Background and objective: Two endothelin receptor antagonists (ETRAs), bosentan and ambrisentan, are approved for patients with pulmonary arterial hypertension (PAH). However, there is little information about the transition strategy between these two ETRAs. We aimed to evaluate the safety and efficacy from ambrisentan to bosentan. Methods: Twenty PAH patients were enrolled into the single-center, open-labelled prospective study. Echocardiogram, WHO functional class (WHO-FC), 6-minute walking distance (6MWD), right heart catheterization, and hemotology were collected. After receiving oral 5 mg ambrisentan daily initially for one year, the patients were divided into two arms: eight patients switched to bosentan, while the remaining 12 patients continued ambrisentan. Characteristics at baseline, 1-and 2-year follow-up points were compared. Results: There were no significant differences in echocardiogram, WHO-FC, hemodynamics, demographics and liver function at baseline, 1-and 2-year points in both arms. 6MWD in bosentan group was significantly shorter at baseline. But there were no significant differences of 6MWD at 1- and 2-year points. Conclusions: It is safe for stable PAH patients to transition from ambrisentan to bosentan without hemodynamic or hematologic deterioration. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increasing pulmonary arterial pressure and pulmonary vascular resistance, leading to right heart failure and ultimately death , 2. EndoSide effects such as liver toxicity and drug interactions differ between these ETRAs . We presn = 8) or ambrisentan (n = 12) group. Data were collected from each patient at baseline, 1-year, and 2-year points. Collected data included 6-minute walk distance (6MWD), NT-pro-brain natriuretic peptide (NT-proBNP), WHO functional class (WHO FC), echocardiography parameters (tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure, LV eccentricity index, pericardial effusion), arterial oxygen saturation, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and uric acid plasma concentrations (UA).We performed a prospective single-center study at our center. All patients included are ethnic Chinese . Twenty Ethical approval was received from the ethics committee of Shanghai Pulmonary Hospital. All patients consented to be included in the study.t tests for normally distributed data and Mann–Whitney U tests for not normally distributed data. Chi-square tests were used to analyze changes of pericardial effusion and WHO FC. Statistical analyses were conducted using SPSS 20.0. A P value < 0.05 was considered statistically significant.Data are presented as mean ± standard deviation, unless stated differently. Comparisons of characteristics, 6MWD, echocardiography parameters, and hematology between two groups were performed using independent Demographic and baseline characteristics are outlined in P < 0.05. 6MWD was 422.3 ± 81.1 m and 409.0 ± 92.0 m at 1 year and 2 year in the bosentan group, and 517.3 ± 60.8 m and 520.0 ± 72.4 m in the ambrisentan group. 6MWD deviation from baseline to 1 year was 10.3 ± 14.5 m and −5.6 ± 38.9 m, and the deviation from 1 year to 2 year was 13.3 ± 29.6 m and −2.8 ± 21.2 m, respectively, in bosentan and ambrisentan groups  at baseline, 1 year, and 2 year in two groups   .P > 0.05) (P > 0.05) from baseline to 1 year or from 1 year to 2 year between bosentan and ambrisentan groups (P > 0.05)  . No sign > 0.05) .P > 0.05). WHO FC was also not significantly different between two groups (P > 0.05)  .Our study is a single-center, open-label prospective controlled study, and we believe that it is the first time to study the effects of transition between bosentan and ambrisentan in PAH. Our data suggested that switching from a selective ETRA ambrisentan to an unselective ETRA bosentan may be reasonable and safe.After transition, there was no marked change in hemodynamics as assessed by echocardiography, or in hematologic parameters, 6MWD, and WHO FC. Cost is commonly cited as a reason for transition to bosentan by Chinese patients. There could be potential bias on the outcomes of the patients because of the unevenness of the socioeconomic status of the patients and the discrepancy of the drug price. In fact, the socioeconomic factors have been balanced to be similar to each other amongst all the patients before their enrollment in this study. Even so, we did not ignore the role of economic factors, as the effect of drug prices on treatment exists in China. Also, if there is intolerance to ambrisentan, transition to bosentan may be an effective choice.Although there was a statistical difference at baseline in 6MWD between the two groups , hemodynN = 5/2/1 and 11/1/0, resp.). Thus, bosentan is similar to ambrisentan in maintaining stability of exercise capacity.Many studies have used 6MWD as the primary end point . 6MWD reNT-proBNP and uric acid levels are biomarkers of heart failure, and their high plasma levels have consistently been reported as predictors of mortality –18. SignThe evaluation of pulmonary arterial hypertension requires a multimodality approach. Echocardiography continues to be a valuable tool to evaluate disease progression as it generates a wealth of information about response of the right heart to elevated pulmonary pressure. Numerous measurements can be used to identify alterations in right heart morphology, pressure, and function. Although each variable in isolation may have little utility, meaningful information is revealed when multiple parameters are considered together . In this


The pathophysiological mechanisms of cisplatin nephrotoxicity include the reduction of renal blood flow, as well as tubular epithelial cell toxicity. The objective of this study was to investigate the influence of lower blood pressure and decreased food intake on the incidence of cisplatin nephrotoxicity.We conducted a retrospective cohort study at a university hospital between 2011 and 2012. We identified hospitalized adult patients with head and neck cancer, esophageal cancer, or gastric cancer, who received intravenous cisplatin administration. The primary outcome was the incidence of cisplatin nephrotoxicity defined as the increase in serum creatinine after cisplatin administration more than 1.5 times from baseline.P = 0.037), while there was no significant difference for patients taking solid food (P = 0.67).The study participants included 182 patients, in whom we observed a total of 442 cycles of cisplatin chemotherapy. The incidence of cisplatin nephrotoxicity was observed in 41 of 182 cycles with initial administration. Multivariate logistic regression analysis showed that systolic blood pressure was independently associated with cisplatin nephrotoxicity . The use of renin-angiotensin system (RAS) inhibitors was also associated with cisplatin nephrotoxicity . Among quartiles of systolic blood pressure in all cycles of chemotherapy, the incidence of nephrotoxicity in the lower blood pressure group was significantly higher than that in the higher blood pressure group for patients taking non-solid food  contains supplementary material, which is available to authorized users. Cisplatin is a platinum-based anticancer drug widely used to treat various types of cancer and contributes to the improvement in outcomes like 5-year survival. However, side effects of cisplatin including ototoxicity, neurotoxicity, nausea, and myelosuppression frequently occur, and the main dose-limiting side effect is nephrotoxicity , 2. PrevThough hydration, monitoring of renal function, and adjustment of cisplatin doses depending on renal function , 11 are The pathophysiological mechanisms of cisplatin nephrotoxicity include its direct tubular epithelial cell toxicity as well as the reduction of renal blood flow as a consequence of endothelial dysfunction and vasoconstriction , 16. HowIn this study, we retrospectively reviewed a cohort of patients treated with cisplatin-based chemotherapy for head and neck cancer, esophageal cancer, or gastric cancer. The subject selection criteria were determined according to the following two reasons: patients with these types of cancer tend to decrease their food intake from trismus, dysphagia, or gastrointestinal symptoms and these cancers are similar in cisplatin dosage and administration interval. The objective of this study was to investigate the influence of lower blood pressure and decreased food intake on the incidence of cisplatin nephrotoxicity.We conducted a retrospective cohort study at University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan. By searching electronic medical records, we identified hospitalized patients aged 18 years or older with head and neck cancer, esophageal cancer, or gastric cancer, who received intravenous cisplatin administration between January 2011 and December 2012. The following patients were excluded from the study: patients who received cisplatin before the observation period, those with a history of previous cisplatin administration at other hospitals, those with an interval of cisplatin administration of less than 2 weeks, and those receiving maintenance dialysis.We analyzed the incidence of cisplatin nephrotoxicity in the first cycle of cisplatin chemotherapy and the relationship of potential risk factors to the incidence of cisplatin nephrotoxicity. Then, we evaluated all cycles of cisplatin chemotherapy during the observation period to investigate the relationship of lower blood pressure and decreased food intake to the incidence of cisplatin nephrotoxicity, because these factors can vary among cycles of chemotherapy even in the same