Presence of macroalbuminuria increased the risk for DME by 177%. Retinopathy remains a significant clinical problem in patients with type 2 diabetes. Metabolic control and blood pressure are relevant factors amenable to treatment. Concomitant kidney disease identifies high risk patients and should be emphasized in interdisciplinary communication.To assess the prevalence and risk factors for early and severe diabetic retinopathy and macular edema in a large cohort of patients with type 2 diabetes Retinopathy grading  and risk factors of 64784 were prospectively recorded between January 2000 and March 2013 and analyzed by Kaplan–Meier analysis and logistic regression. Retinopathy was present in 20.12% of subjects, maculopathy was found in 0.77%. HbA1c > 8%, microalbuminuria, hypertension, BMI > 35 kg/m The eye is considered the primary target of chronic hyperglycemic damage in type 1 and type 2 diabetes . Both, eAnother modifiable risk factor for the development of DR in type 2 diabetes is smoking. Again, studies revealed conflicting results. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy Study (WESDR), smoking was not a factor contributing to DR development, and in the United Kingdom Prospective Diabetes Study (UKPDS) smoking was even protective , 9.As a third at least partially modifiable factor, diabetic kidney disease aggravates retinopathy progression. In type 1 diabetes, concomitant nephropathy in a patient with retinopathy is the strongest predictor for progression .Whether Therefore, the aim of the present study was to identify the prevalence of diabetic retinopathy, the modifiable and non-modifiable risk factors in patients with type 2 diabetes, with a particular focus on parameters of the metabolic syndrome and on the diabetic kidney. We took advantage of a large, mostly Caucasian population from Germany and Austria reflecting current diabetes care according to identical guidelines and ascertained by comparable technology.Analysis of anonymized routine data within the German/Austrian Diabetes Prospective Documentation Initiative (DPV) was approved by the Ethics Committee of the Medical Faculty of the University of Ulm, as reported earlier .www.leitlinien.de/mdb/downloads/nvl/diabetes-mellitus/dm-therapie-1aufl-vers4-lang.pdf). Patients younger than 40 years of age were excluded, as differentiation from type-1 diabetes is more difficult in this age group. Patients with an onset of type-2 diabetes earlier than age 40 are a special subgroup, which differs from the typical type-2 patient with onset above 40 years of age [Methods of data collection including participating centers (see acknowledgment) have been published . Detailss of age , 16.By March 2013, 195145 patients from 328 diabetes centres in Germany and Austria were continuously monitored. We excluded centres who reported lower than 50% retinopathy assessment rates leaving 85813 patients from 166 recruiting centers in Germany and Austria. Complete data sets on retinal examination and covariates were available from 64784 patients.Screening and grading for the presence of retinopathy and DME was performed in accordance with published guidelines and details of the grading for retinopathy have been previously reported , 13. AnyWe included the following independent risk factors into the analysis: age, diabetes duration, gender, HbA1c, hypertension, dyslipidemia and smoking (current and previous). All parameters were assessed according to established procedures.We used the SAS 9.3 statistics software package  for data evaluation and analysis. This included descriptive analysis, Wilcoxon rank sum test for comparison of patient groups , survival analysis using Kaplan-Meier method to describe the presence of retinopathy in relation to covariate stratification, and logrank statistics for homogeneity testing among strata. Multiple logistic regression analysis was used to evaluate relative contributions of covariates (odds ratios and 95% CI) to the risk of early and severe retinopathy, and on macular edema. Bonferroni stepdown correlation of p-values (method of Holm) was used to adjust for multiple testing.Patient characteristics are summarized in Kaplan-Meier analysis revealed that after a diabetes duration of 20 years, 38.2% had any retinopathy, and after 40 years, the proportion had increased to 89.7%. The corresponding figures for severe eyes disease were 19,7% and 67,5%, and for DME 1,6 and 9,8%, respectively.The cohort differed significantly in retinopathy-free survival when grouped for long-term HbA1c above or below a level of 7% (53mmol/mol) . Above this threshold for metabolic control, no significant difference in time to retinopathy was identified between groups.We analyzed the effect of blood pressure on retinopathy onset using cutoffs between 130/80 and 140/90 mm Hg. There was a constant, highly significant difference in time to retinopathy over the entire range , suggesting the absence of any threshold below which retinopathy is being prevented.2to identify a difference in time to retinopathy by univariate analysis and found a significantly higher risk of retinopathy in the obese subgroup .BMI was analyzed for its potential to influence retinopathy development. We used the WHO cut-off of 30 kg/mBoth, smoking  and male gender  were also significant contributors in univariate analysis.2), and smoking, but not dyslipidemia were independently related to any retinopathy. When systolic and diastolic blood pressure were included, only diastolic pressure was significantly contributing.As several of the above factors are interrelated see , we usedNine percent of the entire cohort (5887 patients) had more severe retinopathy. Bivariate analysis revealed glycemic control, blood pressure, dyslipidemia, BMI, but not gender and smoking as relevant contributors. In the multivariable analysis, glycemic control (HbA1c threshold 8% (64 mmol/mol)), blood pressure (threshold 140/80 mm Hg), dyslipidemia, and smoking prevailed . The anaDME was reported in 501 patients (0.77%). This subgroup had the highest age, the longest diabetes duration and the highest proportion with HbA1c > 7% (53 mmol/mol) and hypertension (RR>140/80 mmHg) despite the highest proportion receiving antihypertensive medication  and insulin. Using the Wilcoxon test, age, diabetes duration, HbA1, and LDL-C, but not BMI, blood pressure and HDL-C, triglycerides and smoking were significantly