Reducing cardiovascular risk (CVR) is the main focus of diabetes mellitus (DM) management nowadays. Complex pathogenic mechanisms that are the subject of this review lead to early and severe atherosclerosis in DM patients. Although it is not a cardiovascular disease equivalent at the moment of diagnosis, DM subjects are affected by numerous cardiovascular complications, such as acute coronary syndrome, stroke, or peripheral artery disease, as the disease duration increases. Therefore, early therapeutic intervention is mandatory and recent guidelines focus on intensive CVR factor management: hyperglycaemia, hypertension, and dyslipidaemia. Most important, the appearance of oral or injectable antidiabetic medication such as SGLT-2 inhibitors or GLP-1 agonists has proven that an antidiabetic drug not only reduces glycaemia, but also reduces CVR by complex mechanisms. A profound understanding of intimate mechanisms that generate atherosclerosis in DM and ways to inhibit or delay them are of the utmost importance in a society where cardiovascular morbidity and mortality are predominant. Cardiovascular complications account for more than 70% of all hospital admissions in diabetic patients in the USA . The macThe CAD risk was equal for patients with a history of over 10 years progression of DM and those with cardiovascular disease . FurtherDM is an independent risk factor for stroke. Moreover, diabetic patients present a certain stroke pattern, they suffer more frequently of ischaemic rather than haemorrhagic strokes and the lacunar strokes represent a majority . The preIn this review, the authors’ objectives were as follows: to identify comorbidities of DM patients that share the same pathogenic substrate with DM (insulin resistance and factors that further increased the atherosclerotic risk); to highlight the most common CVR factors in DM and the importance of identifying them early in a patient with diabetes, as well as their management according to the new guidelines. All these objectives were achieved by analysing the information provided by some of the most recent works published in the specialized literature.Dyslipidaemia is frequently found in up to 70–80% of diabetic patients . It is dTriglycerides increase is caused by the classic lipoprotein lipase inhibition in insulin resistance as well as the inhibition of hepatic lipase. Hormone-sensible lipase exhibits increased activity levels which generate an increase in free fatty acids levels that arrive to the liver. Insulin resistance increases hepatic synthesis of apolipoprotein B (apoB) and triglyceride rich VLDL particles . It alsoTriglyceride-rich VLDL-cholesterol particles transfer triglycerides to the LDL and HDL-cholesterol particles . NormallMetabolic syndrome (MS) significantly increases the risk of developing DM and CAD . It is eWorld Health Organization defines MS creating one compulsory criteria: the presence of modified basal glycaemia, glucose tolerance alteration or DM + 2 or more of the following: increased arterial blood pressure values >140/90 mm Hg), hypertriglyceridemia (>150 mg/dL), and/or low HDL-cholesterol  and microalbuminuria  [0 mm Hg, The International Diabetes Federation (IDF) defines MS as central obesity  as well as two of the following components: baseline glycaemia >100 mg/dL, triglycerides >150 mg/dL, HDL-cholesterol <40 mg/dL in men, <50 mg/dL in women, arterial hypertension (SBP >130 mmHg or DBP >85 mm Hg)  althoughNon-alcoholic steatohepatitis is commonly found in type 2 DM patients, its prevalence being around 70% . ObesityCKD represents an independent risk factor for cardiovascular morbidity . CKD preDM itself represents a major CVR factor, the majority of diabetic patients’ deaths being due to cardiovascular complications . The risThere are several CVR factors classifications for diabetics. One of these distinguishes two categories: the glycaemic factors and non-glycaemic ones: arterial hypertension, dyslipidaemia, obesity, smoking, chronic inflammation and microalbuminuria. Another classification mentions traditional  and non-traditional risk factors. The non-traditional risk factors have been the subject of increasing research, although their specific impact on CVR has been difficult to assess—some examples include: insulin resistance, endothelial dysfunction (due to excessive vasoconstriction and reduced vasodilation), inflammation , microalbuminuria, intima-media thickness, and coronary calcium score ,26.Hyperglycaemia is another CVR factor and its control is being highly debated. The UKPDS has shown that for patients with excellent glycaemic control, with a mean HbA1c <7%, it was observed a 16% reduction in cardiovascular complications in comparison with patients with mean HbA1c values of 7.9%, although this reduction was not statistically significant . SimilarOther studies have shown that prompt intensive hyperglycaemia treatment reduces CVR in patients without other risk factors. DCCT study highlighted a 47% risk decrease for any CVD and a 57% reduction of MI, stroke or cardiovascular-related risks causing death . The chaArterial hypertension is one of the most important CVR factors in diabetic patients. Indeed, 77–87% of these subjects suffered from it ,39. ADA ADA recommends lifestyle changes for diabetic patients with values >120/80 mm Hg as they can reduce blood pressure values as well as support glycaemic control . These cAnother CVR factor in diabetic patients is dyslipidaemia. Decreasing LDL-cholesterol may reduce CVR by 20–50%. These patients mainly present small and dense LDL particles which easily traverse the arterial wall transforming into oxidized LDL due to the effects of oxygen reactive species . The intRecent literature data regarding T2DM patients considered that non-HDL cholesterol level measurements associated with LDL-C/HDL-C ratio could be used as markers of dyslipidaemia . Non-HDLDM leads to high activation and aggregation of thrombocytes that is a CVR factor. Primary prevention of cardiovascular disease with aspirin in diabetics remains controversial and is currently indicated only in secondary prevention . The recCVR prediction is important in patients with DM in identifying high-risk patients and choosing the therapeutic strategy. DM represents a CVD factor, considered by some authors to be a CVD equivalent and, in the diabetic patient, the presence of other CVD factors varies from one patient to another, thus leading to different categories of CVD. Each CVR factor present in the diabetic patient, such as hypertension or dyslipidaemia, influences the CVD and it is necessary to apply scores that provide data as close to reality as possible on the CVR by combining the impact that each factor has. There are several risk scores, some of them being specific for patients with diabetes because they take into account the glycaemic parameters while others are more suitable for the general population as they do not take glycaemic parameters into account.Framingham and SCORE risk scores are some of the most commonly used CVR prediction scores in the general population. Within these scores DM is only a factor of CVD, the duration of the disease and the glycaemic control not being taken into account. The Framingham score predicts CVR over the next 10 years and includes the following variables: sex, age, total cholesterol and HDL-cholesterol, systolic blood pressure, blood pressure treatment, smoking status, and the presence of DM . A scoreThe UKPDS risk engine predicts CVR in the diabetic patient, taking into account HbA1c values, DM duration and other CVR factors. Numerous studies have compared CVR scores in terms of risk prediction accuracy. The results are often contradictory. Some studies indicate that both the UKPDS and Framingham scores accurately identify patients with high CVR, but both scores overestimate the risk . CompariThe assessment of CVR in the diabetic patient is particularly important for identifying patients in the high and moderate risk category and for initiating the multifactorial treatment of hyperglycaemia and other risk factors such as hypertension or dyslipidaemia. In newly diagnosed patients, by calculating CVR through the UKPDS risk engine, the category of high-risk subjects had the greatest benefit from reducing CVR, being prescribed drugs with cardioprotective effect. The lowest benefit was for patients registered at low risk category . These dDifferent studies have identified risk categories for diabetic patients with low and high CVR. The categories of patients with high CVR were represented by the elderly, males, smokers and those with low socioeconomic status . Some stTherefore, the evaluation of CVD in the diabetic patient is especially important at the time of diagnosis, as this is the best therapeutic window for long term reduction of CVD, numerous studies proving that after the onset of cardiovascular complications, glycaemic supervision no longer has a significant impact on primary prevention but having an important role in the control of the risk factors. The newly diagnosed diabetic patient, without cardiovascular complications, benefits the most from the multifactorial therapeutic intervention.As far as blood glucose levels recommendations go, ADA 2017 and ADA 2018 advise aiming for HbA1c <7%. This analysis should be done at least twice/year in patients reaching the target and every 3 months in those who have difficulties reaching it or with changes in their therapeutic regime. In newly diagnosed patients it should be aimed for fasting glucose between 80 and 130 mg/dL and post-prandial glucose <180 mg/dL ,37.The first therapeutic step in hyperglycaemia includes lifestyle changes and Metformin. This can be prescribed unless otherwise contraindicated and if HbA1c values are <9%. Patients with higher values than this should be promptly put on dual therapy and those with HbA1c ≥10% should benefit from insulin therapy .Lifestyle changes include diet and increasing physical activity. Diabetics are recommended to consume whole grains, vegetables, fruits, low fat dairy products, lean meat, nuts and seeds. Obese patients should lose at least 5% body weight as this provides better glycaemic and risk factors control. At least 150 min of moderate-to-high intensity physical activity per week are recommended. Smoking cessation and psychosocial support are also very important for diabetic patients .Metformin remains an extremely important antidiabetic in T2DM treatment because it has multiple advantages. Firstly, it is an oral drug which offers cardiovascular protection. One study has compared the effect of metformin vs. sulfonylureas or insulin treatments on a 10-year period; the first group reported a 33% decrease in acute myocardial infarction risk while the latter a 15% decrease . Other sAfter three months of metformin treatment and lifestyle changes, for the patients who have not reached their glycaemic goals a second oral antidiabetic should be added. Studies have shown that any oral antidiabetic drug added to the initial treatment reduces HbA1c levels by almost 1% . The maiAmong the new categories of pharmaceutical formulations used in the therapy of diabetes, GLP-1RA and SGLT2-I are encouraging alternatives. In the treatment of T2DM, SGLT2 inhibitors represent the latest therapeutic category accepted. Their action is to supress, in the proximal convoluted tubule of the kidney, the SGLT2 transport proteins. As these transporters represent almost 90% of the total resorption of filtered glucose in the body, they are valuable instruments in controlling the blood glucose. Being linked to decreases of 0.5–1% in HbA1c, SGLT2 inhibitors represent efficient alternative therapy choices for T2DM .Besides their efficiency in treating diabetes, SGLT2 inhibitors are also helpful in weight loss as well