS) risk factors may allow for early and more operative BS prevention measures to find the main risk factors and moderating effects of survival in patients with BS. In this prospective study, a total of 332 patients were recruited from 2004 up to 2018. Cox's proportional hazard regressions were used to analyze the predictors of survival and the moderating effect by introducing the interaction effects. The survival probability 1-, 5- and 10-year death rates were 0.254, 0.053, and 0. 023, respectively. The most important risk factors for predicting BS were age category, sex, history of blood pressure, history of diabetes, history of hyperlipoproteinemia, oral contraceptive pill, hemorrhagic cerebrovascular accident. Interestingly, the age category and education level, smoking and using oral contraceptive pill moderates the relationship between the history of cerebrovascular accident, history of heart disease, and history of blood pressure with the hazard of BS, respectively. Instead of considerable advances in the treatment of the patient with BS, effective BS prevention remains the best means for dropping the BS load regarding the related factors found in this study. Of these numbers, 5 million dies, and the other 5 million are permanently disabled. High blood pressure contributes to more than 12.7 million strokes worldwide. Europe averages approximately 650,000 BS death each year. These figures indicate the importance of studying BS.Brain stroke (BS) is among the primary sources of mortality and permanent disability in the world. BS is the second leading cause of death in Iran. Besides, it causes more long-standing severe disabilities than any other disease. More than half of patients with BS will die within the subsequent eight years. An approximately three-quarters of all strokes arise in the community over the age of 65. The risk of developing BS would double more than per decade after the age of 55 (U.S. Centers for Disease Control and Prevention). According to the World Health Organization3. It has been suggested that the history of hyperlipoproteinemia is a risk factor for BS and that the increased stroke incidence in persons with long term exposure to the risk factors promotes atherosclerosis and subsequently develops BS Diabetes increases the risk of cardiovascular and cerebrovascular diseases (such as ischemic BS)4. Around 30% of BS patients have diabetes4 neurological deficits and death rates are meaningfully higher in patients with BS who also have diabetes 5. Smoking and passive smoking, as one of the main risk factors for BS, has been identified by some studies7 passive smoking increases the risk of overall BS 30%7. Determining BS risk factors may allow for early and possibly more operative BS prevention.Modifiable factors to support endorse survival among patients with BS are of central public health importance. Hypertension is the most potent risk factor for BS. Age and the existence of other risk factors may alter or improve the result of increased blood pressure on BS incidence 2–5. According to the common risk factors among patients with BS, in developed countries, the incidence of stroke is declining, mainly due to efforts to lower blood pressure and reduce smoking. However, the overall rate of stroke remains high due to the aging of the population. Impaired cardiac function growths stroke incidence at all levels of blood pressureBased on an extensive search, no study was found (if any) to model the risk factors of the hazard of death and their possible moderating effects among patients with BS in Ardabil, Iran. Therefore, this study aimed to model the main predictors of survival in patients with BS, along with the moderating effects of these factors in a period of 10-years follow up.In the current prospective longitudinal study, data were acquired from the BS registry of the Imam Khomeini Hospital, Ardabil, Iran. All patients complied with the International Coding System ICD-10 according to the Computerized Tomography (CT) scan and Magnetic Resonance Imaging (MRI). A total of 332 patients were entered in the ten-year follow-up study (defined as the date of diagnosis from June 2004 up to June 2018). The follow-up time was calculated from the date of hospitalization by acute BS until the death or end of follow-up, whichever came first. Telephone interviews managed post-BS death outcomes only through one of the main authors/researchers (FF) of the study. An exact date of death and cause of death were recorded, except for cases that did not receive a response after multiple follow-ups, and those who died due to non-BS.For all patients and based on hospital document, the demographic variables included age category at diagnosis , sex , employment status , place of residence , education level , smoking , former smoking , waterpipe smoking , history of heart disease , diabetes , oral contraceptive pill use , physical activates , history of cerebrovascular accident type , history of blood pressure history , history of hyperlipoproteinemia , history of myocardial infraction  were used in the analysis.The protocol of the study was approved by the institutional review board of Tabriz University of Medical Sciences (ethics code: IR.TBZMED.REC.1398.667). Every person was free to participate in the study, and the privacy of participants was also preserved. All participants filled and signed the consentment and also, informed consent has been taken from