associated with the development of DME, while gender, blood pressure (≥ 140/80 mm Hg) and the use of insulin were significant contributors in bivariable analysis after Bonferroni correction. Multiple regression analysis identified glycemic control, hypertension and dyslipidemia as the strongest covariates .Finally, the impact of diabetic nephropathy on the development of any retinopathy, severe retinopathy and DME was explored. Microalbuminuria increased the risk for retinopathy by 15.6%  and macroalbuminuria increased the risk by 28.4%. The presence of microalbuminuria on severe retinopathy raised the risk of retinopathy to 20.4%, and of macroalbuminuria raised the risk to50.5% .While microalbuminuria increased the risk for DME by 31.3% , macroalbuminuria resulted in an excess risk of 177% for DME .Our study in a large cohort of subjects with type 2 diabetes revealed that retinopathy remains a significant microvascular complication with glycemia and blood pressure as the most important modifiable risk factors. As a novelty, our data identify macroalbuminuria as the strongest risk factor for DME. Obesity has a rather modest role in early, but not in severe retinopathy.The significance of macroalbuminuria for vision threatening diabetic eye disease is clearly evident from our data. This is of particular clinical importance for two obvious reasons: a. a subgroup of patients exists with an extraordinary malignant clinical course, and b. this subgroup may not benefit from intravitreal before albuminuria is not improved by optimal medical care.While the relative effect size of microalbuminuria on the three prespecified retinal phenotypes falls in between glycemia and blood pressure, macroalbuminuria exceeds this effect by at least twofold. The WESDR study did not find significant associations between early stages of kidney and retina lesions, but only when lesions were advanced (gross proteinuria and CSME) . Higher Mechanistically, vasoregression and increased capillary permeability are the two fundamental characteristics of early DR. Vascular hyperpermeability is a possible shared pathogenetic mechanism between the eye (DME) and the kidney . Knudsen et al. found that albuminuria and the rate of transcapillary albumin escape correlates with diabetic macular edema . The def2) [We observed an effect of obesity on DR. This result is consistent with the Hoorn Study, however with a much smaller effect (odds ratio for retinopathy 3.52 for a BMI range between 28.4 and 45.7 kg/m2) . Of note2) . ADSCs a2) , and can2) . Neither2) .Hyperglycemia, hypertension, and dyslipidemia are well defined modifiable risk factors, which are confirmed as such in our study. Given the size of the study population, calculated ORs reflect to a certain degree the strengths of the individual factors, glycemia being the strongest for any and severe retinopathy. This is in agreement with multiple previous studies, and also with a recent pooled analysis of the global prevalence of and risk factors for DR , suggestSome of the strengths of the study are also weaknesses. Ethnicity, sample size, consistency in phenotyping, and risk factor associations for severe retinopathy stages  reduces heterogeneities usually present in other studies. The main weakness of the study is that diabetic retinopathy was not diagnosed by fundus photography, but by fundus examination by retinal specialists according to standardized protocols. Given the known kappa statistics for diagnosing DME by funduscopy as compared with fundus photography, we might envisage an underestimation of DME in our study . HoweverWe consider our study group being representative because of the only modest differences in relevant risk factor between the group which was included in the study and the group not included because of incomplete retinopathy reporting.In conclusion, our study provides a large-scale estimate of DR and its current risk patterns in modern treatment settings. DR is less frequent than albuminuria in type 2 diabetic patients, and albuminuria is a strong risk factor for severe DR, in particular DME. Patients with type 2 diabetes and albuminuria should be carefully monitored for progressive eye disease, and patients with DME should be evaluated for concomitant kidney disease.


Fractional exhaled nitric oxide (FeNO) is a convenient, non-invasive method for the assessment of active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid diagnosis and monitoring in several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory, infectious, and/or immunological conditions. In this short review, we provide an overview of several clinical studies and discuss the status of potential applications of NO measurements in clinical conditions beyond asthma. In asthma, fractional exhaled nitric oxide (FeNO) is a well-established, non-invasive online method for the assessment of active, mainly T-helper 2 (Th2) -driven airway inflammation, often associated with airway eosinophilia, which is sensitive to treatment with inhaled corticosteroids (ICSs) . In the More recently, FeNO has been evaluated in several other respiratory, allergic, infectious, and/or immunological conditions. In this short review, we provide an overview of studies applying FeNO measurements in several clinical conditions  and undeα), chemokines (IL-8), and acute phase proteins, such as C-reactive protein (CRP) , causing progressive airflow limitation, airway remodeling, and dyspnea. Several studies have underscored the importance of the underlying systemic inflammation in the pathophysiology of COPD –5. The pin (CRP) –8. In liin (CRP) . FeNO lein (CRP) . Patientin (CRP) . In addiin (CRP) . Periphein (CRP) , 14. Surin (CRP) .In asthma, FeNO has been regarded as a marker of ICS responsive, Th2–driven airway inflammation, often associated with airway eosinophilia, with increased FeNO levels during asthma exacerbations. In COPD, exacerbations often follow respiratory infections that can be reflected by increases in FeNO levels  and syst1 and non-specific airway hyperresponsiveness  has gained attention as it is now recognized that these patients have more frequent and more severe exacerbations . This COsiveness . ACOS has  is characterized by a defect in a chloride ion channel across the respiratory epithelium, among other organs, that leads to increased mucus viscosity, accumulation of mucus, chronic infection, and inflammation. FeNO