as in the treatment of macrovascular and microvascular complications associated with T2DM ,81,82. FThese data prove that the administration of SGLT-2 inhibitors has protective effects, opposed to almost all the pathophysiological mechanisms that insulin resistance generates in patients with T2DM , and serp < 0.001) [Numerous studies proved the efficacy of SGLT-2 inhibitors; probably the most cited being EMPAREG-OUTCOME that proved that empagliflozin administration, in T2DM patients and cardiovascular pathology, reduced the cardiovascular mortality by 38%  . Also, t< 0.001) . CANVAS < 0.001) .ADA 2018 mentions that canagliflozin and empagliflozin . Exenatide administered twice a day was also inferior to liraglutide in LEAD-6 study, where liraglutide reduced HbA1c with −1.2% while exenatide reduced Hb1c with −0.79% [GLP-1 receptor agonists (GLP-1 RA), such as exenatide or lixisenatide, act on post-prandial glycaemia, and as dulaglutide or long-acting release exenatide act on the fasting-glycemia . Both tyh −0.79% . GLP-1 Rh −0.79% .p < 0.001) [GLP-1 RA not only reduce hyper-glycemia, helping T2DM to achieve glycaemic targets, but they also have numerous effects on other CVR factors of these patients. GLP-1 RA generally reduce blood pressure; DURATION trials demonstrated a blood pressure reduction between −3 and −5 mmHg with exenatide administration, while in LEAD trials, patients treated with liraglutide benefited from a reduction of systolic blood pressure between −2.7 mmHg and −6.6 mmHg ,93. GLP-< 0.001) . In SUST< 0.001) .In case of T2DM patients with low risk of hypo-glycemia, SGLT2-I and GLP-1RA are efficient alternative therapies and may have positive effects on BP, weight and CV risk. GLP-1 agonists and SGLT-2 inhibitors are superior to current antidiabetic drugs such as sulfonylureas, thiazolidinediones, or DPP-4 inhibitors because of their low risk of hypo-glycemia, their beneficial roles in reducing body weight and reducing the grade of insulin resistance, their action on lowering blood lipids; therefore GLP-1 and SGLT-2 have been promoted as second-line therapeutic agents after metformin . Their vADA 2017 and 2018 guides recommend target values of BP under 140/90 mmHg for most diabetic patients and mean values of 130/80 mmHg for patients with high CVR ,37. The Data from multiple guides highlight the fact that the medical therapy should be very carefully chosen in diabetic patients, in such a way that CVR is reduced without any significant side effects. In recent years, there have been anti-diabetic drugs with pleiotropic effects which not only reduce glycaemic values, but also decrease the cardiovascular morbidity and mortality. It is very important to analyse the exact benefit of these drugs through their pleiotropic effect because there are often contraindications for the maximum reduction of the intensity of a CVR factor such as hypertension, thus the effect of the anti-diabetics which offer a cardiovascular benefit can be useful.Insulin resistance is a major underlying pathophysiological process that is implied in the occurrence and progression of the major CVR factors in T2DM. As shown in the above analysis, dyslipidaemia, hypertension, being overweight, or obesity and fatty liver disease cluster in patients with T2DM, making them vulnerable for cardiovascular morbidity. Novel risk factors or certainly less explored risk factors such as inflammation, hypercoagulation and endothelial dysfunction can also be associated with insulin resistance and hyperglycaemia. Therapies such as SGLT-2 inhibitors or GLP-1 RA emerge as potent molecules that seem to fight every complication that insulin resistance and hyperglycaemia generate. Their role has been acknowledged in high-quality trails, confirming their capability to reduce the cardiovascular death and morbidity. Therefore, they are not to be neglected in the therapy of T2DM patients.Before setting objectives as far as glycaemic control, blood pressure control, blood lipids, and thrombosis in diabetic patients, a very careful analysis of the risk/benefit ratio is needed. There are numerous benefits of optimal control such as reducing the risk of microvascular and macrovascular complications; however, side effects can cancel this out due to the risk of hypoglycaemia, weight gain, hypotension, or drug related side effects. Current research data indicate that the metabolic syndrome, insulin resistance, lipid profiles, and diabetes are strongly linked with CVD.


The aim of this study was to investigate the importance of preprocedural uric acid (UA) level in predicting fractional flow reserve (FFR) results of intermediate coronary lesions in patients with stable coronary artery disease undergoing coronary angiography. We retrospectively analyzed 293 patients who underwent FFR measurement to determine the significance of intermediate coronary stenosis detected by conventional coronary angiography. Patients were divided into 2 groups: Group 1 (n = 127) included patients with FFR of <0.80 , and Group 2 (n = 169) consisted of patients with FFR of >0.80 . Uric acid levels were assessed in both groups with the enzymatic colorimetric method by clinical chemistry autoanalyzer.The mean UA level was significantly higher in patients whose FFR indicated hemodynamically significant coronary lesions . Elevated UA levels are associated with hemodynamically significant coronary lesions measured with FFR. Uric acid may be used as a predictor of hemodynamically compromised coronary lesions before FFR procedures. Determining the functional significance of a coronary artery lesion is essential for revascularization decisions and prognosis estimation in patients with coronary artery disease (CAD). Coronary angiography (CAG) plays a crucial role in the assessment of coronary artery stenosis. However, it is inherently limited in its ability to demonstrate the functional significance of a coronary lesion, particularly in intermediate lesions, defined as those with 50%–70% stenosis [1]. Fractional flow reserve (FFR) is the most accurate method of determining the physiological significance of a coronary lesion and is therefore an important technique in daily cardiology practice [2]. Uric acid (UA) is an end-product of purine metabolism. There is growing evidence that elevated UA levels are correlated with both cardiovascular disease and its leading risk factors, such as hypertension [3]. Recent studies suggested that UA may be associated with endothelial dysfunction, oxidative stress, vasoconstriction, and inflammation, all of which are important in the development and progression of CAD . Furthermore, UA elevation was shown to be positively correlated with CAD severity [6] and it may have a role in the prediction of prognosis after percutaneous coronary intervention in stable CAD [7]. Despite studies suggesting a link between UA and CAD, the relationship between UA and the functional significance of coronary lesions has yet to be determined. The aim of this study was to investigate the significance of preprocedural UA level as a predictor of FFR results in patients with stable CAD undergoing CAG.A total of 293 consecutive patients who underwent FFR measurement to determine the significance of intermediate coronary stenosis detected by conventional CAG were included in this retrospective study. Patients with acute coronary syndrome with or without positive cardiac markers, glomerular filtration rate of <60 mL/min, malignancy, hematological disorders, history of gout, ongoing treatment affecting UA levels such as allopurinol, chronic inflammatory diseases, or active infection were excluded from the study. Clinical risk factors such as age, sex, smoking status, diabetes mellitus (DM), hypertension, low-density lipoprotein (LDL) levels, and obesity were recorded. Written informed consent was obtained from each patient and the study was approved by the institutional ethics committee.Blood samples were collected from the antecubital vein after 12 h of overnight fasting within 1 week before the procedure. Routine biochemistry and hemogram parameters were obtained. Uric acid levels were measured with the enzymatic colorimetric method by a clinical chemistry autoanalyzer .rest − FFRhyperemia.The standard Judkins technique via femoral approach was used for coronary artery visualization. All patients were referred for elective coronary artery angiography by their attending physicians, who were blind to the study’s aim. Coronary angiography was performed using the DFP-8000D Toshiba digital radiography system. Intermediate coronary stenosis was defined as 50%–70% stenosis in any epicardial coronary artery . The SYNTAX I score was calculated using the SYNTAX score website (http://www.syntaxscore.com) by 2 interventional cardiologists who were blinded to the patients and each other. Measurement of fractional flow reserve was performed with a Radi 0.014 XT PW pressure-monitoring guidewire. After the pressure guidewire was calibrated and positioned distal to the lesion, an intracoronary adenosine bolus  was administered to induce maximal vasodilatation by successively increasing the adenosine dose (maximum 600 µg) until no further decrement in FFR value was observed. Fractional flow reserve values were calculated as the ratio of mean distal coronary artery pressure to aortic pressure during basal and maximal vasodilatation. An FFR value of <0.80 after maximal hyperemia with adenosine was defined as hemodynamically significant. ∆FFR was measured using the following formula: FFR< 0.05 was defined as statistically significant.SPSS 21.0 for Windows  was used in all statistical analyses. The variables were investigated using visual  and analytical (Kolmogorov–Smirnov test) methods to determine whether they were normally distributed. Descriptive analyses were presented using means and standard deviations for normally distributed variables and medians and interquartile range for nonnormally distributed variables. Categorical variables were presented as numbers and percentages. Student’s t-test or the Mann–Whitney U test were used to compare continuous variables, while the chi-square test and Fisher’s exact test, if necessary, were used to identify statistical differences for categorical variables. Pearson’s correlation analysis was used to assess correlations between UA and other parameters. Stepwise multivariate logistic regression analysis was done to examine the association between the functional significance of the lesions and other variables. Variables with P < 0.25 in univariate logistic regression were included in a multivariate logistic regression model. In the logistic regression model, UA level was assumed to be a binary variable according to the cutoff point detected in the receiver operating characteristic (ROC) curve analysis. P Baseline characteristic features are shown in Table 1. The 293 patients in the study were divided into two groups: those with FFR values of <0.80  and those with FFR values of ≥0.80  after adenosine infusion. The mean age of the participants was 61.5 ± 9.3 years and 65.5% were male. The groups were similar in terms of age, sex, and prevalence of DM, hypertension, and smoking status. The mean UA level was significantly higher in group 1 . The lactose dehydrogenase (LDH) level was also significantly higher in Group 1, whereas red blood cell (RBC) count and hemoglobin (Hb) level were higher in Group 2. There was no significant correlation between UA level and SYNTAX I score . Baseline FFR before adenosine was significantly lower in Group 1 than Group 2 . There was a weak but significant positive correlation between UA level and ∆FFR  (Table 2). ROC curve analysis revealed that a UA cutoff point of 4.95 mg/dL had 65.1% sensitivity and 66.5% specificity in detecting significant functional