patient. The study was approved by the Ethics Committee on Human Research of Kyoto Prefectural University of Medicine and was carried out in accordance with the Declaration of Helsinki. Patient records/information was anonymized and de-identified prior to analysis.The primary outcome was the incidence of cisplatin nephrotoxicity defined as the increase in serum creatinine after cisplatin administration more than 1.5 times baseline according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 . We usedBaseline characteristics of patients were extracted from electronic medical records as follows: age, sex, smoking status , history of hypertension, history of diabetes, history of cardiovascular disease, cancer types, and combined anticancer drugs. Cardiovascular disease was defined as angina or myocardial infarction, referring to a previous report . The clit test.Data are shown as number (percentage) for categorical variables and mean ± standard deviation (SD) for continuous variables. Categorical variables were compared using chi-square tests or Fisher’s exact tests for small sample sizes. Chi-square test with Bonferroni correction was used for multiple comparisons. Continuous variables were compared using a Welch’s P value.Multivariate logistic regression analysis was performed to evaluate the influence of clinical variables on cisplatin nephrotoxicity in the first cycle of chemotherapy. The variables included age, sex, cisplatin dose per BSA, food form , systolic blood pressure, and the use of RAS inhibitors. Data of logistic regression analysis are given as adjusted odds ratio (OR) with a 95% confidence interval (CI) and To examine the relationship between blood pressure and nephrotoxicity, all cycles were grouped into quartiles based on systolic blood pressure. The incidence of nephrotoxicity and the prevalence of antihypertensive medication use in each group were calculated. Then, the relationship between cisplatin nephrotoxicity, quartiles of systolic blood pressure, and food form (solid or non-solid food) were analyzed.P value was less than 0.05. Statistical analyses were performed using JMP software, Version 10 .Differences were determined to be significant when the two-sided During the study period, 267 patients were assessed for eligibility. Figure The incidence of cisplatin nephrotoxicity was observed in 41 of 182 cycles with initial administration, in which 14 patients discontinued following cisplatin chemotherapy. In addition, cisplatin nephrotoxicity was observed in 71 of the total 442 cycles; 8 patients developed multiple episodes of nephrotoxicity .To investigate the relevant factors for developing cisplatin nephrotoxicity, we compared the clinical characteristics for patients with and without subsequent nephrotoxicity in the first cycle Table . SystoliP = 0.020; Table P = 0.013).To further investigate the risk factors for developing nephrotoxicity, we performed multivariate logistic regression analysis and found that systolic blood pressure was independently associated with cisplatin nephrotoxicity . Despite low blood pressure, approximately 20% of subjects continued antihypertensive medication in the lower quartile. Additionally, there was no significant difference in the prevalence of antihypertensive medication use between quartiles.Then, we divided all cycles into quartiles of systolic blood pressure. As demonstrated in Fig. P = 0.67). By contrast, for patients taking non-solid food, the incidence of nephrotoxicity in the lower blood pressure group was significantly higher than that in the higher blood pressure group . Lower blood pressure had a greater influence on nephrotoxicity in patients taking non-solid food than those taking solid food. For the lower quartile (Quartile 1), the incidence of nephrotoxicity in patients taking non-solid food was significantly higher than that in patients taking solid food .Finally, we classified all cycles according to food form (solid or non-solid food) and quartiles of systolic blood pressure , and compared the incidence of cisplatin nephrotoxicity among these groups  and amount of food intake. The medical records of these data were partially semi-quantitative. The quantitative indicators of food intake or other parameters for nutritional status are needed for further investigation. Third, serum creatinine, used for primary outcome in this study, can overestimate basal renal function and underestimate renal prognosis in patients with weight loss due to cancer. To avoid the latter problem, we evaluated short-term creatinine changes within 4 weeks. Finally, there was the lack of longitudinal data including blood pressure and body weight. These data can elucidate the change in distribution of blood pressure and relevant factors in cancer patients.In conclusion, our study demonstrated that lower blood pressure prior to cisplatin administration and the use of RAS inhibitors was associated with the incidence of cisplatin nephrotoxicity, and lower blood pressure had a greater influence on nephrotoxicity in patients who could not take solid food because of nausea or gastro-intestinal obstruction due to the cancer. We wish to alert oncologists to the risk of cisplatin nephrotoxicity in cases of coincidence of lower blood pressure and decreased food intake. Discontinuation of antihypertensive medication including RAS inhibitors before cisplatin chemotherapy should be considered, which may be beneficial for patients with lower blood pressure.


The objective was to investigate the prevalence of heart attack, angina pectoris, stroke, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, asthma and obesity in relation to the presence and severity of obstructive sleep apnea.The sample consisted of 1887 patients, with mean age of 48.6 years (range 16–83 years), referred to a university hospital on suspicion of obstructive sleep apnea. The patients filled out a questionnaire asking whether they were previously diagnosed with the comorbidities in interest. Obstructive sleep apnea was diagnosed and categorized based on a standard respiratory polygraphic sleep study using a type 3 portable monitor. The patients’ weight, height and blood pressure were measured during the consultations.In total, 37.9% were categorized as not having obstructive sleep apnea (Apnea-hypopnea index <5), 29.6% mild obstructive sleep apnea (Apnea-hypopnea index 5–14.9), 17.3% moderate obstructive sleep apnea (Apnea-hypopnea index 15–29.9), and 15.2% severe obstructive sleep apnea (Apnea-hypopnea index ≥30). The prevalence of heart attack, angina pectoris, hypertension, measured systolic blood pressure ≥140 mmHg, measured diastolic blood pressure ≥90 mmHg, diabetes mellitus and obesity (body mass index≥30) were higher with greater obstructive sleep apnea severity. Logistic and linear regression analyses showed that these comorbidities were positively associated with obstructive sleep apnea severity. This was not the case for stroke, chronic obstructive pulmonary disease and asthma. After adjustment for sex, age, alcohol and smoking in the logistic regression analyses, hypertension, measured systolic blood pressure ≥140 mmHg, measured diastolic blood pressure ≥90 mmHg and obesity remained positively associated with obstructive sleep apnea severity.A higher prevalence of heart attack, angina pectoris, hypertension, diabetes mellitus, and obesity was seen with greater obstructive sleep apnea severity. Obesity and hypertension, conditions easy to clinically assess, appear as the most central comorbidities with greater obstructive sleep apnea severity. Obstructive sleep apnea (OSA) is a common, but often under-diagnosed disorder , 2. The OSA has been recognized as an independent risk factor for cardiovascular disease. Morbidity such as stroke, myocardial infarction, unstable angina, hypertension and diabetes are associated with the disorder , 6. GreaSeveral studies show an association between OSA and hypertension –11, and There is an increasing amount of evidence suggesting a link between OSA and insulin resistance and type 2 diabetes mellitus . A link An increased incidence of stroke has been related to OSA. It has been reported that about half of patients who had an acute stroke have sleep-related disturbances . The risChronic obstructive pulmonary disease (COPD), asthma and COPD combined with asthma have been found to be more prevalent among OSA patients compared to matched controls . A recenth revision of the International Classification of Diseases (ICD-10) obesity is a diagnosis, and defined as BMI greater than or equal to 30 [According to World Health Organization’s (WHO) 10al to 30 . OSA is al to 30 , 14, andal to 30 . The patal to 30 .Patients with OSA are often subject to somatic comorbidity, such as those mentioned above. These conditions address different areas within medicine and there are few previous studies that consider the vast variety of comorbidities related to OSA within a reasonable sample size. Consequently, a study evaluating the association between several of the most common somatic comorbidities and OSA is warranted to enlighten the complexity of this patient group. With this in mind we investigated a large group of patients with suspected OSA referred to a major university hospital in Norway. Using a questionnaire the subjects’ somatic comorbidity was identified and clinically evaluated during the patient visit at the hospital. The main aim of this study was to investigate the prevalence of heart attack, angina pectoris, stroke, hypertension, diabetes mellitus, COPD, asthma and obesity in relation to the presence and severity of OSA.The