levels are reported to be decreased in CF, with further decreases following a mouthwash . The degThe lower NO production is probably related to the reduction of NO production as both constitutional , 28 and In CF, supplementation with L-arginine by infusion , oral adSeveral contradictory reports on levels of CalvNO in CF patients have been published , 45. CalEven if there is evidence for decreased levels of FeNO in CF patients with a link toward at least lower lung function, there is still lack of data regarding the role of repeated FeNO measurements, for example, in the annual follow-up or follow treatment with antibiotics in CF. Presently, there is no evidence for a role for CalvNO measurements in the management of CF.Prematurity and its main respiratory complication, bronchopulmonary dysplasia (BPD), are potentially associated with lifelong lung function abnormalities, but the inflammatory component is most prominent during the neonatal period. Preterm infants with BPD show a weak postnatal increase in FeNO on day 28 as well as at a postmenstrual age of 49 weeks, particularly in those developing moderate or severe BPD , 48. Chivia activation of signal transducer and activator of transcription (STAT)-1 -1 . In cont(STAT)-1 , and nei(STAT)-1 –67. InteIn summary, FeNO measurements do not seem to be useful in the management of respiratory infections. It is suggested that if a patient with (suspected) asthma reports recent or ongoing symptoms of common cold, the patient should be reexamined with regard to FeNO after a symptom-free interval of at least 3–4 weeks.More than 15 years ago, Silkoff et al.  showed iThe mechanism underlying increased NO formation seen in unstable patients after lung transplantation is not entirely clear. Early on, Gabbay et al.  reportedSystemic sclerosis (SSc) is a connective tissue disorder of unknown etiology that is often complicated by pulmonary involvement, with pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) being the major causes of death. In early studies, it has been presented that FeNO is increased in SSc patients , and speSo far, application of FeNO measurement in the management of SSc and ILD patients is not supported by data, whereas increased CalvNO concentrations could be used to non-invasively assess the extent of ILD in conditions including SSc.PAH is characterized by an increase in pulmonary arterial pressure and in pulmonary vascular resistance. This is probably because of an imbalance of local vasodilators and vasoconstrictors. For example, elevated levels of endothelin-1, with vasoconstrictor properties, and decreased levels of NO, with vasodilator properties, or NO metabolites have been described . IdiopatFeNO levels have been shown to negatively correlate with pulmonary arterial pressure, assessed by echocardiography . Recent Presently, insufficient evidence exists for recommending routine use of FeNO measurements to predict or follow response to specific PAH-therapy and hence, additional studies need to be conducted.In patients with liver cirrhosis and/or portal hypertension, hepatopulmonary syndrome (HPS) is characterized by an abnormal oxygenation  due to intrapulmonary vascular dilatations  . The firWhether FeNO or CalvNO measurements can serve to assess the development and the severity of HPS or in the management of this condition awaits further investigation.In parallel to exhaled NO measurements, the value of nasal NO (nNO) samplings in clinical conditions including allergy, primary ciliary dyskinesia (PCD), and CF has been investigated. nNO is produced in the upper airway compartment, especially within the epithelium of the paranasal sinuses, and can be reproducibly sampled , 110. CuIn patients with untreated allergic rhinitis (AR), nasal eosinophilia has been shown to be accompanied by increased nNO levels as a result of enhanced iNOS expression within the nasal epithelium . Pro-infStaphylococcus aureus conditions, we need to more precisely define the cut off values and potential confounders. A high or low value in one condition does not necessarily apply in another. Taking smokers with COPD as an example: smoke exposure suppresses FeNO. However, within the group, it is clear that patients responding to ICS have relatively higher FeNO values compared to non-responders . Thus a According to current recommendations, FeNO is measured at a flow rate of 50 mL/s, reflecting NO production from the central airways . MeasuriPartly for economic reasons and limited availability, FeNO is presently measured only within a limited number of clinical settings and only at a few time points. However, as disease activity shows day to day variation, and even variation within the same day, it is desirable to perform more frequent measurements. An increased diurnal variability in FeNO levels was associated with loss of asthma control whereas peak flow variability did not differ between controlled and uncontrolled asthmatics . We alsoStill today, the majority of clinical decision making is being based on symptom control and lung function parameters. For the future, we will need reliable and simply measurable biomarkers that can guide our clinical and treatment decisions and help us to monitor treatment effects as well as predicting future deteriorations. Together with blood eosinophils, FeNO is the most commonly used biomarker not only in research but also in clinical practice. In asthma, the clinical importance of FeNO as a marker of Th2-driven inflammation that is likely to respond to ICSs is well-established. However, the role of FeNO in other obstructive airway diseases such as COPD and ACOS remains to be further validated following initial studies showing that increased FeNO levels can predict corticosteroid responsiveness , 135. In