all participants. All methods were carried out in accordance with relevant guidelines and regulations.p < 0.1) was utilized. Adjustments were made for background variables including age category, sex, employment status, place of residence, education level and physical activity for the interested BS risk factors including history of hypertension, history of diabetes, history of cerebrovascular accident, history of myocardial infraction, history of blood pressure history, history of heart disease, history of hyperlipoproteinemia history, smoking, oral contraceptive pill use, and cerebrovascular accident type. Also to assess the moderating effect, the interaction effect of the risk factor of BS with background variables were tested in the model8.Statistical analysis was done by STATA software [ver.15] . Data were presented using mean (SD), median (min–max) for the numeric normal and non-normal variables respectively, and frequency (percent/rate) for categorical variables. Survival time was calculated in months and was expressed as the median ). Data were described with frequency, rate, and proportion. The Kaplan–Meier method was used to estimate the rates of BS The survival probabilities were compared in groups by the Log-rank test. Cox proportional hazards regression analysis has been conducted to determine the relationship among related BS risk factors, by estimation of its hazard ratio (HR) and 90% CI. In the multivariate analysis, a backward elimination strategy with  and all individual variables tests (All p > 0.05).Furthermore, Harrell's C index was computed as a measure of concordance between model predictions and real outcomes . The missing data ranged over 0.33%—2.01% which were ignorable and were deleted listwise in the analysis. The Proportional Hazard (PH) assumption was assessed by Shoenfield residuals' testThe study protocol was approved by the institutional review board of Tabriz University of Medical Sciences (IRB No.: TBAMED.REC. 1397.286).Of the 480 patients enrolled in this study, 332 were eligible to participate in this study, 32 (13%) persons were censored within 10-years of follow up. The median follows up time was 81.3  months, respectively. The mean age at diagnosis was 77.42 (SD 10.4) months in BS patients. In these patients, 1-, 5- and 10-year survival probability (95% CI) were 68% (63–72), 59% (53—64), 39% (34—45), respectively. The median survival time (95% CI) of these patients was 77.42 (62.07—104.48).The distribution and comparison of death rate based on demographics of the study participants are presented in Table p < 0.05).Table p < 0.05). Other factors, i.e., employment status, education, were not associated with the survival probability in patients with BS. (p > 0.05). Also, physical activity was inversely and significantly related to the hazard of the event (p < 0.05).For demographic characteristics, higher age categories and being male were significantly related to death rate (p < 0.05), but other clinical variables such as cerebrovascular accident history, myocardial infraction, blood pressure, heart disease, smoking, former smoking, passive smoking, waterpipe smoking were not significantly related to the hazard of the event (p > 0.05)  Table .Table 3Rp < 0.001). Furthermore, Harrell's C index (= 0.71), indicating a fair level of concordance between observed and predicted death in the study sample.The results of the multivariate Cox regression for patients with BS are shown in Table The results to assess the interaction effect of the significant risk factor of BS with background variables are presented in Table The plot of KM survival probability displays that after 2-months of follow up, the survival rate declined to 75%. Then the mortality rate has dropped steadily until 160 months, and later a sudden fall in survival probability was observed .The results of testing the PH assumption indicated that all predictors had satisfied the PH assumption in all cox regression models , having a hemorrhagic cerebrovascular accident, and not being physically active directly predicted the survival in patients with BS. Interestingly, the interaction effect of cerebrovascular accident history with age category and education level, the interaction effect of history of heart disease with smoking, and the interaction effect of history of blood pressure with oral contraceptive pill use were significant on the hazard of BS, indicating that age category and education level moderates the relationship between the history of cerebrovascular accident and hazard of BS, smoking moderates the relationship between a history of heart disease and hazard of BS, oral contraceptive pill use moderates the relationship between a history of blood pressure and hazard of BS.9, however, some controversies could be explained so that confounders have not been adjusted, and also, women were older when they get their first BS10. Other demographic characteristics, i.e., employment status, place of residence, and education level, weren't the significant predictors of survival for BS. Physical activity was a significant prognostic factor of BS based on the results of univariate and multivariate analysis. BS patients with physical activity had a 0.35% hazard rate of less than inactive patients. There is controversy so that Willey et al. reported that any physical activity was not associated with ischemic BS in univariate or multivariable analyses 11. Differences in