total sample consisted of 1929 patients referred to Haukeland University Hospital on suspicion of obstructive sleep apnea during the period of 2011 to 2014. Due to no objective registrations, 42 individuals were excluded, thus the final sample included 1887 patients. The mean age was 48.6 years (range 16–83 years) and 70.6% were men.As described in detail previously , the patThe patients filled out a questionnaire prior to the respiratory sleep study, The patients were asked about their current smoking habits (number of cigarettes per day). For data analyses purposes their answers were categorized into a “no smoking” and “smoking” variable. The latter included 1 and more cigarettes per day.The patients’ alcohol consumption was classified as daily, 3–5 days per week, 1–2 days per week, rarely or never. An “alcohol” variable was generated for data analyses, combining daily consumption and 3–5 days per week. The “no alcohol” variable included 1–2 days per week, rarely and never. This dichotomy was created to ease the analyses and differentiate between alcohol consumption on a regular basis or rarely.The patients were asked about whether they were previously diagnosed with heart attack (yes/no), stroke (yes/no), diabetes mellitus (yes/no), hypertension (yes/no), angina pectoris (yes/no), COPD (yes/no) and asthma (yes/no). Furthermore, the patients were asked whether they currently received treatment with medication for diabetes mellitus, hypertension, angina pectoris, COPD and asthma.During the consultation the patients’ sex and age were noted, and weight (kg) and height (m) measured. Their BMI was calculated by weight in kilograms divided by squared height in meters. Obesity was defined as BMI greater than or equal to 30.The patients’ blood pressure was measured by a nurse and/or doctor during the consultation. Prior to the measurement the patient sat still for 10 minutes. The blood pressure was then measured using an automatic, cuff-style, bicep monitor. Two recordings were done and the second recording was selected. In case of strongly deviating results, the blood pressure was measured manually.The study was approved by the Ethics Board . Written informed consent was obtained from all individual participants included in the study.The data analyses were performed using IBM SPSS Statistics version 22. Pearson chi-square tests were used to evaluate the differences in the patients’ characteristics according to the presence and severity of OSA. Thereafter, bivariate logistic regression (crude) analyses were performed with OSA severity  as the dependent variable. Separate multivariate logistic regression analyses (adjusted) were then done for each characteristic together with age and sex as co-variates. The adjusted analyses were repeated, including smoking and alcohol in addition to age and sex as co-variates. Linear regressions with AHI as the dependent variable were also performed. The comorbidity parameters of interest were further used in crude logistic regression analyses as dependent variables, using OSA severity  as co-variate. The significance level was set to 0.05.Among the patients referred on suspicion of OSA 37.9% had a normal AHI (<5), yielding a prevalence rate of OSA of 62.1%. Out of the referred patients 29.6% had mild OSA, 17.3% had moderate OSA, and 15.2% had severe OSA .Being male and alcohol consumption were associated with greater OSA severity. Smoking was associated with lower OSA severity .The prevalence of heart attack, angina pectoris, hypertension, diabetes, and obesity were significantly higher with greater OSA severity . This waWhen only including the patients who received treatment with medication for the particular comorbidity, diabetes and hypertension showed a significant increase in prevalence with greater OSA severity . Angina Linear regressions with AHI as dependent variable showed a positive association with heart attack , angina pectoris , hypertension , measured systolic blood pressure ≥140 mmHg , measured diastolic blood pressure ≥90 mmHg , diabetes mellitus , and obesity . Linear regressions with AHI as dependent variable showed no association with stroke , COPD  and asthma .The results from logistic regression analyses using the comorbidity parameters as dependent variables and OSA severity  as co-variate are shown in Among patients referred on suspicion of OSA there was a higher prevalence of heart attack, angina pectoris, hypertension, diabetes mellitus, and obesity with greater OSA severity. This was also the case for measured systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg. However, there was no significant association between OSA severity and stroke, COPD and asthma.Hypertension, measured systolic blood pressure ≥140 mmHg and measured diastolic blood pressure ≥90 mmHg proved to be significantly associated with OSA severity also after adjusting for age, sex, smoking and alcohol. These findings support other studies , though Obesity has an indisputable association with OSA , 14, alsAs seen in Fredheim et al. reported that extremely obese patients with type 2 diabetes and prediabetes have higher odds of OSA, even after adjustment for amongst others age, sex, smoking and alcohol consumption . This isCOPD and asthma were not associated with OSA severity in our study. This is in contrast to Greenberg-Dotan et al.’s findings . SteveliIn our study stroke was not associated with OSA severity. This is in contrast to Redline et al.’s findings that increasing OSA severity was significantly associated with increased stroke risk, even after adjustment for amongst others BMI, smoking, systolic blood pressure and diabetes . Their sDiabetes and hypertension showed a significant increase in prevalence with greater OSA severity among the patients receiving medication for the particular comorbidity. These results correlated with the results from the total patient group. This is of interest as treatment for the particular comorbidity can indicate severity of the comorbidity. On the other hand, medication will benefit the patient and a well-medicated disease may provide a healthier individual than without medication. Regarding this, OSA has been reported particularly prevalent in drug-resistant hypertension . Our resAs seen in other studies, being male was positively associated with OSA severity , 4. SurpA variety of associations between OSA and alcohol consumption have been reported , 31, andIn our study, we chose to treat obesity as a disorder. Due to this BMI was not included as a risk factor, nor adjusted for in the analyses. Several of the comorbidities in interest are included in the metabolic syndrome, a cluster of risk factors for cardiovascular disease. While having slightly different definitions , metabolThere are various strengths and limitations to the present study. An important advantage was the study’s large sample size, giving weight to the results. Another strength was that a nurse and a doctor revised the questionnaire filled out by the patient during the consultation, and made changes if necessary. This functioned as a quality control of the answers filled out, in the case the patient had misunderstood the question. Measuring blood pressure and calculating BMI from height and weight provided objective information, hence strengthening the study. Another asset was that we studied the association between OSA severity and several somatic comorbidities treated with medication. Furthermore, both logistic and linear regressions were conducted, adding weight to the findings. One of the limitations to our study was that the somatic diagnoses were based on self-report. This gives room for human error such as the patient delivering misunderstood, subjective or false answers, not detected by the nurse or doctor revising the answers. Another limitation was that the diagnoses proclaimed by the patient were not controlled or set by the means of blood samples, lung function tests or a complete clinical examination. It can also be mentioned that our study did not differentiate between diabetes mellitus type 1 and type 2. The difference in pathogenesis between the two types of diabetes mellitus could indicate different associations with OSA severity. The dichotomy for alcohol consumption also serves as a limitation. Alcohol consumption has a cultural aspect, complicating the classification of “normal” and “excessive” alcohol consumption. This study was based on patients referred to a University hospital on suspicion of OSA. Hence, selection bias may have been introduced compared to the distribution of co-morbid diseases to OSA in the community. However, close to all patients in this region of Norway need to be referred to this hospital for CPAP treatment. It is therefore likely that the results are generalizable to other patients referred to hospital settings with suspicion of OSA, as mentioned previously by Bjorvatn et al. . Our stuIn conclusion, our results emphasize that there is a higher prevalence of heart attack, angina pectoris, hypertension, diabetes mellitus, and obesity with greater OSA severity. However, there was no association between OSA severity and stroke, COPD and asthma in our patient group. Obesity and hypertension, as well as measured systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg, seemed to be central comorbidities with greater OSA severity. These conditions are easy to assess in every level of the health system and should be considered when faced with patients presenting symptoms of OSA.S1 Survey questions(DOC)Click here for additional data file.S2 Survey questions(DOC)Click here for additional data file.