Different treatment strategies are suggested for special situations. Hypertension is common in the elderly and frequently accompanied by or complicates other clinical conditions such as metabolic syndrome, coronary artery disease, heart failure, stroke, diabetes mellitus and chronic kidney disease. Emphasizing out-of-office BP measurements, white coat hypertension (HTN) and masked HTN are acknowledged as new categories of BP by performing ABPM or home BP monitoring. Although the clinical evidence is not established, some expert opinions exist for these two categories. For most subjects with white coat HTN, lifestyle modifications and regular BP monitoring are recommended. Despite the weak evidence, when metabolic disturbance and/or subclinical organ damage occur with white coat HTN, pharmacologic treatment as well as lifestyle modifications could be considered ,2. StricMany hypertensive patients have obesity and metabolic abnormalities with alterations of lipid and glucose metabolism. Furthermore, subclinical organ damage is not uncommon in these patients. Metabolic syndrome involves abdominal obesity, dyslipidemia, dysglycemia, and raised BP. The criteria for clinical diagnosis of metabolic syndrome are 1) abdominal obesity; 2) fasting glucose ≥100 mg/dL (diabetes included); 3) triglyceride ≥150 mg/dL; 4) HDL cholesterol <40 mg/dL in men and <50 mg/dL in women; and 5) BP ≥130/85 mm Hg. Presence of three or more of these criteria confirms the diagnosis of metabolic syndrome .The prevalence of metabolic syndrome has been increasing for the past 10 years, as reported in the Korean National Health and Nutritional Survey. Twenty-five to thirty percent of Koreans over 20 years have metabolic syndrome. However, the prevalence of metabolic syndrome is much higher in hypertensive patients, reaching two times that of the adult population .In Western countries, people with metabolic syndrome are at 1.5 to 2 times higher risk of CV events and death than those without metabolic syndrome,  and inciIn hypertensive patients with metabolic syndrome, antihypertensive treatment aims mainly to prevent CV morbidity and mortality, while lowering or preventing incident diabetes. Antihypertensive treatment in non-diabetic patients with metabolic syndrome is discussed below, while that in diabetic/cardiovascular disease (CVD) patients with metabolic syndrome are discussed in other respective sections of the special situations chapter. Lifestyle modifications, especially weight reduction and regular exercise, are strongly recommended in all hypertensive patients, as they decrease BP, improve metabolic abnormalities, and delay incident diabetes.Antihypertensive drugs to be selected should have adequate BP lowering efficacy, as well as favorable or neutral effects on insulin sensitivity and metabolic abnormalities. Thus, angiotensin-converting enzyme ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium antagonists are preferred. Among beta-blockers, vasodilating beta-blockers such as carvedilol and nebivolol can be selected when angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are avoided. Carvedilol and nebivolol have no unfavorable effects on glucose and lipid metabolism -17. ThesThiazides and thiazide-like diuretics are avoided as monotherapy or at high dose but used as combination therapy or at low dose. These diuretics can induce hypokalemia and new onset diabetes and have unfavorable effects on lipid metabolism. Combination with old generation beta-blockers is avoided. They can be used with potassium-sparing diuretics. The preferred approach is combination with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to minimize their unfavorable effects on glucose and lipid metabolism.The combination of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and thiazide diuretics is less favorable in terms of CV events and incident diabetes than combination of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and calcium antagonists .The prevalence of HTN is twofold in diabetic patients compared to that in the general population, and the occurrence of diabetes is 2.5 times higher in hypertensive patients ,19. The The recommended target for BP in diabetic patients is <140/85 mm Hg. In previous guidelines, the recommended BP was <130/80 mm Hg or <140/80 mm Hg in diabetic patients . HoweverAccording to a recent meta-analysis, all classes of antihypertensive agents, such as ACE inhibitors, ARBs, calcium channel blockers, beta-blockers, and diuretics, are useful . ACE inhThe treatment of HTN in older adults reduces the occurrence of vascular disease and mortality. The benefit of treatment is also observed with regard to isolated systolic HTN. Accordingly, HTN needs to be actively diagnosed and treated in older adults .However, the pharmacological treatment of stage I HTN in patients aged 80 years or older remains undetermined. Thus, the characteristics of the patient should be considered. The characteristic findings in elderly hypertensive patients are increased SBP and pulse pressure due to increased central arterial stiffness. Moreover, atherosclerotic renovascular HTN is commonly observed. Non-dipper, increased daytime BP variability, and orthostatic or postprandial hypotension are also characteristic findings in elderly patients with HTN.The non-pharmacological treatment in elderly HTN patients is effective; however, the impact on patients’ quality of life should be considered . The tarThe initial dose of the pharmacologic treatment is reduced by half in younger patients and gradually increased. Elderly hypertensive patients without comorbidities should be treated with ACE inhibitors, angiotensin receptor blockers, calcium antagonists, and diuretics -36. BetaHTN is a major risk factor of coronary artery disease and is associated with the occurrence of myocardial infarction . The incThe preferred drugs within 1 month after acute myocardial infarction are beta-blockers  and angiHTN is the most important risk factor in heart failure . Most BPAtrial fibrillation is frequently observed  and prevThe progression of carotid atherosclerosis is decreased by lowering the BP. For this purpose, calcium antagonists and ACE inhibitors are superior to beta-blockers and diuretics ,68.Most antihypertensive drugs decrease vascular stiffness because lowering the BP decreases vascular wall stress and pulse wave velocity. Other than the BP lowering effect, inhibitors of the renin-angiotensin-aldosterone system decrease the pulse wave velocity, regardless of BP, -71 whileIt is important to control the CVD risk factors because patients with peripheral artery disease have a higher risk of CV mortality  . LowerinLifestyle modifications such as salt restriction, weight control, moderation of alcohol intake, and regular aerobic exercise are very important. Pharmacologic treatment consists of ACE inhibitors, ARBs, and aspirin. ACE inhibitors decrease long-term CV events from either BP lowering effects or indirect BP lowering effects ,75. Howe2), urinary abnormalities including