stenosis in FFR measurements . When the patients were grouped according to this cutoff level, the group with high UA had significantly lower FFR values at baseline and maximal hyperemia and significantly greater ∆FFR (Table 2). In multivariate logistic regression analysis, UA  and RBC count  were identified as independent predictors of significant functional stenosis (Table 3). The main finding of the present study is that admission UA level is significantly and independently associated with the functional significance of angiographically intermediate coronary stenosis. To the best of our knowledge, this is the first study to report such a relationship. Although RBC count was the other independent predictor of functional stenosis, an odds ratio of 0.999 means that this association is unlikely to be of clinical importance. Intermediate stenosis (50%–70%) is a common finding in CAG, and deciding whether to pursue medical or interventional treatment is difficult for such lesions. Fractional flow reserve is the gold-standard method for decision-making in intermediate lesions because it provides precise information about physiological hemodynamic status rather than a prediction from anatomical appearance [8]. On the other hand, FFR is an invasive method with some cost, and more easily attainable, cheaper, and repeatable markers would be welcomed. Thus, UA may be a valuable marker for both diagnosis and treatment decisions.Studies have revealed that hyperuricemia is associated with hypertension, atherosclerosis, and even sudden cardiac death, but its exact relationship with cardiovascular outcomes remains controversial [9]. Previous studies showed that high UA level is associated with more extensive and severe CAD, poorer coronary collateral circulation, and more coronary calcification, all of which are related to poor prognosis [10]. Ndrepepa et al. also showed that higher UA level was a predictor of increased risk of mortality in 13,723 patients with angiography-proven CAD [11]. The role of uric acid in the formation and progression of CAD is not well established. However, it was shown that UA has some mechanical and molecular effects such as promotion of inflammation, vasoconstriction, and endothelial dysfunction, which may contribute to atherosclerosis and related comorbidities such as CAD. Moreover, hyperuricemia induces oxidative stress by an unknown mechanism. Antioxidant treatment in hyperuricemic rats resulted in hypertension remission and improved proinflammatory effects . Uric acid uptaken by cells stimulates chemokine and inflammatory marker synthesis, which also leads to activation of vasoconstrictor mediators such as thromboxane, endothelin-1, and angiotensin-II . Our data showed that a preprocedurally elevated UA level is associated with hemodynamically significant lesions measured by FFR during index angiography. This result is compatible with previous studies that also reported its correlation with CAD presence and impaired myocardial perfusion . The above-mentioned vasoconstrictor mechanism in hyperuricemia and its role in atherosclerosis pathogenesis results in impaired vasorelaxation. Inducing hyperemia is a key part of the FFR procedure, and hyperuricemia may affect adenosine-related vasodilation. Higher ∆FFR values may be attributable to a reversal of baseline hyperuricemia-induced vasoconstriction by adenosine administration. Hyperuricemia impairs endothelial function in various ways, especially endothelial-dependent vasodilation, thus promoting vasoconstriction. Moreover, as adenosine enhances NO release from the endothelium, endothelial dysfunction will lead to impaired response to adenosine challenge, which is also a possible contributor to lower FFR values. Coronary artery disease causing ischemia eventually results in ATP reduction in the myocardium. Studies have shown that ATP depletion may be an important contributor to uric acid overproduction [17], which in turn increases apoptosis, oxidative stress, and a jeopardized myocardium [18]. We suppose that the relationship between ATP and uric acid level needs to be investigated.Patients with FFR values in the gray zone (0.75–0.80) are the most complicated cases for determining lesion severity, and thus the most challenging in terms of treatment decisions. For these patients, Kocaman et al. proposed using ∆FFR, which is defined as the difference between resting FFR and FFR after adenosine administration, and suggested that ∆FFR represents the compensatory response capacity of the coronary microvasculature [19]. In the present study, higher ∆FFR values were detected in patients with higher UA levels. Thus, higher UA levels may be an indicator of severe lesions in the gray zone.Previous studies have shown positive correlations between SYNTAX scores and serum uric acid levels, unlike our study. However, our study involved a population more likely to have type A lesions and low SYNTAX scores. These findings may be responsible for this unexpected result.Numerous factors influence atherosclerosis and coronary artery lesion severity. In our patients groups, the distribution of risk factors and other biochemical markers  were similar. These well-matched groups strengthened the power of our study, ensuring that UA was the only biochemical and risk factor difference.In conclusion, elevated UA level is associated with hemodynamically significant coronary lesions in FFR. A significant but weak positive correlation was detected between UA levels and ∆FFR values. UA may have a role in the prediction of hemodynamically significant coronary lesions; however, further studies are needed to validate this finding in large-scale trials.This study has some limitations. First of all, the number of patients is a major disadvantage and limits the statistical power of the study. Second, antihypertensive and antidiabetic medications may influence UA levels. Other medications affecting endothelial function  and uric acid level (thiazide diuretics) may also have a role in vascular response. Third, it is more plausible to conduct a prospective study to investigate the direct effect of UA during adenosine administration. Single-center trials may not reflect a nationwide and generalized outcome.


GDF15 was strongly associated with the dialysis vintage. While kidney transplantation led to a significant decrease of GDF15  pg/ml, p < 0.001), kidney donation caused a moderate increase of GDF15 , p < 0.001) one year after surgery. GDF15 levels remained significantly higher in recipients and kidney donors than in healthy controls  pg/ml vs. 384  pg/ml, p < 0.001). GDF15 is increased in patients with kidney disease and is associated with dialysis vintage. Given its decrease after transplantation and its increase after uni-nephrectomy, GDF15 might be a marker of kidney function. However, since it correlates only to the eGFR in transplanted patients it may indicate chronic kidney disease.Growth differentiation factor-15 (GDF15) is associated with inflammatory conditions, chronic kidney disease, cardiovascular disease and mortality. There is very limited data on GDF15 after kidney donation and transplantation. We analyzed serum samples of patients who donated a kidney (54 living donors) or who underwent kidney transplantation (104 recipients) at the University Hospital of Münster (Germany) between 2013 and 2015, for GDF15 levels immediately prior and one year after surgery. GDF15 levels were significantly elevated in end-stage renal disease patients compared to healthy individuals  pg/ml vs. 384  pg/ml,  Growth differentiation factor-15 (GDF15) or macrophage inhibitory cytokine-1 (MIC-1), belongs to the superfamily of transforming growth factor β (TGF-β) widely expressed in mammalian tissues , it is nIts expression is highly regulated and GDF15 is often induced in response to conditions associated with inflammation, oxidative stress, and hypoxia, among others . DependiIn humans, there are few studies linking GDF15 to kidney disease. Nair et al. found circulating GDF15 levels to be correlated with GDF15 expression in the tubulo-interstitial compartment and with the progression of CKD. Since it was found to be independent of other risk factors, the authors postulate that GDF15 is not only a risk factor but rather involved in the progression of CKD . After kidney transplantation (KTx), Connelly et al. observed a significant decrease in GDF15 levels in their patients within twelve months. They found an inverse correlation between GDF15 and eGFR after KTx . The samSince only one longitudinal GDF15 study reporting data of 37 patients within one year after KTx and no study on GDF15 after kidney donation (KD) has been published, our study, which analyzes 4-year data adds substantial insights into the role of GDF15 after KTx and KD, respectively.Plasma concentration of GDF15 was measured by Human GDF15 DuoSet ELISA  according to manufacturer’s instructions. The assay range is 7.81–500 pg/mL, with an unspecified sensitivity for GDF15. Samples above the concentration limit for the test were re-measured after 10-fold dilution in Calibrator Diluent RD6-10 reagent according to manufacturer’s specifications.We prospectively included 104 consented patients (age ≥ 18 years) who underwent kidney transplantation at our transplant center between April 2013 and October 2015. Patients were followed until February, 2019. Fifty-four living kidney donors (LD) served as controls.The GDF15 was measured in a time frame of 24 hours prior and one year after KTx or KD, respectively. After KTx, the initial immunosuppressive regimen consisted of tacrolimus (target trough 6–12 ng/mL), mycophenolate mofetil, and prednisolone. The transplant recipients received induction therapy with basiliximab; anti-thymocyte globulin was administered to those with a high degree of immunization (PRA > 85%) or a previous transplantation. ABO-incompatible patients received rituximab four weeks prior to KTx. Two patients with atypical hemolytic uremic syndrome as underlying disease received eculizumab in combination with basiliximab. Oral CMV-prophylaxis with valganciclovir was administered for 100 days in R+ and for 200 in the D+/R− constellation.The characteristics of the patients and the LD were taken from the electronic patient file. Data of all patients were anonymized before the analysis. Written informed consent was obtained from all participants. All experiments on humans were performed in accordance with the current transplantation guidelines and the Declarations of Istanbul and Helsinki. This study was approved by the local ethics committee .The main outcome measures were renal function ) in years one to four after surgery. Further outcome parameters were patient and overall graft survival. Patient survival was defined as the time from KTx until death (regardless of cause) or last contact for living patients. Overall graft survival was defined as the time from KTx until death (from any cause), graft failure, or last contact, whichever occurred first. Graft failure was defined as the re-initiation of dialysis or re-transplantation. Since too few patients reached the endpoints graft loss or death within our observation period, we analyzed the combined endpoint death, graft failure or eGFR loss > 30% as primary endpoint.Kidney biopsy was performed if creatinine levels increased (≥0.3 mg/dL) and/or a significant proteinuria occurred. The kidney biopsies were evaluated by two pathologists. Rejections were diagnosed by histological biopsy evaluation based on the BANFF classification . Whole bData were analyzed using IBM SPSS Statistics 24 . Normally distributed continuous variables are shown as mean ± standard deviation (SD) and non-normally distributed continuous variables as median and 1st and 3rd quartiles . Absolute and relative frequencies are