methodology, study populations, and interferences are expected to have contributed to these dissimilarities.The results of univariate analysis for demographic characteristics showed that the age category and sex of the participants were prognostic factors of BS Although, the sex wasn't significant in multivariate analysis. Still, the male patients were more likely to die from BS than the female patients (about 40%). Although the finding of some studies confirms this result13. History of diabetes was a significant risk factor of BS in univariate analysis. Though it wasn't statistically significant in multivariate analysis, however, a suggestive effect of this variable has been observed so that diabetes develops BS 29% more likely than non-diabetes3, Ji et al. confirms the same result3. Having the history of hyperlipoproteinemia was a significant risk factor of BS in univariate analysis. Patients without a history of hyperlipoproteinemia develop BS about 36% more than patients with a history of hyperlipoproteinemia, there is a finding in line with our study2. Using the oral contraceptive pill was a significant risk factor of BS in female patients in the univariate analysis, the same finding has been assessed from the studies5. Oral contraceptive pill users were at increased risk of myocardial infarction or BS compared with non‐users: relative risk (RR) 1.6 (95% CI = 1.3‐1.9)5. The overall summary odds ratio for first-ever ischemic stroke risk associated with current oral contraceptive pill use compared with noncurrent oral contraceptive pill use was 2.47 [95% CI = 2.04–2.99]. Hemorrhagic cerebrovascular accident was significant for BS according to the results of univariate and multivariate analysis. However, BS patients with hemorrhagic cerebrovascular accident had 1.5 times worse outcomes than those with Ischemic. There are finding that confirms the results of our study5.Based on the results of univariate analysis for clinical characteristics, having the history of blood pressure was a significant prognostic factor of BS Patients with a history of blood pressure had a worse outcome. Still, it wasn't statistically significant in multivariate analysis. Some studies support this claim15. Fifthly, regular care, living conditions, and the quality of receiving essential care couldn't be considered in the assessments. To implement the concerns as a bias in the statistical models, introducing frailty in the model to account for unobserved heterogeneity can be recommended. Such models, along with the cox model, require some assumptions like PH and the independent censoring, which can be relaxed by statistical learning procedures. In this regard, we recommend the deep learning of artificial neural networks as our future program.The strength of this study is the prospective setting; original features are the instant evaluation of the effect of risk factors on outcomes, allowing assessment of the relative impact of each predictor of survival. However, there are some limitations to this study, and the results should be concluded considering these limitations. Firstly, there may be some evidence of inaccurate responding of the person who accompanied the patients with severe/critical conditions. As the second limitation, some cases of BS immediately lead in death at the time they had been admitted to the hospital that was not included in the study. Thirdly, we hadn’t the NIHSS at baseline in our database as NIHSS may improve the findings and make them more conclusive. Fourthly, we used a simple procedure for follow up over telephone, and there were neither reliability criteria for this nor additional technical/medical work-ups. The telephone-based follow-up is a regular task in survival studiesAccording to the results, age category, sex, employment status, place of residence, education level, physical activity, history of blood pressure, history of diabetes, history of hyperlipoproteinemia, oral contraceptive pill use, cerebrovascular accident were significant risk factors of BS. Also, the age and education, smoking, and using oral contraceptive pill moderates the relationship between cerebrovascular accident history, history of heart disease, and blood pressure history with the hazard of BS, respectively. According to the results obtained in this study, recognizing the BS risk factors provide early and probably more effective BS prevention procedures. Rather than substantial advances for the treatment of a patient with BS, operative BS prevention remains the best action for reducing the BS burden. Also, as modifiable risk factors, increasing physical activity and smoking cessation, the control of high blood pressure, preventing diabetes, and hyperlipoproteinemia may be useful in decreasing the risk of BS for different ages and sexes.