albuminuria , hematuria and pyuria, electrolyte disturbances caused by tubular dysfunction, renal structural abnormalities detected by imaging or biopsy procedures, and renal transplants [Chronic kidney disease (CKD) is defined by the presence of kidney injury for ≥3 months, with the markers of kidney injury being a decrease in estimated glomerular filtration rate  and Kidney Disease Outcomes Quality Initiative (KDOQI) recommended a BP target of <130/80 mm Hg in all CKD patients ,85. HoweLifestyle modification should be used as a basic tool for BP control in all hypertensive CKD patients. Although no large scale randomized controlled trials have reported the effects of lifestyle modification on clinical outcomes in CKD patients, the beneficial effects can be inferred from the results reported in previous studies in general populations -101. ThePharmacologic treatment in CKD patients includes single or multiple antihypertensive therapies to achieve the target BP. Although any antihypertensive can be used in CKD patients, ACE inhibitors or ARBs have been reported to be renoprotective owing to the reduction in proteinuria and improvement in the rate of decline in glomerular filtration rate ,103-105.It should be noted that there are occasions when the BP target and the preferred agent mentioned above may be inappropriate. Treatment should be individualized based on the patient’s age, presence of albuminuria, and comorbidities. Diabetic or elderly patients need to be asked about orthostatic dizziness because of the possibility of postural hypotension -108. ACEThe risk of ischemic and hemorrhagic stroke increases proportionally as the BP increases, with HTN being the most common adjustable risk factor in stroke prevention and having the highest attributable risk for stroke in the population. HTN treatment, particularly SBP control, will remarkably reduce the incidence of stroke. For the management of high BP, lifestyle modification  must routinely precede drug therapy. According to an epidemiologic study, with each increase of 20/10 mm Hg for BP > 115/75 mm Hg, deaths from stroke increased at least twofold. Conversely, a 10/5 mm Hg decrease in BP resulted in a 40% decrease in deaths from stroke . In addiIn general, the BP rises in acute ischemic stroke. It is assumed that BP increases owing to the acute stress, previous HTN, and the automatic compensation in an attempt to maintain perfusion of the brain tissue in the ischemic state . Thus, cWhen thrombolytic therapy is used in the hyperacute period of an ischemic stroke, the incidence of bleeding is closely related to the BP before and after thrombolysis; hence, the target BP should be <185/110 mm Hg. For thrombolytic therapy using t-PA, the drug could only be administered after the BP was <185/110 mm Hg. The antihypertensive regimens consisting of intravenous drugs such as labetalol, nicardipine, diltiazem, nitroglycerin, and nitroprusside are recommended -120.In the acute phase of the ischemic stroke, it is recommended to use antihypertensive drugs only when BP is >220/120 mm Hg, to avoid a decrease in the cerebral perfusion around the infarct area . Target From a theoretical viewpoint, the optimal BP treatment in the acute phase of a parenchymal hemorrhage could prevent re-bleeding and subsequent expansion of a hematoma and edema; hence, it is recommended to lower the BP during the acute phase of the hemorrhage. If the SBP is ≥200 mm Hg or if the mean BP is ≥150 mm Hg, the BP should be lowered by monitoring BP every 5 min. In patients with increased intracranial pressure, BP should be lowered by maintaining the cerebral perfusion pressure between 60 to 80 mm Hg using an intracranial pressure monitoring device only when the SBP is >180 mm Hg or the mean BP is >30 mm Hg. Because a sudden drop of BP during the acute phase is associated with higher mortality rates, it is recommended to maintain a cerebral perfusion pressure of ≥60 mm Hg. When the SBP is 180 mm Hg or the mean BP is 130 mm Hg—as long as there is no evidence of increased intracranial pressure, with the assessment of BP every 15 min—the BP should be lowered below the level of 80% of baseline BP, 160 mm Hg in SBP and 90 mm Hg in DBP, or 110 mm Hg in the mean BP. The antihypertensive regimens including intravenous drugs such as labetalol, nicardipine, diltiazem, nitroglycerin, and nitroprusside are recommended . DespiteHTN treatment as a measure of secondary prevention after stroke significantly reduces mortality and the recurrence of stroke or vascular diseases ,125,126.In patients with aortic aneurysm, it is strongly recommended to lower the BP to the lowest levels tolerated by the patient . Beta-blErectile dysfunction in hypertensive patients is considered to be one of the CV risk factors  associatIn general, the prevalence of erectile dysfunction in patients with HTN is reported to be 0% to 25%, but its evaluation is difficult because of the impact of the underlying diseases. Erectile dysfunction related to the administration of a specific drug is usually observed within 4 weeks. If the association is clear, the drug could be replaced, but the possibility that the preexisting peripheral vascular disease is exaggerated should be kept in mind when the drug is replaced. Beta-blockers and diuretics are known to cause erectile dysfunction, and ACE inhibitors and calcium antagonists are neutral, whereas ARBs are sometimes reported to be beneficial .With respect to the conventional beta-blockers administered for patients with erectile dysfunction, a vasodilating beta-blocker may be an alternative . In patiHigh BP occurring during pregnancy can be divided into four categories: 1) chronic HTN in pregnancy: existing HTN or taking antihypertensive medication before the 20th week of pregnancy, 2) gestational HTN: new HTN diagnosed after the 20th week of pregnancy in the absence of proteinuria, 3) preeclampsia: HTN diagnosed after 20 weeks of pregnancy accompanied by proteinuria , and 4) preeclampsia superimposed on chronic HTN: preeclampsia is diagnosed in the chronic HTN in pregnancy. According to the level of BP, it is classified as mild: 140 to 149 mm Hg/90 to 99 mm Hg, moderate: 150 to 159 mm Hg/100 to 109 mm Hg, and severe: 160/110 mm Hg or higher.Generally, there are few controversies about the drug treatment for BP of >160/110 mm Hg or higher. A study reported that a patient with BP of >150/95 mm Hg is more likely