given for categorical variables.Pairs of independent groups were compared using the Student’s t-test for normally distributed data, Mann–Whitney U test for non-normally distributed data, and Fisher’s exact test for categorical variables. To model the relationship between a dependent variable and one or more explanatory variables, we applied linear regression analysis.n = 17). Sixty-seven (64.4%) of the recipients were male. The mean age of the recipients at the time of KTx was 50.39 years (16.9–76.8 years). The demographic and clinical characteristics of the recipients are shown in p < 0.001, GDF15 levels were significantly elevated in the patients with ESRD compared to the healthy controls  pg/ml vs. 384  pg/ml, respectively, p < 0.001 vs. baseline, p < 0.001, p = <0.001, KTx led to a remarkable decrease of the GDF15 levels of recipients. One year after surgery, GDF15 values had decreased on average by 1,934 pg/ml to 913  pg/ml  showed the lowest GDF15 levels compared to patients treated with hemo- or peritoneal dialysis  to an eGFR of 66.9 ± 14.5 ml/min/1.3 m2. An overview of the association between eGFR and GDF15 values of recipients and donors is provided in One year after KTx, the mean eGFR of the recipients was 56.8 ± 20.5 ml/min/1.3 mp = <0.001, two years: r = −21.908, p < 0.001, three years: r = −18.026 p < 0.001, four years: r = −17.897, p < 0.001), p = <0.001, AUC = 0.828, CI 0.743–0.914, overall model quality 0.74, The GDF15 levels of recipients after one year correlated with the eGFR at 1–4 years after KTx   .p = 0.208, r = −6.021) or with eGFR one year after KD . In addition, donors´ GDF15 levels one year after Nx were not associated with eGFR after Nx . In LD, GDF15 levels prior to Nx were not associated with the donors` eGFR prior to Nx , and when the UPCR two years after KTx was analyzed, the association became significant . However, UPCR after three years was not significantly associated with GDF15 any more .In terms of UPCR, GDF15 at one year after KTx tended to be associated with UPCR at the same time (p = 0.365).Forty-six of the patients (44.2%) were diagnosed with at least one rejection episode during the follow-up, but the incidence of at least one rejection was not associated with the GDF15 value after KTx  nor the C/D ratio  were associated measurements of GDF15 values on the same day one year after KTx.In our patient cohort, 81 patients (77.9%) received a tacrolimus-based immunosuppression one year after KTx. Neither the tacrolimus trough levels (p = 0.003).Of the 104 studied patients, 20 (19.2%) suffered from CVD. CVD was defined as myocardial infarction, stroke and/or symptomatic peripheral arterial disease. We evaluated, whether GDF15 values prior to KTx or one year after KTx were associated with CVD in our patient cohort. We found that patients with CVD showed significantly higher GDF15 values prior to Tx than patients without CVD .The same applies to GDF15 levels one year after Tx . We could not find any association between GDF15 values one year after KTx and the number of CMV copies in the peripheral blood (p = 0.332).Since GDF15 plays a role in infection, we assessed the occurrence of cytomegalovirus (CMV) and BKPyV DNAemia in our cohort. During follow-up, 20 patients (19.2%) developed CMV DNAemia; 16 of them within the first year after KTx. The median onset time of CMV-DNAemia was 7.5 months after KTx. None of the 20 patients suffered from invasive CMV organ disease. Patients with active CMV replication within the first year showed higher GDF15 levels one year after KTx compared to patients without replication .Nineteen patients (18.3%) developed BKPyV DNAemia. Patients who developed BKPyV DNAemia in the course did not show significantly different GDF15 levels after one year , rejection episodes (p = 0.245) and proteinuria after one year (p = 0.968) did not show any association to GDF15. However, UPCR after two years was still significantly associated with the GDF15 level one year after KTx in recipients (p = 0.002).Since CMV-DNAemia, proteinuria and rejection show a strong association with renal function , we adjup < 0.001, p < 0.001, Multivariable linear models confirm that the GDF15 level of recipients are independently associated with eGFR one or two years after KTx dialysis. In contrast, KD increased the GDF15 level noticeably one year after LD. After KTx and LD, GDF15 was clearly related to eGFR, not only as a biomarker of current eGFR, but also as a prognostic marker for future kidney function. A clinical consequence could be a closer monitoring and more rigorous elimination of metabolic risk factors in patients with higher GDF15 values. Further, our study should stimulate prospective studies evaluating the relationship between GDF15 of the donor and the graft as well as the role of GDF15 in LD. The question that now needs to be answered is: “Can GDF15 potentially be utilized as an additional parameter for the evaluation of LD to prevent unfavorable outcomes after KD due to early stage kidney disease not manifested by renal function or underestimated cardiovascular morbidity?” In particular, the strong response of GDF15 after KTx, and also LD, provides a rationale to prospectively assess its value in both settings.


IntroductionOpiate-induced chest wall rigidity is a syndrome that largely goes unrecognized. To date, no study has presented significant objective data to better understand this syndrome.ObjectiveThe aim of this study was to explore the correlation between the dosage of opiates and the incidence of chest wall rigidity, ventilatory changes, and effects of naloxone administration.MethodsA total of eight patients were identified as having episodes of chest wall rigidity, with half of the population being females, with an average age of 54.8 ± 9 years. Physiological changes, ventilator data, vitals, and opiate dosage prior to chest wall rigidity episodes and after reversal with naloxone administration were analyzed using the Wilcoxon rank sum test for statistical significance.Results2 , respiratory rate , or peak airway pressure . Additionally, there is a statistically significant correlation between morphine equivalent potency dosing within 24 hours and the change in tidal volume .Significant changes were observed in dynamic wall compliance without positive end-expiratory pressure (PEEP) , dynamic wall compliance with PEEP , tidal volume , and ventilator airflow . However, no statistically significant changes were detected in end tidal COConclusionsOur study is the first to demonstrate significant objective data on the ventilatory responses seen with opiate-induced chest wall rigidity. These findings may assist clinicians in better understanding the presentation and management of chest wall rigidity. Chest wall rigidity (CWR) is a phenomenon first described by Hamilton and Cullen in 1953 . Many prDespite many hypothesized theories, the actual incidence of CWR is largely unknown. This is largely due to underreporting and the inability to properly identify patients who have experienced the syndrome. Since it was first described, numerous case studies have been published detailing the occurrence of CWR. Comstock et al. described extreme difficulty in ventilating cardiac surgery patients after the use of high-dose fentanyl during anesthetic induction . Çoruh eTo date, there are minimal literature and objective data available to characterize CWR. This case series aims to clarify the pathophysiological changes and response to treatment when faced with this syndrome. It is hoped that these examples will provide physicians with an objective method to identify and treat CWR in an effective fashion, with objectively derived factors.2 during episodes of CWR and after administration of naloxone were recorded.This case review is a retrospective study that reviewed patients from 2014 to 2017 at Arrowhead Regional Medical Center, a level II trauma center located in Southern California. Electronic medical charts of patients who were on ventilator management were reviewed. Patients identified to have complicated or difficult ventilation were reviewed for physical presentation and ventilator findings indicative of CWR. Patient characteristics including age, sex, nature of admission, nature of injury, history of narcotic use prior to admission on urine drug screen, pattern of ventilator breathing, BMI, dose, and type of narcotic prior to the episode of CWR were assessed. Narcotic dosages were converted into morphine equivalent dosages to maintain consistency. Vital signs six hours prior to identified CWR episodes and two hours after naloxone administration were reviewed. Objective ventilator data including respiratory rate, peak airway pressure, dynamic compliance with and without positive end-expiratory pressure (PEEP), ventilator flow rate, tidal volume, and end-tidal COTo obtain these data, ventilator waveform tracings during episodes before and after naloxone were plotted for statistical analysis. Descriptive statistics were presented as medians and interquartiles (first and third quartiles) for continuous variables, along with frequencies and proportions for categorical variables. The Wilcoxon rank sum test was used to analyze ventilator responses seen during CWR and after naloxone administration. Pearson’s correlation coefficient test was performed to assess for possible correlations between narcotic dosage given within 24 hours of CWR and ventilator variables.A total of eight patients were identified to have episodes of opiate-induced CWR. Males and females were equally distributed, with an average age of 54.5 years . Patient characteristics are presented in Table Opiate-induced CWR is a syndrome that has limited reported understanding despite its appearance in multiple case reports. However, the pathophysiological mechanism behind this syndrome has yet to be defined. With a large amount of ambiguity, the medical community has yet to come to a consensus. Our study is the first to demonstrate significant objective data on the ventilatory changes seen with this syndrome.Our case series expands on the consensus reported in previous literature. To begin, the airway and ventilatory response seen in airway compliance with the paucity of flow reached statistical significance in our study. Scamman characterized the main pathological finding for CWR episodes to be a reduction in chest wall compliance, as characterized in our results . ScammanThe relationships between CWR, narcotic type, dosing, and duration have all been implicated in its severity. The majority of literature surrounding CWR lists fentanyl as the most common perpetrator , 9,11-13Without the historically reported changes in airway pressure seen in previous studies, the actual presentation of CWR, in part, may be a misnomer. Our theory is that CWR may, in fact, result from an active process of prolonged forceful exhalation that limits airflow with a subsequent relaxation in the musculature and resumption of airflow. This characteristic pattern perpetuates until the inciting medication effect is reversed. A French study proposed similar thoughts implicating GABAergic inter-neuron disinhibition and eventual ventral horn activation as the proposed mechanism behind CWR . NeidharThe incidence and mechanism behind CWR secondary to opiates are largely unknown. The results of our study are paramount, as the ventilatory pattern seen in our study controlled for airway pressure. The observations seen in our case series show a reduced pattern of airflow without subsequent pressure increases. This suggests that CWR due to opiate administration may be caused by an apneic-type response with prolonged forceful exhalation that is active and not entirely centrally-mediated. Given our small sample size, further studies are needed to confirm these findings.