Several studies suggest that serum ferritin concentrations reflect systemic inflammation, and high ferritin levels can increase the risk of hypertension in adult men. Shift work is also known to increase the risk of hypertension; however, there has been no study about the relationship between serum ferritin levels and the prevalence of hypertension according to the working type.This cross-sectional study included 4,442 male participants  who participated in the fifth Korean National Health and Nutrition Examination Survey. Hypertension was defined as a systolic blood pressure greater than or equal to 140 mmHg, a diastolic blood pressure greater than or equal to 90 mmHg or the current use of antihypertensive medications regardless of blood pressure values. For the statistical analyses, serum ferritin levels were reclassified into quartiles, and complex sample analyses were used to evaluate the relationship between serum ferritin levels and the prevalence of hypertension according to the working type in this study.Serum ferritin and shift work were positively associated with the prevalence of hypertension. The effect of interaction was above multiplicative. When compared to participants in the lowest serum ferritin quartile, the odds ratio for hypertension for participants in the highest serum ferritin quartile was 1.372 (1.027–1.833) in daytime workers and 2.009 (1.042–3.873) in shift workers after adjustment.The prevalence of hypertension increased as ferritin levels increased in individuals, especially in shift workers. Iron plays an important role in maintaining the body’s physiological homeostasis , 2. SeruAccording to several studies, results are relatively consistent regarding the relationship between shift work and increased blood pressure –21. The There has been no study about the relationship between serum ferritin and hypertension according to the working type. This study was based on large-scale national data representative of the population of the Republic of Korea. We conducted this research to investigate the association between serum ferritin levels and hypertension according to the type of work.We used data from the fifth Korean National Health and Nutrition Examination Survey (KNHANES) conducted by the Korea Centers for Disease Control and Prevention between 2010 and 2012. In the fifth KNHANES, the survey was conducted by extracting 20 households randomly from 192 regions with approximately 100,000 people over the age of one. People were divided to three groups: pediatric (one to 11 years old), adolescents (12 to 18 years), and adults (19 years or older). The survey was composed of a health interview, health examination, and a nutrition survey . Data isn = 5621). We excluded participants if there was missing data on serum ferritin and blood pressure. We also excluded participants who had inflammatory diseases like arthritis, liver cirrhosis, chronic liver disease, chronic renal disease, malignancy or probable hemochromatosis based on serum ferritin levels (> 300 ng/mL for men) [The fifth KNHANES had 25,534 initial participants. We included male workers who were over the age of 19 and who included information on the duty hours section of the health interview survey (for men) . Partici2 (kg/m2). Blood pressure was measured on the right arm in a sitting position using a standard mercury sphygmomanometer. Blood pressure was measured three times, with a 30s rest between each measurement, and the participant’s blood pressure was calculated as the mean blood pressure of the second and third measurements. Blood samples were obtained from the participants from the antecubital veins after an overnight fast. Serum ferritin concentrations were measured using a 1470 WIZARD gamma-Counter with Immunoradiometric Assay (PerkinElmer/Finland). Total cholesterol (TC), triglycerides, fasting blood sugar (FBS), hemoglobin, total iron binding capacity (TIBC), WBC counts, creatinine, vitamin D (VitD) and liver enzymes (AST and ALT) were also recorded [The health interview surveys and health examination surveys were completed at mobile health examination centers. The health examination survey assessed body measurements, blood pressure and pulse measurements, various diagnostic examination and etc. The health interview survey assessed various factors such as working hours, disease morbidity, physical impairment, medication use, smoking and alcohol history. Trained medical investigators performed physical examinations following standardized procedures. Height and body weight were measured respectively to the nearest 0.1 cm and 0.1 kg. For the measurements, participants were asked to remove their shoes and dress in disposable examination gowns. Waist circumference (WC) was measured to the nearest 0.1 cm at the midpoint between the lower border of the rib cage and the iliac crest. Body mass index (BMI) was calculated as the ratio of weight/heightrecorded . AlcoholHypertension was defined as a systolic blood pressure (SBP) greater than or equal to 140 mmHg, or a diastolic blood pressure (DBP) greater than or equal to 90 mmHg. Those taking antihypertensive medications were also considered to have hypertension regardless of blood pressure values.The two working types were classified as “daytime workers” and “shift workers” using the duty hour information collected in the interview. Those who worked from 6 am to 6 pm were consider daytime workers while those who worked from either 2 pm to 12 pm in the evening or 9 pm to 8 am overnight were considered shift workers. Those who indicated that they worked “shift work,” “day and night regular shifts,” “24 hour work shifts,” “split work,” or “irregular shift work” were categorized as shift workers.Complex sample analyses were used for the KNHANES data for weighting all values following the guidance of statistics from the Korea Centers for Disease Control and Prevention in this study . The datThe general and clinical characteristics of the study participants according to the quartile groups of serum ferritin levels are presented in Table Table Table This cross-sectional study was conducted to determine the association between serum ferritin level and hypertension according to the type of work in male, using large-scale national data representative of the population. This study showed the risk of having hypertension was greater in shift workers than in daytime workers as serum ferritin levels increased.Some studies have consistently reported significant associations between hypertension and serum ferritin level in men –18. Two There is insufficient evidence to explain the underlying mechanism. There are several possible mechanisms about the association between serum ferritin levels and hypertension. One of which includes the development of atherosclerosis by elevated ferritin levels. Ferritin is a ubiquitous intracellular protein that is the key to controlling iron homeostasis and is a widely used biomarker for the diagnosis of iron deficiency –3. SerumMany reports and studies over the past several decades have suggested that the endogenous circadian rhythm can collapse due to the effects of shift work on health and ultimately to the destruction of biological homeostasis , 30–32. Inflammation has a relationship with prevalent and/or incident hypertension and is also related to the ferritin level, which is also known as a positive inflammatory marker . FurtherThis study has some important strengths. First, this study was conducted using a representative sample of the general South Korean population. In addition, complex sample analyses for weighting instead of simple statistical analyses, and strict quality controls have been applied to the study procedures in KNHANES. Second, to our best knowledge, this is the first study investigating the association of serum ferritin levels and prevalence of hypertension according to the working type.There are some limitations in this study. First, our study population was composed of only men. The level of serum ferritin can change dramatically before and after menopause. Ferritin levels are generally low in women of childbearing age due to iron lost during menstruation, and then the levels increase after menopause. In addition, serum ferritin concentrations in women are difficult to study because they are affected by many variables such as pregnancy, hormone therapy, and gynecological diseases. Therefore, it is unclear whether our results can be extrapolated to women. Second, our study was conducted cross-sectionally, so it was insufficient to clarify the causative relationship between serum ferritin levels and working type on the development of hypertension. Third, our study is an epidemiological study that used existing data from the National Health and Nutrition Survey and therefore we could not assess all known variables related to our research topic. For example, considering the health effects of shift work, the working duration could be an important variable , 33, 34,In conclusion, this study showed that the prevalence of hypertension in male increased according to incremental increases in ferritin levels, especially in shift workers. In addition, serum ferritin levels can also be used as a subsidiary indicator to evaluate hypertension on high variant blood pressure checks.


BSG rs8259 polymorphism was associated with BSG expression and risk of acute coronary syndrome. Therefore, we investigated whether rs8259 polymorphism contributes to risk and prognosis of CHF in Chinese patients. In total 922 adult patients with CHF and 1107 matched healthy controls were enrolled. BSG rs8259 polymorphism was genotyped using PCR-restriction fragment length polymorphism. Whole blood BSG mRNA expression data from Genotype-Tissue Expression project was accessed. Evaluation of follow-up data was performed in only 15.2% (140) of the patients with CHF. BSG rs8259 TT genotype was associated with a decreased risk of CHF , especially in patients with hypertension  and coronary heart disease  after adjustment for multiple cardiovascular risk factors. Rs8259 T allele was associated with decreased BSG mRNA in whole blood from 338 healthy normal donors (p = 1.31 × 10−6). However, rs8259 polymorphism failed to exhibit an association with cardiovascular mortality (p = 0.283). BSG rs8259 polymorphism may contribute to decreased risk of CHF in a Chinese Han population.Left ventricular remodeling is an essential risk factor contributing to the pathogenesis of chronic heart failure (CHF). Basigin (BSG) promotes cardiovascular inflammation and myocardial remodeling processes by induction of extracellular matrix metalloproteinases and inflammatory cytokines.  