An SVI(NO test) value above 39.86 mL/m2 was associated with 100% five-year survival rate . The results of the analysis suggest that the SVI(NO test) measured during the initial diagnostic RHC could be a very valuable prognostic factor in the PAH patients.The aim of the study was to determine the prognostic value of hemodynamic parameters measured during initial diagnostic right heart catheterization (RHC) in standard conditions and using a nitric oxide reversibility test. A retrospective observational study of 62 patients with pulmonary arterial hypertension (PAH) was performed. Clinical, biochemical, echocardiographic, and hemodynamic data obtained at the time of the PAH diagnosis were precisely analyzed. Patients were followed for five years. Death or lung transplantation was considered as a primary endpoint. The mean follow-up period was 1090 ± 703 days and the median age was 46.84 years. In the studied group, 25 patients survived, 36 patients died, and one underwent a lung transplantation. From all the examined parameters, only stroke volume index during reversibility test with iNO (SVI It is a < 0.05) . Any sig < 0.05) .Ernst Von Romberg is the author of the first mentioned changes in pulmonary circulation characterized as the “pulmonary vascular sclerosis” which he described in 1891. The following years were a period of arduous search for the etiology and pathophysiology of what researchers at that time saw as a clinical manifestation of PH but it wasn’t until 1973 that the World Health Organization (WHO) set up a group of experts in order to systematize the existing knowledge about PH and standardize clinical and pathological nomenclature . Only 2.2 and SvO2 > 65% enable to classify patients with PAH to the group with low death risk (<5%) whereas the RAP > 14 mmHg, CI < 2.0 L/min/m2 and SvO2 < 60% has characterized the group with high death risk (>10%) [Intensive research is underway on new drugs and combination therapies, but equally great attention is being paid to the regular assessment of patients with PAH. Right heart catheterization (RHC) variables currently recommended by ESC to evaluate one-year mortality are: right atrial pressure (RAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2). Value of the RAP < 8 mmHg, CI ≥ 2.5 L/min/mk >10%) . Attemptk (>10%) ,10. Desp% . AttemPAH patients require special care from the moment the diagnosis is made, with a strong emphasis on capturing the moment of deterioration of cardiovascular function. Therefore, the main aim of this study was to evaluate hemodynamic parameters measured in the initial RHC, both in a normal environment and with the reversibility test using inhaled nitric oxide (iNO) as prognostic factors.A single center retrospective study was conducted in the 2nd Department of Cardiology in Zabrze, Medical University of Silesia in Katowice, Poland in which patients with PAH diagnosed and treated between 1994 and 2013 were enrolled.The inclusion criteria were confirmed in RHC diagnosis of arterial pulmonary hypertension, performed pulmonary arterial hypertension reversibility test with iNO at the diagnostic stage of RHC, completed by five-year follow-up.The exclusion criteria comprised patients <18 years of age during diagnostic RHC, uncorrected congenital heart disease, Eisenmenger syndrome and any life-threatening disease other than PAH such as active malignancy of any type or history of a malignancy within previous five years, history of unstable angina, myocardial infarction or stroke within 3 months prior diagnostic RHC, significant renal dysfunction, defined as serum creatinine >250 μmol/L (>2.8 mg/dL), liver disease, defined as any liver function tests >3 times the upper limit of normal. The study protocol was reviewed and approved by the Bioethics Committee of the Medical University of Silesia. The endpoints of the study were death or urgent lung transplantation in the five-year follow-up.Clinical assessment included: physical examination, pharmacological treatment, six-minute walk test distance (6MWT), and the WHO functional class (WHO-FC).Echocardiography images were acquired in standard views recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging, and following parameters were measured and calculated: right ventricle end-diastolic diameter (RV-d), right atrium area (RAA), tricuspid annular plane systolic excursion (TAPSE), maximum velocity of tricuspid regurgitation (TR V max.), right ventricle systolic pressure (RVSP), pulmonary flow acceleration time (AcT), vena cava inferior diameter (VCI), and its collapse >50% during inspiration. The presence of fluid in pericardium was also determined.Concentrations of hemoglobin, sodium, uric acid, and creatinine were determined by the routine techniques. N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration was measured by the chemiluminescence method on Roche Cobas 6000e501 .All patients underwent RHC, which was performed via right jugular access under local anesthesia and in a supine position at rest. A flow-directed Swan–Ganz catheter  was advanced to the right heart and pulmonary artery under fluoroscopy. After 10 min of stabilization of circulation following parameters were measured: RAP, pulmonary artery pressures systolic (PAPs) and diastolic (PAPd), pulmonary artery wedge pressure (PAWP). All the measurements were performed during end expiration. CI was measured by thermodilution, using a rapid bolus injection of 10 cc of cold saline. Blood pressure was measured non-invasively. PAWP and RAP was measured two times, before and after CI measurements, systolic blood pressure (SBP) and diastolic blood pressure (DBP) was measured three times: before, during third and after fifth CI measurements. Two samples of mixed venous blood for gas analysis were collected. The degree of oxygenation of arterial blood was evaluated using a pulse oximeter.Mean values of RAP, PAPs, PAPd, PAWP, and heart rate (HR) were used for final evaluation. Acquired data enabled calculation of PAPm and mean blood pressure (MBP), transpulmonary gradient (TPG), pulmonary vascular resistance