This quality improvement (QI) project was performed at a single center to determine the incidence of postoperative complications associated with use of cuffed airway devices. An educational program was then completed that involved training our anesthesia providers about complications related to excessive cuff pressure and how to utilize a quantitative cuff pressure measurement device (manometer). The impact of this educational initiative was assessed by comparing the incidence of postoperative complications associated with the use of airway devices before and after the training period.After approval by our institution’s Institutional Review Board, a pre-intervention (baseline) survey was obtained from 259 adult patients after having undergone surgery with general anesthesia with the use of an endotracheal tube (ETT) or laryngeal mask airway (LMA). Survey responses were used to determine the baseline incidence of sore throat, hoarseness, and dysphagia. Once these results were obtained, education was provided to the anesthesia department members addressing the complications associated with excessive cuff pressures, appropriate cuff pressures based on manufacturer recommendations, and instructions on the use of a quantitative monitor to determine cuff pressure (manometry). Clinical care was then changed by requiring intraoperative cuff pressure monitoring throughout our institution for all surgical patients. After this educational period, 299 patients completed the same survey describing postoperative airway complications.p = 0.045), moderate to severe hoarseness , and moderate-to-severe dysphagia .The use of manometry reduced the incidence of moderate-to-severe postoperative sore throat in the pre- vs. post-intervention groups (35 patients vs 31 patients, Caring for patients in the perioperative setting frequently entails placement of an airway device. This procedure is associated with several potential complications, including sore throat, coughing, and vocal cord damage. Our quality improvement initiative has shown that intraoperative management of intra-cuff pressure based on manometry is feasible to implement in clinical practice and can reduce postoperative airway complications. Sore throat, dysphagia, and hoarseness are multifactorial postoperative complications after general anesthesia in which manipulation of the airway is required. The incidence of post-operative sore throat (POST) has been reported to occur in 17.5–26% of postoperative patients , 4. The p < .05) within the first 2 post-operative hours [There are reports of mixed efficacy in prevention of POST by pharmacologic modalities, such as topical anesthetics . Moreoveve hours .p = .003) [Chang et al. demonstrated that tapered ETT cuffs, as compared to cylindrical ones, reduce post-operative sore throat by as much as 22% ( = .003) . Interes = .003) , 13. Koy = .003) . Another = .003) . Interes = .003) . In lieu = .003) , 18. NonMost clinicians employ subjective measures to mitigate the burden of POST, such as manually palpating the pilot balloon to assess intra-cuff pressure. However, objective measurements of ETT cuff pressures to obtain and maintain recommended ranges provide a more significant reduction in these postoperative complications . A revieOne of the most important etiologies of POST is tissue ischemia secondary to cuff over-distension. In our study, we sought to eliminate overinflated cuffs by measuring and ensuring appropriate intraoperative intra-cuff pressure. Our project aimed to determine the incidence of postoperative airway complications at our institution, and inform our anesthesia providers of these patient care concerns. We also sought to educate our department about airway complications that might be due to excessive airway device cuff pressures. Finally, we adjusted clinical practice to incorporate routine measurement of cuff pressures after airway manipulation and then investigated whether this practice change had an impact on the incidence and severity of POST.p < 0.05. To reach statistical significance, a total of 200 patients (n = 200) were considered for inclusion. Of note, during the pre-intervention time period, physicians and nurse anesthetists were blinded to the project intent.After receiving Institutional Review Board (IRB) approval, a pre-intervention baseline assessment of POST complications was conducted through an originally developed questionnaire ,  Fig. . This inThe post-intervention questionnaire was collected over 10 months, and contained questions identical to the pre-intervention questionnaire with additional fields for initial and adjusted cuff pressures, where applicable. Data analysis was performed using a two-tailed Fisher’s exact test to determine the impact our educational intervention on initial cuff pressures, adjusted cuff pressures, as well as the frequency of POST, hoarseness, and dysphagia.p = 0.045, respectively). Moderate to severe hoarseness was also reduced with the application of manometry when comparing pre-intervention  and post-intervention (adjusted pressure) groups , respectively. Finally, moderate to severe dysphagia was also reduced with the use of manometry when comparing pre- and post- intervention groups , as identified in Table 2O. Average adjusted pressure for ETTs was 27 ± 4 cm H2O. Mean initial pressure for LMAs was 66 ± 18 cm H2O. Mean adjusted pressure for LMAs was 55 ± 8.4 cm H2O , hoarseness (p = < 0.001), and dysphagia (p = 0.03)  Table .p = < 0.001) as well as decreased injury to tracheal mucosa as indicated by blood streaked expectoration (p = 0.089) [p = 0.022), and dysphagia (p = 0.007) [Our findings were in congruence with previous studies. Liu et al. evaluated 509 patients undergoing elective surgery with general anesthesia and endotracheal intubation. These investigators determined that patients who had their cuff pressures adjusted had a lower incidence of post-operative sore throat (= 0.089) . A simil= 0.007) .While it is difficult to quantify the total cost of postoperative airway complications, the cost of the intervention is minimal. For instance, the AG CUFFILL device can be reused up to 100 times, since measurement of cuff pressures needs not be performed in a sterile fashion. The AG CUFFILL syringe, for instance, has a local cost of $20.00 per unit, resulting in a “cost per use” of only $0.20. The cost of reusable manometers such as the Cufflator™  and the Portex Cuff Inflator Pressure Gauge  require a more substantial initial investment of $309.00 and $84.95, respectively. These devices are also larger than the AG CUFFILL syringe, making their use and storage in the limited OR setting much more problematic. These devices also need to be calibrated regularly and require routine maintenance, increasing their cost of use. In comparison, the AG CUFFILL device does not require routine calibration. While it is difficult to quantify the financial burden of postoperative airway complications, patient safety and satisfaction are universally paramount. Future endeavors describing the effects of confounders may help develop more appropriate and simpler methods to alleviate and prevent postoperative airway complications.There are several limitations to our project. Manometry represents one objective measure to reduce postoperative respiratory complications; however this is a dilemma with a multitude of variables. Other factors not evaluated in our project that can contribute to POST include preoperative sore throat, trauma during instrumentation of a difficult airway, size of the airway device, the use of neuromuscular blocking agents, presence/absence of cuff lubrication, and length of surgery. Our project may have also been influenced by the Hawthorne Effect as providers knew that cuff pressures were going to be checked after our educational intervention.As with any new endeavor, there will be challenges to implementation and resistance to alteration of current practice. Our initiative provides insight into such a process, with emphasis on brief, straight-forward education. With the marked reduction in unadjusted and adjusted cuff pressures during the post-intervention phase, our results reinforce how common overinflated cuff pressures are and establishes that utilizing a quantitative device to guide cuff pressure is feasible. In addition, the EMR  can provide visual cues and reminders to the provider requiring the clinician to measure, adjust, and document the ETT and LMA cuff pressures. The online module, instructional videos, hands-on tutorial, as well as EMR reinforcement solidified the behavioral modification for cuff pressure monitoring. Future investigations are warranted to confirm such findings.Caring for patients in the perioperative setting often entails placement of an airway device with potential adverse effects and complications that warrant further investigation. Our quality initiative has shown it is feasible to implement manometry into everyday practice, which resulted in a marked reduction in postoperative airway complications. As technology continues to advance, it is imperative for us to utilize the tools provided to our advantage, for the benefit of our patients, and the establishment of a refined standard of care.Additional file 1. Postoperative Pharyngeal Assessment Questionnaire This is an internally developed questionnaire by our institution to assess the severity of sore throat, dysphagia, coughing and hoarseness of postoperative patients.


Patients with aspirin-exacerbated respiratory disease (AERD) are known to have poor clinical outcomes. The pathogenic mechanisms have not yet been completely understood.de-novo synthetic pathway of sphingolipid metabolism in patients with AERD compared to those with aspirin tolerant asthma (ATA).We aimed to assess the involvement of the ORMDL3 SNP (rs7216389) was performed.A total of 63 patients with AERD and 79 patients with ATA were enrolled in this study. Analysis of mRNA expression of serine palmitoyl transferase, long-chain base subunit 2 (SPTLC2) and genotyping of 4 . The levels of SPTLC2 mRNA expression showed significant negative correlations with the level of FEV1 and FEV1/FVC . Genotype frequencies of ORMDL3 SNP (rs7216389) showed no significant differences between the AERD and ATA groups. Patients with AERD carrying the TT genotype of ORMDL3 had significantly lower levels of FVC (%) and PC20 methacholine than those carrying the CT or CC genotype (P = 0.026 and P = 0.030).Significantly higher levels of SPTLC2 mRNA expression were noted in patients with AERD, which showed significant positive correlations with peripheral/sputum eosinophil counts and urine LTEde novo synthetic pathway of sphingolipids may be involved in the eosinophilic inflammation and airflow limitation in AERD.This is the first study that shows the dysregulated  Asthma is a heterogeneous disease characterized by chronic airway inflammation affecting 1%-18% of the general population worldwide . Airway Aspirin-exacerbated respiratory disease (AERD) is characterized by persistent asthma and chronic rhinosinusitis with nasal polyp as well as aspirin/nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, where eosinophilia is a common finding in the upper and lower airway mucosa . A recen4 (LTE4) have been reported to be higher in patients with AERD than in those with ATA, which increased after aspirin challenge [4 can be used as a potential biomarker for identifying AERD [Traditionally, dysregulation of arachidonic acid metabolism is well-known pathophysiology involved in AERD. Baseline levels of