Heart failure is a complex clinical syndrome of insufficient cardiac output resulting from myocardial injury. To date, heart failure remains a leading cause of morbidity and mortality worldwide . ChronicBasigin (BSG), also known as CD147 and extracellular matrix metalloproteinase inducer (EMMPRIN), is a member of the immunoglobulin super family and expressed in tumour cells, tumour-associated fibroblasts, and cardiovascular cells . BSG is BSG may be a potential candidate gene associated with risk of CHF. However, there is no report about association between BSG polymorphisms and risk of CHF yet. Notably, a miR-492 binding-site polymorphism (rs8259 A > T) in BSG 3′UTR was associated with decreased BSG mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) or plasma from healthy subjects and patients with psoriasis and acute coronary syndrome (ACS) [BSG rs8259 polymorphism, we herein performed a case-control study to investigate the association between rs8259 polymorphism and risk of CHF in a Chinese population.Numerous evidences have suggested that pathological ventricular remodeling is an essential risk factor contributing to the pathogenesis of CHF . Considephism rs89 A > T ime (ACS) . Also, rphism rs89 A > T ime (ACS) . To makePatients referred to Department of Cardiovascular Medicine, Xiangya Hospital, Central South University between November 2011 and December 2014 were screened for potential inclusion in the study. The eligibility criteria were described previously . EligiblControl individuals with similar age and gender were selected from physical examination center of the same hospital. According to the inclusion criteria, these subjects were unrelated to one another and apparently healthy as assessed by physical examination, serum biochemical testing, and electrocardiogram. Hypertension was defined by systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg and/or being on antihypertensive therapy. Coronary heart disease (CHD) was defined as luminal stenosis ≥50% in at least one major coronary artery branch or myocardial infarction. Type 2 diabetes mellitus was defined as a fasting plasma glucose ≥7.0 mmol/L and/or on antidiabetic medication. The healthy subjects were free of a history or symptoms of hypertension, CHD, diabetes mellitus, or any other cardiovascular diseases. All subjects were Han Chinese origin as ascertained by their resident identity cards. The study protocol was approved by the ethic committee of School of Pharmaceutical Sciences, Central South University and registered in Chinese Clinical Trial Registry (registration number: ChiCTR-RCC-12002817). Statement of informed consent was obtained from all participants.BSG rs8259 polymorphism was genotyped by PCR-restriction fragment length polymorphism as described previously [BseG I restriction enzyme  at 55 °C overnight. The digested PCR products were then analyzed on an agarose gel followed by ethidium bromide staining. In addition, a random selection of 5% of the samples was also genotyped by Sanger sequencing with the ABI PRISM 3730XL DNA sequencer  and the genotyping were confirmed in 100%.The venous blood samples were collected into tubes containing EDTA and stored at −20 °C until analysis. The standard phenol/chloroform protocol was used to extract genomic DNA from whole blood. t-test for continuous variables. Deviation from Hardy-Weinberg equilibrium was assessed by means of a Chi-square test. Logistic regression method was used to analyze the effect of BSG polymorphism on the risk of heart failure adjusting for multiple cardiovascular risk factors. In genetic association analysis, three genetic models  were generally used. Kaplan-Meier curve and Cox proportional hazards regression model were used to assess the effect of BSG polymorphism on disease survival. All of the above analyses were performed with SPSS software . A two-sided p-value < 0.05 was considered as statistically significant.The results were presented as the mean ± SD for continuous variables and as numbers and percentages for categorical data. Chi-square test was used for comparison of the categorical variables and Mann-Whitney U test or independent sample The demographic and clinical characteristics of study participants are reported in BSG rs8259 polymorphism is presented in p = 0.263 and 0.634, respectively). The frequency of rs8259 TT genotype was significantly lower in heart failure subjects than controls . After adjustment for age, gender, smoking status, and dyslipidemia, the association was still significant .The distribution of genotype frequencies of controls . Logistip = 0.011; recessive model: OR = 0.84, 95% CI = 0.72–0.98, p = 0.030). Moreover, when the patients were stratified by CHD, rs8259 TT genotype still exhibited a significant association with decreased risk of CHF in patients with CHD . However, no association was observed between rs8259 polymorphism and risk of CHF in patients without hypertension and CHD . Briefly, associations between genotypes and gene expression levels were determined by linear regression on quantile normalized gene-level expression values, after correction for known and inferred technical covariates, using Matrix eQTL [http://www.gtexportal.org), we accessed the database to determine whether rs8259 polymorphism was associated with BSG expression in multi-tissue . As shown in BSG mRNA in whole blood from 338 healthy normal donors (p = 1.31 × 10−6).The Genotype-Tissue Expression (GTEx) Project is a resource project designed to develop expression quantitative trait loci (eQTL) on the basis of data from 900 relatively healthy donors over 53 sampled sites . The anarix eQTL . Based oBSG rs8259 polymorphism affects CHF prognosis, only 15.2% (140) of the patients were followed up for a median period of 38.7 months. No significant difference was observed for cardiovascular mortality between rs8259 genotype groups , the frequency of rs8259 T allele ranges from 0.31 to 0.44 in East Asian, South Asian, and African populations. As a comparison, the frequency of rs8259 T allele ranges from 0.62 to 0.70 in American and European populations. It will be interesting to investigate whether rs8259 polymorphism exhibit an association with CHF in different ethnic groups.Despite considerable advances in early diagnosis and therapeutic interventions for heart failure, the survival estimates for heart failure are only 50% and 10% at 5 and 10 years, respectively [diseases , includiBSG should be evaluated for their association with CHF. Finally, functional study of rs8259 polymorphism was not performed. Therefore, further research is necessary to elucidate the exact relationship between this variant and heart failure.The present study had several limitations. We only enrolled a relatively limited sample size of Chinese Han subjects. Considering the minor allele and its frequency of rs8259 varies with race, whether the findings of the present study are generalized to other ethnicity still needs to be clarified on the basis of larger sample size. In addition, only rs8259 polymorphism was investigated in the present study, other potentially functional polymorphism in BSG rs8259 polymorphism was associated with decreased risk of CHF. Further investigations in larger cohorts may be required to verify our findings. More comprehensive survey and functional experiments are also needed to illuminate the exact mechanism behind our findings.In conclusion, our study firstly demonstrated that


PGDT protocols help to titrate fluids, vasopressors, or inotropes to hemodynamic target values. There is considerable evidence that PGDT can improve patient outcome in high-risk patients if both fluids and inotropes are administered to target hemodynamic variables reflecting blood flow. Despite this evidence, PGDT strategies aiming at an optimization of blood flow seem to be not well implemented in routine clinical care. The analysis of the arterial blood pressure waveform using invasive uncalibrated pulse contour analysis can be used to assess hemodynamic variables used in PGDT protocols. Pulse contour analysis allows the assessment of stroke volume (SV)/cardiac output (CO) and pulse pressure variation (PPV)/stroke volume variation (SVV) and thus helps to titrate fluids and vasoactive agents based on principles of “functional hemodynamic monitoring.” Pulse contour analysis-based PGDT treatment algorithms can be classified according to the hemodynamic variables they use as targets: PPV/SVV, SV/CO, or a combination of these variables. From a physiologic point of view, algorithms using both dynamic cardiac preload and blood flow variables as hemodynamic targets might be most effective in improving patient outcome. Future research should focus on the improvement of hemodynamic treatment algorithms and on the identification of patient subgroups in which PGDT based on uncalibrated pulse contour analysis can improve patient outcome. PGDT aims at an optimization of basic and advanced global hemodynamic variables to maintain adequate oxygen delivery to the end-organs. PGDT protocols help to titrate fluids, vasopressors, or inotropes to hemodynamic target values that can be assessed with different hemodynamic monitoring technologies.The analysis of the arterial pressure waveform using uncalibrated pulse contour analysis can be used to estimate stroke volume (SV), cardiac output (CO), and dynamic variables of cardiac preload .In this article, we will describe the physiological background and the clinical application of PGDT using invasive uncalibrated pulse contour analysis for the assessment of hemodynamic values.Numerous randomized-controlled trials and meta-analyses demonstrate that there is an increasing body of evidence that PGDT can contribute to an improvement in patient outcome –9 and guA meta-analysis including 29 studies demonstrated that preemptive PGDT strategies targeting cardiac index (CI) or oxygen delivery improve patient outcome in terms of mortality and postoperative complications in moderate- and high-risk surgical patients .In accordance, a meta-analysis including 32 randomized-controlled trials showed that protocol-based optimization of tissue perfusion in terms of optimization of hemodynamics decreases postoperative mortality and organ dysfunction in high-risk surgical patients, particularly when CI, oxygen delivery, and oxygen consumption are used to guide therapy  allows not only the monitoring of arterial blood pressure but also the estimation of SV, CO, and PPV/SVV Figure . An arteThere are a variety of different algorithms for pulse contour analysis that enable SV to be estimated from the arterial blood pressure waveform , 17. TheBesides the estimation of SV, pulse contour analysis allows the assessment of dynamic cardiac preload variables  that—based on heart-lung interactions during mechanical ventilation—can be used to predict fluid responsiveness .Although pulse contour analysis can be easily used in patients with an arterial catheter, the method has several limitations that are crucial to know to avoid erroneous measurements. First, pulse contour analysis depends on an optimal arterial pressure signal. Therefore, to assure impeccable arterial blood pressure waveform recording, one has to meticulously avoid clotting of the arterial catheter, over- or underdamping of the tubing system, or incorrect zeroing of the pressure transducer and monitoring system. In addition, the clinical usefulness of pulse contour analysis is limited in patients with high-grade cardiac arrhythmias and rapid changes or profound abnormalities in vasomotor tone  . The useThe cardiac function curve  describes the relation of ventricular preload or left-ventricular end-diastolic pressure and SV. A left ventricle functioning on the steep part of the cardiac function curve will increase SV after an increase in cardiac preload . This state of “preload reserve” is clinically referred to as “fluid responsiveness,” i.e., an increase in blood flow following fluid administration. Because ventricular function is a major determinant of the shape of the cardiac function curve, fluid administration must be performed cautiously to avoid fluid overload and circulatory failure, especially in patients with poor ventricular function in whom the heart is already working on the flat part of the curve.Based on these basic physiologic principles, pulse contour analysis provides crucial hemodynamic variables reflecting fluid responsiveness  and blood flow  that can be used in PGDT protocols to titrate fluids and vasoactive agents based on principles of “functional hemodynamic monitoring” . FunctioInvasive uncalibrated pulse contour analysis is frequently used for the assessment of hemodynamic variables within PGDT protocols , 26, 27.These treatment algorithms can be classified according to the hemodynamic variables they use as targets: some algorithms are solely based on either dynamic cardiac preload variables  or blood flow variables ; other algorithms combine these dynamic cardiac preload and blood flow variables .The OPTIMISE trial is an example for a study using pulse contour analysis solely to optimize blood flow . In thisCompared with the approach of maximizing SV by using the full cardiac preload reserve, PGDT algorithms targeting both dynamic cardiac preload parameters and SV/CO may help to better tailor the hemodynamic management to the individual patient , 29.In the ongoing follow-up study of the OPTIMISE trial  as a member of the medical advisory board and received honoraria for giving lectures and refunds of travel expenses from Pulsion Medical Systems SE. BS received institutional research grants, unrestricted research grants, and refunds of travel expenses from Tensys Medical Inc. . BS received honoraria for giving lectures and refunds of travel expenses from CNSystems Medizintechnik AG . BS received research support from Edwards Lifesciences . DR collaborates with Pulsion Medical Systems SE as a member of the medical advisory board and received honoraria for giving lectures and refunds of travel expenses from Pulsion Medical Systems SE. DR provided advising services for and received honoraria for giving lectures from Masimo  and Fresenius Kabi .