index (PVRI) and SVI. Body surface area was calculated by angiograph software including patient’s height and weight.2), and heart rate as a number of heart beats per minute (bpm). PVRI was expressed in WU × m2 and stroke volume index as milliliters per square meter (mL/m2).Blood pressure parameters were expressed in millimeters of mercury (mmHg), CI as liters per minute (L/min/mThe hemodynamic measurements were carried out at baseline air conditions and during testing with iNO 60 parts per million (ppm). iNO  was administered through the nasal mask in a mixture with oxygen (10 L/min.) from a source tank equipped with a microflow gauge .Ten minutes of iNO inhalation were performed before consecutive hemodynamic measurements. At each measuring point, five results were acquired and then an arithmetic mean was calculated. A positive acute response was detected if the reduction of the PAPm ≥ 10 mmHg and reached an absolute value of PAPm ≤ 40 mmHg with an increased or unchanged cardiac output (CO).n = 25) and the second group, patients who died or had a lung transplant in this period (n = 37).Factors potentially influencing the prognosis of the PAH patients were analyzed in a subgroup of 62 patients selected according to the above-mentioned inclusion and exclusion criteria. The patients were divided into two groups: the first group comprised patients who survived the five-year follow-up  and were compared with the p ≤ 0.1 at univariate analysis were included to multivariate Cox proportional hazards regression model with stepwise algorithm selection (p < 0.2). The results of the Cox analysis were reported as relative risks with corresponding 95% confidence intervals.Cox proportional hazards regression analysis was applied to identify the variables associated with long-term outcome. All demographic, clinical, echocardiographic, and hemodynamic variables were included in a univariate Cox analysis but only complete unrelated variables with a value of The receiver operating characteristic (ROC) curve was used to measure the cut off value of the significant prognostic factors.Survival analysis of all deaths or lung transplantations, based on Kaplan-Meier curves and log-rank tests were used to assess the event-free survival between groups of patients separated on the basis of the cut-off points determined by the ROC curve analysis.p < 0.05. Lack of statistical significance was presented as NS (non-significant). Statistical analysis was performed using STATISTICA 13.1 PL .The results were considered statistically significant if A total of 62  patients in mean age 44.55 ± 15.41 met the inclusion criteria. During the five-year follow-up 36 patients died and one patient underwent lung transplantation. Patients who survived the five-year observation period initially were in the lower WHO-FC, passed a significantly longer distance in 6MWT, and were borderline significant more often responders in the reversible pulmonary hypertension test compared to patients who had died. In addition, they had lower serum concentrations of NT-proBNP, uric acid, and creatinine, as well as a higher sodium concentration. In the group of patients, echocardiography showed smaller RV-d, RAA, TR V max., and TAPSE. There were no differences in AcT values. For survivors the VCI collapsed during inspiration in all cases but in the group of death below five years of observation only for 14.8% such dependence was detected. There were no statistically significant differences between the groups in the etiology of pulmonary hypertension and pharmacotherapy .2) and SvO2 compared to patients who died during the follow-up  statistically significant improvement was observed for all measured parameters except for PAWP and CI .The survollow-up .p ≤ 0.1 is considered significant for univariate Cox analysis. The factors that reached this included WHO FC, response for iNO inhalation, distance in 6-MWT, sodium serum concentration, RVd, RAA, TR Vmax., presence of fluid in pericardium, HR(baseline), CI(baseline), SVI(baseline), SaO2, SvO2, HR(NO test), CI(NO test), and SVI(NO test). For incomplete data, in analogical analysis, p ≤ 0.1 have been reached by NT-proBNP and uric acid serum concentration, AcT, and presence of VCI collapse during inspiration  and SVI(NO test) for multivariate analysis, we decided to include SVI(NO test). In comparison to the SVI(baseline) in the analysis of ROC curves, this parameter has got much higher predictive value. Results of ROC analysis are presented in Bearing in mind that HR, CI, and SVI are strongly related variables and this relationship also exists between SVI(NO test) and SaO2 are independent predictors of worse prognosis. Both higher SVI(NO test) by 1 mL and resting SaO2 by one pp were connected with a 9.00% probability reduction of death or lung transplantation in five-year follow-up  and SaO2 did not show the usefulness of uric acid and natrium serum concentration, VCI collapsing during inspiration and AcT as prognostic factors in the studied group of patients. On the other hand, the inclusion of the NT-proBNP serum concentration to the regression model analysis abolished the SaO2 prognostic value with the unfavorable, statistically borderline (p = 0.063) prognostically higher prognostic value of the NT-proBNP serum concentration, while the SVI(NO test) hazard rate was unchanged (Three-factor Cox regression models built on the basis of SVInchanged .