leukotriene Ehallenge . A recening AERD . Cysteining AERD –10, whering AERD ,10.de novo synthetic pathway of sphingolipids, genome-wide association studies revealed that single nucleotide polymorphism (SNP) of oroscomucoid-like protein 3 (ORMDL3) at the 17q21 locus increased the risk of asthma [ORMDL3 (rs7216389) has been reported to be associated with asthma exacerbation and the severity of asthma [ORMDL3 has inhibitory effects on serine palmitoyl transferase (SPT) in physiological conditions, while it enhances ceramide formation and affects airway inflammation and hyperresponsiveness in pathological conditions [de novo pathway of sphingolipids in patients with AERD. In the present study, we aimed to assess the involvement of the de-novo synthetic pathway of sphingolipid metabolism in patients with AERD compared to those with ATA.Alterations in sphingolipid metabolism have been reported to play a role in asthma pathogenesis –17. Mostf asthma –22. The f asthma ,24. A renditions ,14. HoweA total number of 63 patients with AERD and 79 patients with ATA were recruited for this study at Ajou University Hospital  and Kangdong Sacred Heart Hospital  from March 2018 to March 2019.1 were higher than 70% of the predicted value in the Lys-ASA BPT. All anti-asthmatic drugs, including leukotriene modifiers, were stopped for at least 3 days before the Lys-ASA BPT. The result of the Lys-ASA BPT was considered positive if FEV1% was decreased by more than 20% after the challenge. Subjects who showed negative results to the Lys-ASA BPT or denied any changes in upper or lower respiratory tract symptoms after ingestion of aspirin/NSAIDs were defined as ATA. A diagnosis of severe asthma was made according to the definition of international ERS/ATS guidelines [Asthmatics who have been diagnosed by allergy specialists according to the Global Initiative for Asthma guideline (GINA) 2020 were enrolled. Exclusion criteria were as follows: 1) asthmatics who are not maintaining asthma medications regularly and 2) asthmatics who experienced severe asthma exacerbation during the previous month. AERD was defined as a typical clinical history (recurrent exacerbations of upper or lower respiratory reactions after ingestion of aspirin/NSAIDs) and/or a positive response to the lysine-aspirin bronchial provocation test (Lys-ASA BPT). The Lys-ASA BPT was conducted with increasing doses of Lys-ASA solution up to 300 mg/mL using the method previously reported . The astidelines .Peripheral blood and urine samples were collected from the subjects in the morning when their asthma was in a stable state. Written informed consent forms were obtained from all the study subjects, and the study was approved by the Institutional Review Boards of Ajou University Hospital and Kangdong Sacred Heart Hospital .5’-CCA GAC TGT CAG GAG CAA CCA T-3’(forward), 5’- TTC GTG TCC GAG GCT GAC CAT A-3’(reverse), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), 5’- GTC TCC TCT GAC TTC AAC AGC G-3’(forward), 5’- ACC ACC CTG TG CTG TAG CCA A-3’(reverse). The relative values for target mRNA expression were calculated after normalization to the Ct value from GAPDH gene expression using the ddCt method.Total RNA was isolated from the whole blood by TRIzol reagents , and cDNA was synthesized from 1 μg of total RNA according to the manufacturer’s instructions using a ReverTra Ace qPCR RT Kit . Real-time PCR was performed using PowerUp SYBR Green Master Mix  on the ABI 7500 system (Applied Biosystems). Primers were designed at Primer 3 (version 4.1.0). The primer sequences were SPT, long chain base subunit 2 (SPTLC2): ORMDL3 SNP (rs7216389) was performed as previously described, according to the primer extension method using a SNaP shot ddNTP primer extension kit (Applied Biosystems) [Genomic DNA was isolated from the peripheral blood using the Puregene DNA purification kit , according to the manufacturer’s instructions. Genotyping of systems) .4-d5 was used as the internal standard for LTE4. Chromatographic separation was performed using a Waters Acquity UPLC system (Waters) with a Hypersil GOLD column  under gradient conditions. The mobile phases consisted of water in 0.1% formic acid (solvent A) and acetonitrile in 0.1% formic acid (solvent B) at a flow rate of 0.4 mL/min. Data were obtained using an API5500 triple quadrupole mass spectrometer  equipped with an ESI source. Negative electrospray ionization in the multiple reaction monitoring (MRM) mode was employed. The MRM was based on m/z transition of 438>333 for LTE4 and 443>338 for LTE4-d5. The calibration curve was linear over the range of 0.064 to 8 ng/mL with a coefficient of correlation (r) greater than 0.99 for all instances. The between-run precision and accuracy of the quality control samples  were less than 4.7% and 92.5%, respectively. For the quantitative determination of creatinine in urine samples, 10 μL of the urine sample were applied to Creatinine Parameter Assay Kit .The concentrations of LTE4 in the urine samples were analyzed using liquid chromatography-tandem mass spectrometry after solid phase extraction with Oasis HLB . LTEt test, and Pearson’s chi-squared or Fisher’s exact test was used for categorical variables. P values for genotype frequencies were obtained by a generalized linear model adjusted for age and sex as covariates using the co-dominant, dominant and recessive models. Pearson’s and Spearman correlation analyses identified associations among continuous variables. These computations were performed using SPSS software, version 22.0 . GraphPad Prism 5.0 software  was used to produce graphs.Continuous variables were compared using Student’s P<0.001). The baseline levels of FEV1/FVC (%) were significantly lower in patients with AERD (P = 0.004). There were no significant differences in other variables between patients with AERD and ATA. None of the study subjects were regularly taking systemic corticosteroids.de-novo pathway of sphingolipid synthesis. The SPT complex is composed of the 3 different subunits SPTLC1, SPTLC2 and SPTLC3. SPTLC2 has generally been used to assess the SPT activity, especially with the SPTLC2 knockout model or the SPTLC2-specific inhibitor myriocin [P = 0.012) . In the subgroup analysis of eosinophilic asthma , the mRNA expression level of SPTLC2 was significantly higher in patients with AERD than with ATA . In non-eosinophilic asthma , there was no significant difference between the 2 groups  . AERD wa2 groups .4 ; however, they did not with FeNO (1 (%) and FEV1/FVC (%) showed significant negative correlations between the mRNA expression levels of SPTLC2 in the study subjects  (1 (%) and FEV1/FVC (%) . Peripheral blood/sputum eosinophil counts, predicted level of FEV1% or FEV1/FVC (%) showed no correlation with the mRNA expression level of SPTLC2 in patients with ATA  . In patiwith ATA .ORMDL3 in susceptibility to AERD, the genetic polymorphism of rs7216389 in the ORMDL3 gene was genotyped. Genotype frequencies were not significantly different between patients with AERD and ATA .To evaluate the genetic effect of  and ATA . The rs720 methacholine were significantly associated with the genotype of ORMDL3 (rs7216389). Asthmatics carrying the TT genotype of ORMDL3 showed significantly lower levels of PC20 methacholine than those carrying the CT or CC genotype . The peripheral eosinophil count, FeNO, predicted value of FEV1, FVC or FEV1/FVC was not significantly different between asthmatics with the TT genotype and those with the CT or CC genotype.The levels of PCORMDL3 on the clinical parameters of AERD, subgroup analysis was performed. Patients with AERD carrying the TT genotype of ORMDL3 had significantly lower levels of FVC (%) and PC20 methacholine than those carrying the CT or CC genotype   . The prede-novo synthetic pathway of sphingolipids in patients with AERD. We report here the increased expression of SPTLC2 mRNA (involved in the rate-limiting step in the de novo synthesis of sphingolipids) which closely correlated with the eosinophilic inflammation and airflow limitation in patients with AERD. Although the genotype frequencies for SNP within ORMDL3 (rs7216389) showed no significant difference between AERD and ATA patients, AERD patients carrying the TT genotype of ORMDL3 showed a lower level of lung function parameters and a higher degree of airway hyperresponsiveness than those carrying the CT or CC genotypes. Taken together, the de-novo synthetic pathway of sphingolipids may contribute to eosinophilic inflammation and airflow limitation in AERD.This is the first report that observed the involvement of the Sphingolipids have been postulated to contribute tp asthma pathogenesis in terms of airway inflammation and bronchial hyperresponsiveness . S1P wasde novo synthetic pathway of sphingolipids in asthma pathogenesis [de novo synthetic pathway has been suggested from the GWAS studies showing that ORMDL and CerS2 were significantly associated with the risk of asthma [de novo synthetic pathway of sphingolipids, SPT plays an important role along with ORMDL3 [4 levels and airflow limitation in patients with AERD. Collectively, increased SPTLC2 may contribute to eosinophilic airway inflammation and lung dysfunction.Despite accumulating evidence for the recycling synthetic pathway of sphingolipids ,28,30,31ogenesis . The patf asthma ,22,32,33h ORMDL3 . Pharmach ORMDL3 ,28. The ORMDL affects ceramide levels and airway pathophysiology [ORMDL3 expression decreases ceramide levels in normal physiological conditions, while high ORMDL3 expression increases ceramide levels, followed by increased inflammatory responses in pathological conditions [ORMDL3 (rs7216389) showed no significant differences between the AERD and ATA groups. Meanwhile, consistent with the previous studies, the TT genotype of ORMDL3 (rs7216389) is associated with asthma exacerbation and the severity of asthma [20 methacholine than those with the CT or CC genotype, while ATA patients did not. Collectively, these findings imply that the genetic polymorphism of ORMDL3 may affect gene expression and subsequently sphingolipid synthesis and can play a pathogenic role in airway hyperreactivity of AERD. Further studies are needed to evaluate the potential therapeutic effect in AERD management by inhibiting the de novo synthetic sphingolipid pathway.There have been numerous inconsistent and confusing mechanistic reports reporting on how ysiology ,34–36. Anditions . In our f asthma ,24. The de novo synthesis of sphingolipids and eosinophilic inflammation in AERD provides a new insight into the mechanism of AERD.Eosinophils are cardinal effector cells in asthmatic patients. Eosinophil infiltration in the sinus and bronchial mucosa has been recognized as major characteristics of AERD . Patientde novo synthetic pathway of sphingolipids may be involved in the eosinophilic inflammation and airflow limitation in AERD. Although there have been several in vitro and mouse model studies regarding the de novo synthetic pathway of sphingolipid [de novo synthetic pathway of sphingolipids. Further studies to investigate the whole pathway of sphingolipid synthesis and to integrate the levels of metabolites, mRNA expression of individual enzymes, genotype frequencies and the degree of eosinophilic inflammation are warranted.To our knowledge, this is the first study showing that the dysregulated ngolipid ,37, we fde-novo sphingolipid metabolic pathways may play a crucial role in eosinophilic inflammation in AERD.In conclusion, our results suggest that dysregulated S1 File(XLSX)Click here for additional data file.