Hypertension, or high blood pressure, is a prevalent yet modifiable risk factor for cardiovascular disease. While there are many effective treatments available to combat hypertension, patients often require at least two to three medications to control blood pressure, although there are patients who are resistant to such therapies. This short review will briefly update on recent clinical advances and potential emerging therapies and is intended for a cross-disciplinary readership. Blood pressure is considered to be elevated at hypertensive levels when systolic blood pressure (SBP) is ≥140 mmHg and/or diastolic blood pressure is ≥90 mmHg. Hypertension is generally considered to be one of the strongest modifiable risk factors for cardiovascular disease. Its asymptomatic clinical presentation means that there is a long exposure time that contributes to cardiovascular complications and ultimately leads to a detrimental impact on global health.3, although blood pressure and associated cardiovascular diseases are still on the increase, particularly with our ageing population. The importance of blood pressure lowering can be seen with the outcomes from the recently published SPRINT trial4. When SBP was intensively controlled to a target of <120 mmHg compared with the standard treatment target of <140 mmHg, intensive anti-hypertensive treatment resulted in ~25% reduction in primary composite outcome of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. Because of the striking findings, the trial was stopped ahead of time after a median follow-up of 3.3 years. While there is ongoing debate as to the applicability of such findings given the usually less rigorous clinical practice settings occurring in the general community, together with key patient exclusions (e.g. diabetes mellitus and stroke)5, the high relevance of blood pressure control for organ protection is clearly evident. These findings are consistent with previous meta-analysis data on one million adults that demonstrated an association between increasing cardiovascular risk and blood pressure6.Pharmacological treatment of hypertension decreases the likelihood of cardiovascular events such as heart attack, heart failure, and stroke occurring1] receptor antagonists; B=β1-adrenoceptor antagonists; C=calcium channel antagonists; D=diuretics) are likely to be key initial choices. However, these drugs do not always adequately control blood pressure or are not appropriate in all hypertensive patients who usually exhibit various co-morbidities. Notwithstanding important issues such as noncompliance, it is still estimated that 10–15% of hypertensive patients are resistant to current treatment options, where blood pressure is uncontrolled with three or more different classes of anti-hypertensives, including a diuretic8. Therefore, the need for new treatment strategies to treat the multi-faceted nature of hypertension, including organ protection, is still an area of intensive research. This short review will discuss emerging novel approaches currently being investigated to treat hypertension.Many anti-hypertensive therapies are currently being used when lifestyle and behavioural changes are not sufficient. As our undergraduate students quickly learn, the “ABCD” of commonly prescribed anti-hypertensive agents , one could speculate that additive multi-site therapy would result in maximal RAS blockade leading to enhanced anti-hypertensive effects and reduced end organ damage. Indeed, dual RAS blockade did show positive results from short-term studies using blood pressure and albuminuria as surrogate outcomes16.Perhaps reflecting the need for rigorous blood pressure management, in an era of relatively few first-in-class anti-hypertensive agents, there have been numerous fixed double- and triple-dose combinations approved by the FDA this millennia, as recently reviewed17. Just as the RALES trial18 led to a resurgence in the use of spironolactone and later eplerenone for the treatment of severe heart failure, there is renewed interest in the use of mineralocorticoid receptor antagonists for treatment-resistant hypertension (TRH), if this is caused by aldosterone breakthrough in patients already being treated with an ACE inhibitor or an AT1 receptor antagonist, leading to sodium retention17.There have been two mineralocorticoid receptor antagonists available for many decades. The second-generation compound eplerenone has reduced affinity for androgen and progesterone receptors compared with the first-generation antagonist spironolactone, but it is also less potent than spironolactone at blocking aldosterone receptors, hence the greater anti-hypertensive potency exhibited by spironolactone17, the strongest evidence for the use of spironolactone in TRH has recently been obtained from the PATHWAY-2 trial19. All patients who were already receiving A+C+D medications were randomised to receive 12-week sequential treatments of placebo, spironolactone, the α1-adrenoceptor antagonist doxazosin, and the β1-adrenoceptor antagonist bisoprolol. In this study, spironolactone reduced home blood pressure recordings by approximately double that of other active treatment arms and showed for the first time a direct drug comparison in the same TRH patients. There was also a significant inverse correlation between plasma renin and blood pressure reduction by spironolactone, suggesting that sodium retention contributed to TRH. In this study19 and earlier studies17, there was a low incidence of adverse effects. While it has been argued that these results should influence treatment guidelines19, it will be of great interest to determine long-term TRH outcomes in this particular cohort, including potential adverse outcomes, given the combined use of an ACE inhibitor or an AT1 receptor antagonist together with mineralocorticoid receptor blockade. Of interest, newer nonsteroidal mineralocorticoid receptor antagonists, such as finerenone, have been developed to target the heart and are being trialled in heart failure20.While there have been a number of short-term (4–24 weeks’ duration) placebo-controlled trials that have shown beneficial effects of spironolactone in TRH21. However, the higher rate of angioedema noted by omapatrilat (most likely involving raised bradykinin levels) in large-scale heart failure trials has led to the discontinuation of this therapeutic strategy, despite clinical efficacy22. Given that AT1 receptor antagonists, unlike ACE inhibitors, do not inhibit bradykinin metabolism, other combinations of RAS and neprilysin inhibition have been considered. Indeed, there is much interest in a new combination of equal proportions of the AT1 receptor antagonist valsartan and a neprilysin inhibitor sacubitril, known as LCZ696.Neprilysin  is an enzyme responsible for the breakdown of natriuretic peptides and has long been considered a target for hypertension. Indeed, inhibition of neprilysin increases natriuretic peptide levels, resulting in natriuresis, vasodilation, and functional inhibition of the RAS. However, any blood-pressure-lowering effect of neprilysin inhibition is offset, since this enzyme also degrades peptides such as endothelin-1 and Ang II that cause vasoconstriction. Indeed, combined neprilysin and ACE inhibition, achieved using omapatrilat, evoked greater anti-hypertensive effects than did the ACE inhibitor enalapril alone23. Anti-hypertensive efficacy of LCZ696 was confirmed in Asian populations with minimal safety and tolerability issues24. The effect of LCZ696 has also been examined on biomarkers in heart failure patients with preserved ejection fraction (PARAMOUNT)25 and on clinical outcomes in heart failure patients with reduced ejection fraction (PARADIGM-HF)27. The latter trial was terminated early since there was a 20% reduction in cardiac death compared with an ACE inhibitor. Interestingly, in all trials, blood pressure reductions were greater than the RAS inhibitor used as the comparator. The beneficial effects of the valsartan/sacubitril combination are described in detail elsewhere29. Moreover, their striking effects in systolic heart failure patients and the prospects of benefits in future outcome trials for heart failure patients with preserved ejection fraction29 begs the question of the potential role of such vasopeptidase inhibition in resistant hypertension.Clinical trial data for LCZ696 demonstrated significantly greater blood pressure reductions compared