to be hospitalized due to incident stroke during the peripartum period ,134. In Antihypertensive drugs used during pregnancy are methyldopa, labetalol, and nifedipine . The speGestational HTN and preeclampsia are associated with a relatively high risk of developing HTN in the future, and preeclampsia is a risk factor for CVD. Patients with a history of preeclampsia have about a twofold risk for ischemic heart disease, stroke, and venous thrombosis  and a foIn younger population, the woman has lower prevalence of HTN than the man. But after menopause, the prevalence of HTN in women increases rapidly that it catches up the prevalence in men in their 60s. And it becomes even higher than that in men in their 70s or 80s. As for age, the increase in pulse pressure is the same between men and women; however, the SBP and DBP are higher in women after menopause than before menopause. Care should be taken in the diagnosis of HTN in menopausal women, because white coat HTN occurs more frequently in these women.After menopause, weight gain, hormonal changes, and psychological changes occur . EspeciaThere is no difference in HTN treatment between women and men. Additionally, there is no difference in BP reduction and drug effects between women and men . Oral co


Objectives. Hypertension and hypervolemia relationship was proven among renal disease, although it is not known in normal population. Present study determines the fluid distribution defects in relation to blood pressure. Material and Methods. In a population-based survey in Turkey demographics, height, weight, blood pressure, urine analysis, and serum creatinine measurements were recorded. Bioimpedance measured with the Body Composition Monitor. Results. Total 2034 population of 71.6% male, mean age 47 ± 12.6 (18–89) years, systolic blood pressure (SBP) 134.7 ± 20, diastolic blood pressure 77.9 ± 11.6 mmHg. Body mass index (BMI) was 28.5 ± 4.5 (15.8–50.6) kg/m2; overhydration was 0.05 ± 1.05 L. There was a correlation between extracellular water (ECW)/height and SBP . Receiver operating characteristic (ROC) curve with the performance of 0.60 (P < 0.001) that showed cut-off value of ECW/height was 10.06 L/m, with the 69% sensitivity and 45% specificity for SBP: 140 mmHg values. Risk factors for high SBP were increase of ECW/Height, age, BMI and presence of diabetes. ECW/height, SBP, and fat tissue index (FTI) increased in BMI categories  and in diabetics. SBP and FTI were lower in smokers. Conclusions. High blood pressure may be accompanied by increased extracellular volume indices. In the future volume status assessment could be of use in evaluating the effectiveness of pharmacological intervention in the treatment of hypertension. Hypertension is one of the most important health problems in the world. The mortality and morbidity are related to the severity and duration; therefore, early diagnosis and treatment provide favorable clinical outcome. It has been proposed that abnormal ion transport by the kidney and subsequent disruption of body fluid volumes are responsible for the development of hypertension .Etiology has been defined in only 5% of hypertensive subjects, while the essential hypertension is the classification in the majority of subjects meaning that no clear underlying cause can be found. Up to now obtaining data about body fluids have many difficulties; therefore, studies performed in this field were in small size and related to a specific disease group . It is nIn bioimpedance spectroscopy (BIS), complex impedance is measured over a wide range of frequencies and the data are fit to a well-known model of biological tissue. The extracellular and intracellular resistance are obtained by Cole model , 4. TotaA new tool (FMC BCM) (based on plausible scientific principles) has been introduced to the medical field that allows the ECW and ICW (and overhydration) to be measured routinely with reasonable accuracy for the first time in history. This tool has revealed that significant overhydration (OH) is present in 30% of European HD and PD patients  and a stAim of this epidemiologic study is to determine the assessment of body fluids and the estimation of the compartmental distribution in ICW and ECW via BIS in a healthy population and their relation to blood pressure. It is the first study to show the compartmental distribution defects with relation to blood pressure in such a large population.We performed a population-based, national survey in Turkey on population aged over 18 years. All subjects included in this survey gave informed consent to participate in the field study. Exclusion criteria were the presence of pacemaker or defibrillator, artificial joints, pin, or amputation; presence of serious life-limiting comorbid situations, like malignancy; uncontrollable infection; end-stage cardiac, pulmonary, or hepatic disease; and pregnancy or lactating.The study was approved by Turkish Ministry of Health and was conducted in accordance with ethical principles of the Declaration of Helsinki; all patients provided written inform consent.A random sampling was used to select the study participants. A sampling frame was defined as the five official geographical regions of Turkey. The study sample comprised 17 cities including both the city with the highest population and a randomly selected city with a low population in each geographical area.The data were collected through Turkish Population Renal Health Screening Programme organized by Turkish Society of Nephrology. Measurements and interviews of potential participants by specially trained field study teams . During interviews, the study questionnaire included questions on subject demographics current diseases and drugs, family history, and other relevant medical history. In addition, height, weight, and blood pressure were measured. Blood pressure was measured from right arm in sitting position. Bioimpedance measurements were performed in supine position by a trained medical doctor.Spot urine analysis (by dipsticks) was performed before BCM measurement, and results were recorded on the study questionnaire. Urinary measurements were excluded in menstruating women and in all patients suffering from febrile illness . Serum cAfter measurement of body weight and height and with subjects following voiding, bioimpedance spectroscopy (BIS) was measured with the Body Composition Monitor (BCM) from Fresenius Medical