Gout as well as asymptomatic hyperuricemia have been associated with several traditional cardiovascular risk factors and chronic kidney disease. Both in vitro studies and animal models support a role for uric acid mediating both hemodynamic and tissue toxicity leading to glomerular and tubule-interstitial damage, respectively. Nevertheless, two recent well designed and carried out trials failed to show the benefit of allopurinol treatment on kidney outcomes, casting doubts on expectations of renal protection by the use of urate lowering treatment. With the aim of providing possible explanations for the lack of effect of urate lowering treatment on chronic kidney disease progression, we will critically review results from all available randomized controlled trials comparing a urate-lowering agent with placebo or no study medication for at least 12 months and report renal clinical outcomes. The relationship between hyperuricemia (HU) and chronic kidney damage is bidirectional. Although a reduction in glomerular filtration rate (GFR) can precede and lead to the development of hyperuricemia, increased serum uric acid (SUA) levels per se can adversely impact renal function ,2,3. SevWhile population-based association studies cannot prove causation, it is fair to report that several observational studies showed elevated SUA levels are strong and independent predictors of early GFR decline and albuminuria in a very large study population with and without diabetes ,12.In intervention studies, xanthine oxidase inhibitors (XOIs) have been shown to reduce mean systolic and diastolic blood pressure in adolescents , and to With the aim of selecting the best quality studies, we decided to include in this analysis only the RCTs that investigated the renal effect of a ULT compared to placebo or no treatment for at least 12 months. Therefore, despite the rising interest in the new anti-hyperuricemia drugs, studies analyzed in this review cannot include RCTs on uricosurics drugs and are forcibly limited to those on XOis . Topiroxostat, a new XOi approved for therapeutic use only in Japan, demonstrated a renoprotective effect by attenuating the reduction in eGFR in patients with diabetic nephropathy  and by iWe found that four studies were able to demonstrate a protective role of ULT ,18,23,242 or significant GFR loss (>3 mL/min/1.73 m2/year) in the previous 3–5 years [2, respectively. Mean SUA decreased in the allopurinol group from 6.1 at baseline to 3.9 mg/dL during treatment whereas it remained at 6.1 mg/dL in the placebo group. Despite this sustained 36% reduction in SUA, the eGFR decreased at similar rates in the two treatment groups.The Preventing Early Renal Loss in Diabetes (PERL) trial enrolled 530 patients with T1D, SUA levels ≥ 4.5 mg/dL, mild to moderate increase in urine albumin excretion and eGFR 45–100 mL/min/1.73 m–5 years . At baseSeveral aspects that characterize the population recruited in this study could suggest that allopurinol therapy would hardly be able to confer renal protection to these patients. First of all, the PERL study includes patients with SUA ≥4.5 mg/dL, which is a very low cut-off to think that modulation of SUA may have a decisive impact on the progression of kidney disease in these patients. While results were similarly neutral in pre-specified subgroup analyses based on SUA levels (≤6.0 vs. >6.0 mg/dL), in the two trials by Siu and Goicoechea ,17 showiDue to the well-known relationship between low eGFR and increased SUA levels, at least in part imputable to a decreased urate excretion rate, hyperuricemia and gout are frequently observed in patients with CKD ,30. TherFurthermore, patients included in the study showed a very long duration of diabetes. The 530 patients experienced a 34.6 years’ length of T1D, which obviously affected the natural history of their kidneys. The hyperfiltration distressing each individual nephron of these patients has inevitably triggered a vicious process leading to a progressive loss of nephronic mass that cannot be effectively countered with the ULT.Furthermore, this population is largely represented by fast progressor patients as confirmed by the high slope of eGFR (about 2.5–3 mL/min/year) observed despite minimum or no renal damage at baseline. The FEATHER study provides a hint that febuxostat is presumably more effective for patients with less kidney damage such as those without proteinuria and those for whom serum creatinine concentration was lower than the median . In a laIn addition, the mean glycated hemoglobin level was 8.2 ± 1.3%, which means that a subset of patients was not at the target. As previously reported, severe hyperglycaemia may induce a reduction in SUA levels due to the uricosuric effect of sodium-glucose co-transporter-9 (SGLT9) activation secondary to increased glucose traffic in the tubular lumen. This mechanism leads to a J-shaped relationship between SUA and glycosylated hemoglobin, making it more complex to understand the relationship between the pharmacological modulation of urate and kidney damage.Moreover, in the PERL study, blood pressure values were, on average, at target. This could account for the lack of nephroprotection by ULT observed in this trial. In fact, favorable cardiovascular (CV) and renal effects of SUA lowering treatment may be mediated by preventing endothelial dysfunction, vascular stiffness, and CV related events.Finally, the large heterogeneity in the study population together with the small sample size makes it difficult to correctly interpret the data.n = 185) or placebo (n = 184) [2 in the preceding 12 months. Overall, baseline age (62 years), eGFR (32 mL/min/1.73 m2), and SUA levels (8.2 mg/dL) were nearly identical in the two groups. The median urinary ACR (717 mg/g), the eGFR between 15 and 59 mL per minute per 1.73 m2, or its decrease of at least 3.0 mL per minute per 1.73 m2 in the preceding year, depict a figure of very high risk of progression. As discussed before, this is not the setting in which clinicians and researchers can expect the desired effect from ULT.The CKD-FIX randomized 369 patients to either allopurinol (n = 184) . EligiblThe trial, as clearly stated by the Authors in the limitation section, is underpowered as a result of incomplete enrollment and a high percentage of patients who discontinued the study regimen. In fact, in 20 months, recruitment reached 60% of the target number  and, based on trial logistics and funding, it was stopped by the steering committee. Moreover, during the study period, 54 patients (30%) in the allopurinol group and 45 patients (25%) in the placebo group discontinued the assigned regimen and a post hoc power calculation showed that the sample required to accommodate the discontinuation rate of 30% was 1006 patients. An interesting hypothesis is that the pathogenic role of SUA may be different in different CKD strata. In the CKD FIX, mean SUA levels remained constant in the placebo group and decreased in the allopurinol group to 5.1 mg/dL at 12 weeks and remained at 5.3 mg/dL along the study period with a ~35% reduction substantially superimposable to that observed in the PERL study. Nevertheless, the trial did not have a serum urate level-based inclusion criterion, and this contributed to the heterogeneity of the sample study with some participants with normal and others with elevated serum urate levels at enrollment.Once again, while the CKD-FIX Study failed to demonstrate any benefit of allopurinol on renal functional decline, this lack of effect has several possible explanations, comprising the selection of an underpowered study population with a very high risk of progression. As a matter of fact, increased SUA levels have been proven to be more predictive of kidney disease progression in the early stages of CKD and in patients without proteinuria than in patients with more severe kidney damage  as is thThe gold standard for renal protection in CKD are RAAS-I and SGLT2-inhibitors although this has mainly been demonstrated in subgroups of patients with clinical proteinuria and/or diabetes. Interestingly Losartan (an Angiotensin II Receptor Blocker) and gliflozins share a potentially renal protective features in that they lead to increased urinary excretion of urates. Sodium-glucose cotransporter-2 (SGLT2) inhibitors block the reabsorption of glucose at the proximal convoluted tubule and the glycosuria that results causes uric acid to be secreted into the urine. A recent meta-analysis of more than 60,000 patients showed that adults randomly assigned to receive an SGLT2 inhibitor had significantly lower SUA levels as compared to those assigned to receive a placebo or comparator medication . In a loSimilar data linking a reduction of SUA levels to a positive effect on CV and renal events derives from the RENAAL Trial. Treatment with the antihypertensive drug losartan lowers SUA probably by inhibiting URAT1, leading to reduced UA reabsorption at the tubular level. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the RENAAL, approximately one-fifth of losartan’s renoprotective effect that has been proposed could be attributed to its effect on SUA .While several clinical practice guidelines emphasize the usefulness of serum urate evaluation for risk stratification , the magIn line with these concerns are the results of a very recent meta-analysis including 28 prospective, randomized, controlled trials assessing the effects of ULT for at least six months on CV or kidney outcomes . Chen QiIn summary, although the two recently published RCTs were unable to provide the expected answers to our questions on the nephroprotective role of allopurinol, the analysis of the literature does seem to leave it open to the possibility of demonstrating the beneficial effect of ULT in future trials. Due to inclusion criteria or insufficient power, it was foreseeable that these RCTs showed no protective effect of allopurinol. Numerous data seem to suggest that the renal or vascular damage attributable to uric acid cannot regress once it has established itself. Accordingly, the presence of increased SUA levels at baseline not only predicted the development of hypertension, but also significantly blunted the decrease in blood pressure associated with lifestyle changes in children, suggesting that such children might have progressed to the irreversible phase and structural renal damage may have occurred . At firs


Hypertension continues to be an important public health concern because of its associated morbidity, mortality, and economic impact on society. The aims of this study are to compare the secular changes in age-stratified hypertension prevalence, incidence, co-morbidity, and 3 years of cardiovascular outcome in Taiwan in the years 2005 and 2010.We enrolled hypertensive individuals from the datasets of the Longitudinal Health Insurance Database (LHID) in 2005 and 2010 in Taiwan separately. We analyzed the hypertension prevalence, incidence, medication treatment, and associated morbidities. The risks of cardiovascular and cerebrovascular events and all-causes mortalities among the hypertensive individuals were evaluated in 3 years of follow-up.There was an increased prevalence of hypertension but decreased incidence of hypertension in those over 65 from 2005 to 2010. Dyslipidemia was the highest rate of co-morbidity in 2005 and 2010. The most frequent categories of anti-hypertensive agents prescribed was 1 or 2 for both 2005 and 2010. Calcium channel blockers were the most common anti-hypertensive agents prescribed, followed by Angiotensin converting enzyme inhibitors/Angiotensin receptor blockers. After 3 years of follow-up, the risks of coronary artery disease (CAD), cerebrovascular diseases (CVD) as well as death were less in 2010 than in 2005 in Taiwan.Our study showed that hypertension individuals had an increased prevalence, younger age, decreased incidence, increased medication treatment associated with decreased the CAD, CVD, and mortalities in 2010 compared to 2005 in Taiwan. It has been reported hypertension was present in 69% of patients who experienced their first heart attack, and 77% of those suffering from their first stroke.–5 Prevalence estimates were significantly higher in the elderly (≥65 years old) compared with young adults (<65 years old). Previous research also reported the effective reduction of blood pressure is closely related to decreased cardiovascular disease and stroke. Additionally, antihypertensive therapy is directly associated with reduced blood pressure. A systematic review compiling 1479 related studies in these 40 years indicated the global prevalence of adult hypertension increased from 26.4% in 2000 to 31.1% in 2010, 28.5% in high-income countries such as the West and Asia Pacific area and 31.5% in low- and middle-income countries such as East Asia, Southeast Asia, South Asia, Oceania, and the South African region below the Sahara. An estimated 1.39 billion people had hypertension in 2010. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries but increased by 7.7% in low- and middle-income countries.As a well-known risk factor for cardiovascular morbidity and mortality,,9 Therefore, monitoring blood pressure changes in epidemiological data, treatment type, and the quality of care must be ongoing. Early recognition and treatment of hypertension is important to improve morbidity and mortality, especially for cardiovascular and cerebrovascular diseases (CVD). Even in hemodialysis patients, blood pressure control was independently associated with all-cause mortality and cardiovascular events.A lot of research clearly shows the occurrence of high blood pressure increases the number of complications and even death, bringing a heavy financial burden to a country.,12 The latter would be various recommendation treatment guidelines in different countries and times, such as WHO/ISH; Prevention, Detection, Evaluation and Treatment of High Blood Pressure by the US Joint National Committee (JNC); the British Hypertension Society (BHS); and the European Society of hypertension / European Society of Cardiology (ESH / ESC), etc. Taking JNC7 published in 2003 for instance, hypertensive patients in stage I (140/90 mm Hg) are recommended thiazide-type diuretics, as well as other drugs such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and others if complications existed. In addition, patients with different severity and treatment goals have corresponding recommendations for the number and type of medicine. Two-drug combinations as a first step antihypertension treatment have been emphasized in recent years. An updated JNC8 with stronger evidence and revisions for treatment targets and medication choice was released after 10 years.Generally, the treatment of hypertension can be divided into 2 parts: lifestyle modification changes and drug treatment. The former includes salt and alcohol intake restrictions, weight loss, smoking cessation, diet control, and exercise.,16 However, since following the guidelines is not compulsory in actual clinical practice, many studies focused on the prescription pattern of antihypertensive agents and factors affecting these patterns.The Taiwan Society of Cardiology also published 2 versions of guidelines for tackling high blood pressure in 2010 and 2015. These were more Asian-oriented, such as more emphasis on the importance of stroke when considering the cardiovascular prognosis. The most commonly used medication varies according to the country. For instance, ACEIs are the most frequently prescribed medications in Canada, the United Kingdom, and the United States; while BBs are popular in Finland, Iceland and Sweden; CCBs are often prescribed in Norway and Denmark. The factors leading to distinct prescription pattern involve the individual-level  and environmental-level . The findings of this study explore the real public health data of hypertension, confirm the health care achievements of NIH in Taiwan, and are anticipated to provide a reference not only for caregivers but also for the policy makers of national health insurance to achieve reasonable and cost-effective drug recommendations.There have been several studies focused on the medication pattern for hypertension over the last few decades in Taiwan. In general, CCBs are the class of medication with the highest use frequency. Diuretics are uncommon on the other hand; and there has been a gradual trend for the replacement of ARBs to ACEIs.2To evaluate secular changes in the prevalence and incidence of hypertension and the subsequent cardiovascular or CVD and mortality, we conducted a retrospective study cohort study by analyzing 2 independent datasets of the Longitudinal Health Insurance Database (LHID) 2005 and LHID 2010.2.1 The Health Insurance program is a nationwide healthcare system in Taiwan established in 1995, and its coverage rate exceeded 99% in 2007. There were no significant differences in the age and sex distribution between the selected sample and all enrollees.The outpatient records dataset of the LHID 2005 and LHID 2010 were used in this study. Both LHID 2005 and LHID 2010 contain the entire original claim data of 1,000,000 beneficiaries randomly sampled from the corresponding year of the National Health Insurance Research Database (NHIRD). This corresponded to about 4% of all enrollees in the National Health Insurance program.The LHID contains information on each member, including an encrypted personal identification number, sex, date of birth, diagnostic codes using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), drug prescriptions, medical cost, medical care facilities, and specialty of care providers. All datasets are interlinked by the personal identification number of the patient.2.2The study diagram is presented in Figure 2.2.1st to December 31st for the year 2005 from the LHID 2005 dataset and 2010 from the LHID 2010 dataset, respectively, to evaluate the prevalence of hypertension by age group. The date of diagnosis of hypertension was the earlier date of either: the third outpatient visit, or the first outpatient visit with an antihypertensive prescription.Individuals whose records showed ICD-9-CM codes 401–405 for 3 outpatient visits, or those prescribed an antihypertensive agent at any outpatient visit were diagnosed as hypertensive from January 12.2.2Further, hypertensive individuals would be enrolled after excluding the hypertension history 1 year prior to the year of enrollment. The incidence of hypertension was calculated by age groups in the 2 different datasets.2.2.3To compare the history of the concomitant conditions of patients between 2005 and 2010, outpatient records were traced for up to 1 year prior to the date of hypertension diagnosis for any diagnosis containing the following ICD-9-CM codes: 250 (diabetes mellitus), 272 (hyperlipidemia), 440–459 , 140–208 (cancer), 580–589 , 490–496 (lung disease), 531–534 (ulcer). Patients with records of any of the above-mentioned codes during that time were considered to have the corresponding comorbid conditions.For evaluating CAD and CVD risk, hypertensive individuals with the ICD-9-CM code 410–429 (heart disease), 430–432 (hemorrhagic stroke), and 433–438 (ischemic stroke) prior to the individuals were excluded.2.2.4Antihypertensive agents were categorized into 6 major categories, including alpha-blockers, BBs, CCBs, diuretics, ACEIs or ARBs, and others. This study examined the prescription of antihypertensive medication classes in hypertensive individuals on the date of diagnosis and the number of agent(s) prescribed. ACEIs and ARBs were treated as 1 class because of their similar treatment effects.2.2.5Hypertensive individuals were followed up for 3 years. Individuals hospitalized for coronary artery disease (CAD) (ICD-9-CM 410–414) including myocardial infarction and angina (ICD-9-CM 410–414), and CVD ((ICD-9-CM 430–438) were identified as outcome event. We also compared the events of all-cause deaths  for 3 years.2.3t-test for continuous variables. Subsequently, univariate and multivariate binary logistic regression was performed for the likelihood of prescribing any anti-hypertensive agents, as well as each type of agent. The different outcomes of 3-year cumulative incidences were analyzed by Cox proportional Hazard models. The univariate factors with P < .05 were then entered into the multivariate model. P < .05 was considered statistically significant. All the data processing and statistical analysis were performed using SAS statistical software . The study was approved by the Institutional Review Board at the Chi-Mei Medical Center.For comparing 2005 and 2010, the Chi-Squared test was used for categorical variables and 33.1There were 97,187 (13% of sample population) 122,265 (15.71% of sample population) individuals meeting the criteria of hypertension in 2005 and 2010, respectively   (Table Characteristics of the hypertensive population are summarized in Table 01) Fig. b, and thOf the types of anti-hypertensive agents prescribed Table , the ranThe most frequent number of anti-hypertensive agents prescribed was 1, 2 and none for both 2005 and 2010. For more details, more patients were not prescribed any agent (13.29%–15.95% from 2005 to 2010); fewer patients were prescribed 1 agent (44.79%–41.78% from 2005 to 2010). The trends for the proportions of patients with 2 agents were stable (29%). The mean numbers of antihypertensive drugs were about 1.3 in both the 2005 and 2010 cohorts (Table 3.2P < .0001), the CVD is 0.07 (in 2005) vs 0.06 (in 2010) (P < .0001) and the death is 0.04 (in 2005) vs 0.03 (in 2010) (P < .0001)  revealed the cumulative incidence of CAD is 0.13 (in 2005) vs 0.10 (in 2010)  above the target of <140/90 mm Hg.In our study, the mean numbers of antihypertensive drugs were about 1.3 in both 2005 and 2010. This information helps us modify the clinical practice that early combination therapy is better than monotherapy to achieve the target blood pressure.The 3-year-outcome revealed less cumulative incidence of CAD, CVD, and deaths in 2010 than in 2005. This was partly due to more patients being included in the National Health Insurance and greater awareness of hypertension and its complications. More people received early treatment of hypertension and more potent end organ protective drugs were prescribed.–32 Owing to the limitations of real-world blood pressure information, we could not offer the BP management result that may be needed after full consideration of age and sex which can significantly influence health behaviors. Second, the LHID 2010 and 2005 did not include personal risk factors for hypertension, including smoking, body mass index, exercise, salt intake, and drinking. These risk factors may influence the prevalence of hypertension, but the confounding factor may be small because of this studys large sample size which is needed to evaluate the effects of many risk factors simultaneously. Future directions of the study should include the blood pressure data of the patients because the treatment rate and blood pressure level are related to the cardiovascular events.,27–32 The third limitation is we did not have LHID datasets earlier than 2005 or later than 2010 and these have helped in understanding these trends. This also aims our consideration for future study to collect more variables about the clinical patient data, including BMI, waist circumference, metabolic syndrome, lipids, exercise, smokers, liver steatosis, alcohol intake, lung disease¸ gout, atrial fibrillation, high-sensitivity C-reactive protein, Fasting glucose, depression, valve disorder, complete blood tests, family history of stroke, CAD, peripheral arterial disease, and stroke subtypes which may significantly affect clinical decisions.There are some limitations to our study. First, we were unable to obtain the blood pressure (BP) measurement data of the patients in the LHID 2010 and 2005. Blood pressure control, especially high systolic blood pressure and low diastolic blood pressure, is related to the clinical cardiovascular and cerebrovascular outcome.,25 Due to the convenience of the National Health Insurance System in Taiwan, more patients have access to affordable health care for hypertension and as a result the CAD, CVD, and mortalities in hypertensive individuals in Taiwan have improved.In conclusion, in Taiwan, the hypertension incidence rates among those over 65 years old decreased in 2010 compared to 2005. CCB and ARB/ACEI were the top 2 most common categories prescribed for hypertension and more than 1 drug category used on average, suggesting more aggressive treatment as well as combination treatment as the first step in antihypertensive therapeutic intervention.Conceptualization: Chia-Te Liao, Jung-Chang Shih, Tain-Junn Cheng, Wen-Shiann Wu.Data curation: Chia-Te Liao, Pei-Chih Wu, Jung-Chang Shih, Tain-Junn Cheng.Formal analysis: Chia-Te Liao.Funding acquisition: Tain-Junn Cheng.Investigation: Chia-Te Liao, Jung-Chang Shih, Tain-Junn Cheng.Methodology: Chia-Te Liao, Pei-Chih Wu, Tain-Junn Cheng, Wen-Shiann Wu.Project administration: Wen-Shiann Wu.Validation: Wen-Shiann Wu.Visualization: Wen-Shiann Wu.Writing – original draft: Chia-Te Liao, Wen-Shiann Wu.Writing – review & editing: Wen-Shiann Wu.