to valsartan in patients with mild-to-moderate hypertension30, although its current status is not clear.In addition, a dual vasopeptidase inhibitor called daglutril, combining neprilysin and endothelin-converting enzyme inhibition, has been developed and was reported to lower blood pressure in hypertensive type 2 diabetics who were already receiving losartan31. However, data are emerging showing that new anti-diabetic drugs can lower blood pressure, perhaps contributing to their therapeutic effects to improve glycaemic control and cardiovascular outcomes. The glucagon-like peptide 1 (GLP-1) analogue liraglutide reduced blood pressure in hypertensive diabetic patients32. There was a small reduction in blood pressure in the recent LEADER trial, studying over 9,300 patients, in which liraglutide improved cardiovascular outcome  assessed over 3.5–5 years33. Inhibitors of sodium-glucose cotransporter 2, such as empagliflozin, are another new class of anti-diabetic compound that impairs renal glucose reabsorption. In high-risk cardiovascular patients with type 2 diabetes, empagliflozin, added to standard care, lowered the rate of the primary composite cardiovascular outcome and of death from any cause34 and reduced blood pressure versus placebo in patients with type 2 diabetes and hypertension35. Thus, while these compounds are not strictly anti-hypertensive agents, even modest blood pressure reductions are likely to contribute to other cardiovascular protective mechanisms evoked by these novel anti-diabetic agents36.The regulatory requirement to obtain robust cardiovascular safety data to approve new diabetes drugs has increased the number of trials focused on a lack of cardiovascular toxicity rather than examining longer-term studies on the effects of glucose lowering on cardiovascular outcome data1 or type 2 (AT2) receptors. Given the ubiquitous AT1 receptor expression, Ang II and Ang III both evoke predominant AT1 receptor-mediated peripheral vasoconstriction and pressor responses. Interestingly, preclinical studies have shown that centrally administered Ang III more effectively raised blood pressure than did Ang II 38. Such studies provided the rationale for inhibition of APA as a potential therapeutic strategy to treat hypertension39. RB150 is a dimer of EC33, which is a selective APA inhibitor that inhibits the conversion of Ang II to Ang III39. While the clinical efficacy of RB150, also known as QGC001, in the treatment of hypertension is yet to be evaluated, it was well tolerated in healthy male volunteers and did not significantly change heart rate or blood pressure40. However, it remains to be seen if any centrally mediated anti-hypertensive effect of QGC001, due to decreased bioavailability of Ang III in the brain, is offset by an increase in peripheral Ang II accumulation and consequent vasoconstrictor potential in hypertensive patients. It is also less common nowadays for the development of centrally acting anti-hypertensive drugs because of central side effects.Aminopeptidases are involved in the metabolism of Ang II into shorter Ang peptide fragments. Aminopeptidase A (APA) converts Ang II into Ang III by removing N-terminal aspartate, which can also activate AT1 receptor arm of the RAS, there are two separate but related “protective” arms of the RAS, so called because their activation generally opposes AT1 receptor-mediated cardiovascular effects. These include the Ang III/AT2 receptor arm42 and the ACE2/Ang (1–7)/Mas receptor arm45. Within the RAS, there are a number of bioactive Ang peptides in addition to the main effector Ang II. For example, Ang III can also exert more subtle depressor effects and natriuretic responses in preclinical studies that are mediated by AT2 receptor stimulation42. A number of selective AT2 receptor agonists have been developed45, of which compound 21 (C21) has been the best studied in preclinical hypertension-related models. Indeed, selective AT2 receptor stimulation reduces hypertension-induced target organ damage, even in the absence of blood pressure reduction in most but not all instances46. The AT2 receptor field has been hampered by a lack of selective ligands, but there is great interest in the clinical effects of AT2 receptor activation and the potential for additive effects of AT2 receptor agonists with conventional RAS blockade. However, C21 has only entered phase I testing in healthy volunteers at this stage, so this field will be watched with interest.In addition to the ACE/AT47. Given the ability of ACE2 activation to facilitate conversion to the “cardioprotective” Ang (1–7) at the expense of (decreasing) levels of the substrate Ang II, research has focused on developing compounds that activate these RAS pathways. Indeed, there are a number of Mas receptor and AT2 receptor agonists45 that have not yet progressed beyond preclinical studies. Moreover, there are compounds that activate ACE2, such as diminazene aceturate (known as DIZI). Interestingly, this ACE2 activator, structurally related to xanthenone, is used clinically for the treatment of the parasitic disease African trypanosomiasis47, so there is already translational potential. Similarly, recombinant ACE2 (rACE2) has been used in preclinical studies where it has been reported to lower blood pressure and exert cardioprotective effects47. Human rACE2 was tested in phase I studies in which single intravenous injections of varying doses were given to healthy subjects48. Human rACE2 was well tolerated and increased plasma ACE2 without affecting blood pressure and evoked a prolonged, marked suppression of plasma Ang II levels48. Clearly, additional clinical trial data are required to assess the veracity of this form of therapy.ACE2 is a carboxypeptidase that differs to ACE in that it cleaves one (not two) amino acids from the C-terminal of peptides. In the context of RAS, Ang I and Ang II can be converted by ACE2 to Ang (1–9) and Ang (1–7), respectively. In particular, there is much preclinical evidence to indicate that Ang (1–7) can protect against hypertension-related target organ damage via another G-protein-coupled receptor known as the Mas receptor20, the effects of renal denervation are highly relevant and very topical. This interventional treatment was aimed at ablating the effects of augmented sympathetic drive to the kidney, which contributes to the pathogenesis of hypertension primarily owing to sympathetic activation and the release of renin. To this end, Symplicity HTN-149 and Symplicity HTN-250 trials used a minimally invasive catheter-based radiofrequency strategy to cause renal nerve denervation in an attempt to lower blood pressure in patients with TRH. These trials were very successful, with the reductions in blood pressure maintained for up to 3 years in many cases52. However, procedural concerns were raised about the study design (including lack of blinding or true resistant hypertension53), which prompted the large multi-centre, sham-controlled, blinded Symplicity HTN-3 trial54. Surprisingly, no significant blood pressure reductions were observed between the renal denervation and the sham groups after 6 months of follow-up54, which has resulted in considerable controversy in the field of renal denervation. This discrepancy from earlier trials has been attributed to incomplete ablation after renal denervation, since later analysis revealed that complete renal denervation was rarely achieved in patients in Symplicity HTN-355, most likely related to the inexperience of many trial operators and lack of procedural checks56. Recently, it has been cogently argued that the rationale for renal denervation for TRH remains valid56. However, “smarter” renal denervation trials, with respect to design, location of ablation energy delivery, and testing of achieved denervation56, are awaited with intense interest. The devil will be in the detail as to how this field, which holds great promise, progresses.Of the non-pharmacological methods being investigated to lower blood pressureDespite the effectiveness of the currently available anti-hypertensive medications, there is always a need for novel treatment strategies that are more effective in particular hypertensive patient groups and to provide additional resources to tackle TRH. Most of the newer drugs mentioned, including the emerging therapies, are likely to be useful for lowering blood pressure and/or limiting hypertension-related target organ damage.