Care, Deutschland GmbH. Four electrodes were placed on the right hand and foot on the side contralateral to the arteriovenous fistula, of supine patients. Two electrodes were dorsally placed on the hand in the metacarpophalangeal articulations and in the corpus, respectively, 5 cm apart. The pair on the foot was located in the metatarsophalangeal and in the articulation, 6 cm apart. The BCM analyses total body electrical impedance to an alternate current (0.2 mA) with fifty different frequencies (5–1000 kHertz). First the ECW, ICW, and total body water are calculated via determining electrical resistances. Then values of OH, body mass index, lean tissue index, fat tissue index, and body cell mass are provided by the BCM software .The reference ranges are defined by the 10th and 90th percentiles of the reference population and are specific to age and gender .Serum creatinine levels, estimated GFR, and spot urine microalbuminuria were studied as markers for kidney function. CKD was defined as kidney damage with or without a decrease in GFR, which was calculated using a simplified version of the Modification of Diet in Renal Disease (MDRD) formula [186 × (Scr) − 1.154 × (Age) − 0.203 × (0.742 if woman) × (1.212 if African American)] . Since t2) and fat tissue index (FTI = Fat/height2). The values for LTI and FTI were compared to an age- and gender-matched reference population (n = 1248) [The fluid volumes extracellular (ECW), intracellular (ICW), and total body water (TBW) were determined using the approach described by Moissl et al. . The hyd = 1248) .2).Body mass index (BMI) was calculated as weight (kg)/height  was established as SBP 100–140 mmHg, OH (−1.1)–(1.1) L.Region Dx. SBP 100–150 mmHg and a typical weight gain of (−1.1)–(2.5) L. The selection of 2.5 L is completely arbitrary.Region I. This region represents patients with a OH > 2.5 L and an increased SBP > 140 mmHg. There is a high likelihood that hypertension in these patients is indicative of the gross OH observed.Region I-II. This represents a population with mild elevation of –OH between 1.1 and 2.5 L concomitant with an increased SBP > 150 mmHg.Region II. This represents patients in a state of normohydration, but SBP > 150 mmHg. Patients in this region are clearly hypertensive, but there is far less likelihood that volume is a contributing factor.Region III. It characterises underhydrated patients with normal or low SBP < 140 mmHg.Region IV. This represents patients with gross OH, OH > 2.5 L, and a normal or low SBP ≤ 140 mmHg. In this patient population, the gross OH is not reflected in SBP [d in SBP .t-test or Mann-Whitney U test and categorical variables were compared using Pearson's Chi-square test. Pearson and Spearman correlations were used for the linear relation between two numerical dates. Receiver operating curve (ROC) analysis was used for the detection of cut-off values. Binary logistic regression analysis with forward stepwise method was used for determination of risk factors. P value of less than 0.05 was considered statistically significant for all tests.Statistical analysis was performed with SPSS 18.0 software . Continuous variables were expressed as mean ± standard deviation and categorical variables as numbers and percentages. Continuous variables were compared with the Independent Sample Study cases were aged between 18 and 89, with the mean of 47 ± 12.6 years. Characteristics of the study population were given in Mean BCM measurement quality given by the device itself was 93.22 ± 4.6 percent; measurement duration was 69.2 ± 33.6 seconds.2, body surface area (BSA) was 1.89 ± 0.17 (1.33–2.47) m2, OH (L) was 0.05 ± 1.05 L, OH/ECW (%) was 0.01 ± 5.94, ECW/height was 10.46 ± 1.36 L/m, TBW (L) was 39.9 ± 6.6, ECW (L) was 17.6 ± 2.79, ICW (L) was 22.3 ± 4.15, LTI (kg/m2) was 16.3 ± 2.85, FTI (kg/m2) was 11.9 ± 5.3, adipose tissue mass (ATM) was 32.82 ± 13.32 kg, lean tissue mass (LTM) was 46.44 ± 10.63 kg, and body weight was 79.2 ± 13 kg.Mean systolic blood pressure (SBP) was 134.7 ± 20.0, and diastolic blood pressure was (DBP) 77.9 ± 11.6 mmHg. BMI was 28.5 ± 4.5 (15.8–50.6) kg/mr = 0.21, P < 0.001). There were a strong correlation between BMI and FTI , correlation even more pronounced among females , whereas no correlation between BMI and LTI in both genders but a weak positive correlation in male group . There was a negative correlation between eGFR and ECW/Height .There was a weak positive correlation between ECW/height and SBP .There was a statistical significance in relation to diabetes, smoking habits, and measurement time (whether morning or afternoon) in relation to SBP. In 52.5% of diabetics and 25.8% of cigarette smokers, 32.1% of afternoon measurements had SBP ≥ 140 mmHg, and in 68.2% of nondiabetics and 64.9% of nonsmokers, 61.2% of morning measurements had SBP < 140 mmHg , respectively, (P < 0.001)  (P > 0.05), FTI of 9.5 ± 4.1  12.3 ± 5.4 kg/m2 (P < 0.001), SBP of 131 ± 18, 9.5 ± 4.1, and 135 ± 20 mmHg (P < 0.001) were lower in smokers than in nonsmokers  . ECW/hei< 0.001) . ECW/heinsmokers .P = 0.001)).Mean overhydration (OH) measured in the afternoon was more than morning measurements  that showed cut-off value of ECW/height was 10.06 L/m, with the 69% sensitivity and 45% specificity for SBP: 140 mmHg values.Receiver operating characteristic (ROC) curve with the performance of 0.60 (P < 0.05). In Region 2 increased incidence of DM and CAD and increased BMI  (P < 0.001). In Region 3 increased BMI 28.6 kg/m2(P < 0.001). In Region 4 increased incidence of CAD 13.6%, (P < 0.001).  