(NO test) value, with the cut-off point = 39.86 mL/m2 ((NO test) above cut-off point is associated with a 100% five-year survival rate.Kaplan-Meier survival curve has been estimated depending on the SVI86 mL/m2 . SVI(NO (NO test) and SaO2 were recognized as independent predictors of death or lung transplantation in multivariable Cox regression, however SaO2 despite its high specificity has had low sensitivity. SV seems to be a new, very valuable prognostic parameter, both for RHC carried out under standard conditions and in the reversibility test with NO. ROC curve analysis results are similar for results of SV obtained during initial measurements and iNO inhalation along with SVI in normal environment, however the attention is drawn to a high predictive properties of the SVI(NO test) value.The univariable analysis confirmed the previously described relationships between worse prognosis and many clinical, laboratory and hemodynamic parameters . Among hp < 0.001) but also and at the second ECG after the initial treatment  [SV is a parameter which combines the prognostic value of two parameters: CO (and CI as mentioned above) and HR. Increasing HR is a predictor of worse prognosis for the patients with PAH ,12,13. I< 0.001) .BSA) as SVI, which allows better comparison of parameters between patients.Patients with PAH have got reduced RV ejection fraction, which decreases even more with disease progression and during exercise. These factors lead to SV reduction. The mechanism adjusted to keep SV stable is a RV enlargement, but the compensation possibilities are limited. This is why increased heart rate through sympathetic hyperactivity  is one o2  is associated with significantly better survival  [2  in the first follow up is a variable associated with increased risk of the death or transplantation and each reduction of SVI per 10 mL/m2 increases the risk of adverse event 1.28 times .It should be noted that a low SVI still identified patients with poorer prognosis even when they had CI ≥ 2.5 L·min−1·m−2 [Despite the common knowledge about the physiology of pulmonary circulation, data on the usefulness of SVI are limited. One of the first works that confirmed usefulness of SVI was the study of van Wolferen et al. where for patients with pre-capillary PH (PAPm ≥ 25 mmHg and PAWP ≤ 15 mmHg) has been confirmed in magnetic resonance measurements that a baseline SVI > 25 mL/m< 0.010) . Weather(NO test) prognostic value has not been considered so far and to understand its predictive value it is necessary to refer to the physiology of vasoreactivity testing. Inhaled iNO through diffusion directly into the smooth muscle of pulmonary vessels can cause a selective local pulmonary vasodilatation without reducing the systemic arterial pressure [(NO test) allows for an additional assessment of potential reserve in improving the function of pulmonary circulation and hence right ventricular functions exist. In regard to the examined population of patients in the group with five-year survival, a higher prevalence of patients with reversible pulmonary hypertension is seen (24% vs. 5.41%). However, being a non-responder does not mean that a five-year observation period will not be achieved, and being a responder is not an absolute indicator of good prognosis. It should be remembered that patients with pulmonary hypertension mainly die from right ventricular failure as a consequence of pulmonary circulation remodeling and SVI is an indicator directly related to the right ventricular function. The SVI value is an objective parameter that allows assessing the severity of heart failure, and the SVI(NO test) below 39.86 mL/m2 was established as an independent factor of worse prognosis. All patients with SVI(NO test) above the cut-off point completed a five-year follow-up period. SVI assessed at the time of diagnosis of the pulmonary hypertension allows to isolate at the very beginning a group of patients with particularly poor prognosis. Taking into account the fact that vascular remodeling in PH may be partly reversible through a reduction of PAP, the hemodynamic stress in pulmonary arteries [The SVIpressure . The prepressure . The resarteries  should barteries ,22, but arteries .When assessing work limitations, the low population size should be mentioned, as well as the fact that, until 2007, treatment options for PAH were very limited in Poland. Available drugs were only PDE-5i  and CCB. After 2007, the therapeutic options for patients with PAH expanded but still they depended on administrative requirements and not on the patient’s clinical condition.(NO test) measured during the initial diagnostic RHC seems to be an early parameter with a large prognostic and therapeutic potential, but studies on a large population are essential.Despite a significant improvement in the survival rate of patients with PAH, it remains a disease not only significantly shortening the expected survival time, but also affecting the quality of life. There is no treatment that could completely reverse the pathomorphological changes occurring in the pulmonary circulation and thus cure the disease. Hence, the present therapeutic options are mainly focused on the pharmacological inhibition of major pathways and heart failure treatment. In the current situation, it is particularly important to assess the severity of cardiovascular dysfunction in order to capture the moment when it is necessary to intensify or change the treatment. SVI