Hypertension is highly prevalent in Florida, but surveillance through the Behavioral Risk Factor Surveillance System (BRFSS) is limited to self-reported hypertension and does not capture data on undiagnosed hypertension or measure blood pressure. We aimed to characterize the hypertensive population in the OneFlorida Clinical Research Consortium by using electronic health records and provide proof-of-concept for using routinely collected clinical data to augment surveillance efforts.We identified patients with hypertension, defined as having at least 1 outpatient visit from January 2012 through June 2016 with an ICD-9-CM or ICD-10-CM diagnosis code for hypertension, or in the absence of a diagnosis, an elevated blood pressure (systolic ≥140 mm Hg or diastolic ≥90 mm Hg) recorded in the electronic health record at the most recent visit. The hypertensive population was characterized and mapped by zip code of patient residence to county prevalence.Of 838,469 patients  who met the criteria for hypertension, 68% had received a diagnosis and 61% had elevated blood pressure. The geographic distribution of hypertension differed between diagnosed hypertension  and undiagnosed hypertension . Uncontrolled hypertension was concentrated in southern Florida and the western Panhandle.Our use of clinical data, representing usual care for Floridians, allows for identifying cases of uncontrolled hypertension and potentially undiagnosed cases, which are not captured by existing surveillance methods. Large-scale pragmatic research networks, like OneFlorida, may be increasingly important for tailoring future health care services, trials, and public health programs. Hypertension is a leading modifiable risk factor for cardiovascular disease, chronic kidney disease, stroke, and death ,2 and thThe implementation of public health programs to mitigate the burden of hypertension is hampered by a lack of information about the disease’s regional distribution, especially the distribution of undiagnosed and uncontrolled hypertension. Most published data on these measures come from surveys conducted nationally, which, because of their sampling design, do not allow for detailed analysis below the state level  or provide data on self-reported measures of hypertension but no clinical correlates . Thus, a gap exists for regional or statewide evidence, and new data sources are needed to better surveil disease prevalence, treatment, and health inequities at the state and local level .The development of large-scale clinical research networks has created opportunities for studying diseases and their treatments through use of “real world” electronic health record (EHR) data. Such networks, particularly those that integrate clinical data from routine medical care, can augment existing surveillance efforts with more detailed, longitudinal patient-level data. We examined data on hypertension in the OneFlorida Clinical Research Consortium , a collaborative research network of health systems, providers, and insurers in Florida, the third most populous state, which has a diverse population and is a bellwether for demographic trends. The primary objective of this study was to characterize the hypertensive population in OneFlorida . Second,We performed a retrospective cross-sectional study of data on adult patients in the OneFlorida Data Trust, a component of OneFlorida . OneFlor through the most recent date (June 2016) for which the Data Trust data had been certified as research ready by the PCORnet Coordinating Center at Duke University. To be certified as research ready, data must meet predetermined thresholds for the percentage of fields containing valid data, the patterns of health care use among patients, and the amount of missing data. We included only patient visits coded as ambulatory visits or outpatient encounters. Being designated as hypertensive was operationalized by 1) an ICD-9-CM fication ) , recorded blood pressure, and clinical characteristics (body mass index [BMI] and comorbidities). If BMI was not recorded, we calculated BMI from weight and height measurements at that visit. The following measurements were considered errors, recoded as missing, and excluded from analysis: BMI of less than 5 or 90 or more, a height of less than 3 feet or 8 feet or more, and a weight of 40 pounds or less or 500 pounds or more. We also assessed the type of antihypertensive medications used by each patient during the 4.5-year study period.We used descriptive statistics to characterize the OneFlorida hypertensive population overall and by age group . Hypertension prevalence was defined as the proportion of patients meeting our hypertension criteria among all patients with at least 1 ambulatory visit or outpatient encounter during the study period. Prevalence of uncontrolled blood pressure was defined as the proportion of patients with systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more, or both, among all patients with hypertension who had at least 1 valid blood pressure measurement recorded. No weightings were applied for the overall characterization. Because our intention was to assess the suitability of using OneFlorida data to augment existing surveillance efforts by qualitatively assessing the extent to which these data accord with data from previous research, we opted not to conduct statistical tests for comparisons across age groups or other subgroups.Using zip code of patient’s residence, we aggregated counts  to Zip Code Tabulation Areas (ZCTAs) and county equivalents. Of 983 ZCTAs in Florida that contain residential housing, 90% exist completely within the boundary of a single county. ZCTAs that are bisected by a county boundary comprise only 1% of Florida’s population. We matched zip codes to counties by using the US Census Bureau relationship files and constructed county-level equivalent counts of hypertension prevalence and uncontrolled blood pressure prevalence. ZCTA counts were aggregated to create county rates, by quintile, and mapped, by using ArcGIS (Esri) to characterize distributions geographically.Among 3.01 million adults included in this analysis, 838,469 were characterized as having hypertension. Of these, 570,664 (68.1%) were based on ICD-9-CM or ICD-10-CM diagnosis and 267,805 (31.9%) were based on blood pressure measurements  . The oveCounties with the highest prevalence of diagnosed hypertension and the highest overall prevalence of hypertension (diagnosed and undiagnosed) were concentrated primarily in northern Florida , panel CAmong patients with hypertension, most were women (53.7%), white (65.6%), and non-Hispanic (76.7%). Among those with data on BMI (90.2% of hypertensive patients), 48.4% had a BMI of 30.0 or more, and 31.3% had a BMI of 25.0 to less than 30.0. The most prevalent comorbidities were dyslipidemia (38.9%), diabetes (24.2%), and coronary artery disease (13.3%); the prevalence of comorbidities differed by age group .Blood pressure data were available for 722,623 (86.2%) hypertensive patients. Mean (standard deviation [SD]) blood pressure in the population was 139 (19) mm Hg systolic and 80 (12) mm Hg diastolic. Increasing age was associated with increased mean systolic blood pressure and decreased mean diastolic blood pressure. Overall, 61.0% had uncontrolled blood pressure. Among hypertensive patients, the prevalence of blood pressure control was lowest among those aged 18 to 44 (28% controlled) but was generally similar (~40% to 42%) across older age groups.Collier County, in southwestern Florida, had the highest prevalence of uncontrolled blood pressure (85.6%), regardless of diagnosis, and the coastal-retirement destination counties of Monroe, Indian River, St. Lucie, and Martin each had a prevalence of 78% or more , panel AData on prescribed medications were available for 519,879 patients, or 62.0% of the overall hypertensive population. Of these, 13.2% were prescribed no medications, 27.9% were prescribed medications other than antihypertensive medications, and 58.9% were prescribed at least 1 antihypertensive medication. Among those with diagnosed hypertension , the mosOur study, to our knowledge, is the largest cross-sectional study of Floridians with hypertension and among the first wide-scale efforts to use clinical data from real-world usual care in a health system that spans an entire state. We observed an overall hypertension prevalence of 27.9% among adult patients with at least 1 ambulatory visit or outpatient encounter. Of these, approximately two-thirds had diagnosed hypertension, and the remainder had elevated blood pressure but no diagnosis. This overall prevalence is lower than the 33.5% of adults in the 2015 BRFSS who reported having ever been told they had high blood pressure . As we aOur data source allowed for mapping of hypertension prevalence. We observed the highest overall hypertension prevalence in northern Florida, an area that is demographically and geographically similar to much of the southeastern United States, which has among the highest rates of hypertension in the nation. Not coincidentally, the areas in northern Florida also comprise the southern border of the US stroke belt, which historically has had higher levels of age-adjusted stroke mortality than other areas of the United States. Our results are also consistent with those of previous studies that combined NHANES and BRFSS data and showed that the highest prevalence of hypertension in Florida is in the northern part of the state . LikewisFinally, we explored data on common antihypertensive medications to better understand their real-world use among Floridians with hypertension. Not surprisingly, the 4 most commonly used classes of medication were ACE inhibitors, β-blockers, calcium channel blockers, and diuretics . These data appear consistent with national estimates based on NHANES data from 2001 to 2010 . Our datOur study and data source have several strengths. First, we used clinical data, rather than patient-reported data, to identify hypertension cases. Our approach allowed for ascertaining cases of physician-diagnosed hypertension and cases of hypertension with no documented diagnosis. Detection of hypertension, particularly cases for which no diagnosis is documented, may allow for more focused interventions in the health care system, public health sector, or both, to prevent the adverse sequelae of uncontrolled blood pressure. Second, the detailed information on patients in the OneFlorida Data Trust allowed for a more granular view of hypertension in Florida than provided by surveys such as BRFSS and NHANES. Our study produced data on overall hypertension prevalence; prevalence by age, sex, race/ethnicity, and geographic region; and detailed characterization by age group. Areas of future study include analyzing time trends in hypertension prevalence, blood pressure control, antihypertensive treatment, and other parameters related to hypertension for the overall population in Florida and subgroups. Furthermore, development and validation of outcome measures in the PCORnet common data model will allow for a transition from descriptive studies of individual populations  to use of inferential statistics to better understand care and treatment effects across larger populations from which these patients are sampled. Third, because these data are collected as part of routine care, they do not require substantial financial investment to update regularly, beyond the initial and ongoing infrastructure costs for the clinical data research network. Although such data are not expected to supplant ongoing surveillance efforts, they may be a useful and cost-effective adjunct to identifying disparities and areas of need for public health investment.Several limitations should also be noted. First, our data are not necessarily generalizable to the entire adult population of Florida or adult populations in other states. Although OneFlorida partners provide care for nearly half of all Floridians, outpatient data were available only for approximately 25% of Floridian adults when we conducted this study. Moreover, systematic differences exist between persons who engage the health care system and those who do not. For example, patients in the health care system are sicker than the general population, which could prompt overestimation of hypertension prevalence in the general population. Conversely, some adults with low socioeconomic status and who lack medical insurance  may forgo routine outpatient visits. Data on such patients, who are at elevated risk of having both hypertension and uncontrolled blood pressure , would nWe analyzed data on more than 3 million patients in OneFlorida for evidence of hypertension and found an overall prevalence of 27.9%. We further provided proof-of-concept for the use of a large, integrated, clinical data repository in augmenting surveillance of chronic diseases such as hypertension. The advantages to our approach include the use of existing clinical data , which allows for identifying patients with uncontrolled blood pressure but no hypertension diagnosis, and the ability to parse outcomes on the basis of detailed patient-level data such as age, race/ethnicity, and geographic location. As the nation moves toward the goal of creating health systems in which patient care informs evidence as much as evidence informs patient care, pragmatic research networks, like OneFlorida, may be increasingly relied on to inform future health care, support the design and conduct of clinical trials, and enhance public health efforts.