cases in Region 1, 405 (19.9%) in Region 2, 164 (8.1%) in Region 3, 22 (1.1%) in Region 4, 1431 (51.4%) in DX, and 1047 (51.4%) in Normal region . All cas 0.001). .P < 0.01) [Hypertension is a public health problem. According to recent meta-analysis including 966 patients with masked hypertension (MH) and 2640 healthy controls with sustained normotension, controlled hypertension, and white coat hypertension, the prevalence of LVH ranged from 7 to 66% in MH and from 0.4 to 42% in non-MH counterparts  . DefinitBioelectrical impedance spectroscopy is a noninvasive, inexpensive, and portable method that has been used mainly for body-composition analysis over the past decade. It is a suitable tool for large epidemiological studies. Our data showed that high blood pressure subjects had increased volume parameters which are consistent with previous observations –16.In present study E/I was higher in hypertensive group. But we know that E/I could be affected by changes in ICW as well as by ECW varying with hydration. This may lead to the spurious impression of overhydration in subjects with smaller ICW volumes so it does not reflect hydration alone . TherefoBomback et al. has reported that kidney handicap results in an altered aldosterone-ECV relationship that extends into the general population having negative volume, load, and inflammatory effects –20. The A decrease in vascular compliance, such as what occurs with aging in larger blood vessels such as the aorta, may also contribute to the development of isolated systolic hypertension. Even in these conditions, however, it is quite possible that the kidney plays a role in maintaining the hypertensive response . In presVisser et al. showed that young healthy men with a higher BMI are associated with a larger increase in ECW during high salt intake, suggesting that altered sodium and fluid handling may be an early phenomenon in the pathophysiological consequences of weight excess and that dietary sodium restriction may have preventive potential in overweight subjects . In presIn present study high blood pressure group have lower GFR measured by MDRD. In the literature the relation of ECW increase and a positive correlation between ECW and HT in patients with poor renal function were demonstrated , 30. RecDiabetes history, smoking, and bioimpedance measurement time afternoon were all associated with increased ECW. Brizzolara et al. demonstrated that poor glucose control positively correlated with ECW and E/I ratio . These oA causal relationship between exposure to smoking and increase in blood pressure (BP) is not yet clearly demonstrated . In a stIn present study for the cut-off value 10.06 L/m of ECW/height; high blood pressure predicted positively in 69% and excluded in 45%.To our knowledge, there were no such studies comparing the effect of time period on bioimpedance measurement. We revealed that afternoon measurements were associated with increased OH, may be due to circadian rhythm of cortisone or likely whole body measurements . The othAlthough the cross-sectional design of our study and other limitations preclude to infer a causal relationship between high blood pressure and ECW/height ratio, increased age and BMI and diabetes history. All these risk factors must be taken into consideration for hypertension.There is no satisfying explanation of changes of body water composition in high blood pressure. BIS a noninvasive, cheap, and easily repeatable method has the potential to improve the etiology and management of the various hypertensive states in the majority of patients all over the world.Bioelectrical impedance analysis is a practical method for the followup of antihypertensive therapy in pregnancy  and in tExpected OH in the BCM device used is setup from a largely Caucasian population, but it remains to be demonstrated whether there are differences in hydration status in different ethnic groups. In the Turkish population however the results indicate no bias in hydration when measured with BCM. So other population studies will be needed in this field.More than half of the studied population is in “N” region of the hydration reference (Wabel plot). Most of the cases are in DX region (includes N region) 70.4%. Region 1 (overhydrated-hypertensives) composed of a minor group of population (0.6%) and having statistically significant DM and absence of CAD. Hypertension may be volume dependent just as seen in most dialysis patients. In this group hypertension treatment strategy must be adjusted towards diuretics. Region 2 (normo/hypovolemic-hypertensives) composed of nearly 1/5 of the population and having statistically significant DM, CAD and obese cases in this group. Etiology of hypertension seems as volume independent and may be speculated as rennin dependent. Accordingly angiotensin converting enzyme inhibitors and angiotensin receptor blockers might be the first choice for probable etiology and related comorbidities. Region 3  composed of 8.1% of whole population with increased number of obesity. Region 4 (overhydrated-normo/hypotensives) composed of 1.1% of population with increase incidence of CAD. This group needs further cardiac evaluation for congestive heart diseases and salt restriction must be logical approach for such cases.Normal BP in the presence of overhydration would also be an important group to identify/screen to target treatment strategies appropriately. Hypertensive subjects who are not overhydrated would likely need different treatment strategies also. Measuring BP and hydration and taking into account the traditional risk factors may allow for better diagnosis and treatment. Blood pressure and hydration can be measured readily and this could help to direct the line of investigation in the search for primary causes.High blood pressure may be accompanied by increased extracellular volume indices. In the future volume status assessment could be of use in evaluating the effectiveness of pharmacological intervention in the treatment of hypertension.


Objectives. To investigate if androgen deprivation therapy exposure is associated with additional risk factors for cardiovascular disease and metabolic treatment-related toxicities. Methods. One hundred and seven men (42–89 years) with prostate cancer undergoing androgen deprivation therapy completed a maximal graded objective exercise test to determine maximal oxygen uptake, assessments for resting metabolic rate, body composition, blood pressure and arterial stiffness, and blood biomarker analysis. A cross-sectional analysis was undertaken to investigate the potential impact of therapy exposure with participants stratified into two groups according to duration of androgen deprivation therapy (<3 months and ≥3 months). Results. Maximal oxygen uptake  and resting metabolic rate  were significantly higher in those with shorter exposure to androgen deprivation. There were no differences between groups for peripheral and central blood pressure, arterial stiffness, or metabolic profile. Conclusion. Three months or longer exposure to androgen deprivation therapy was associated with reduced cardiorespiratory capacity and resting metabolic rate, but not in a range of blood biomarkers. These findings suggest that prolonged exposure to androgen deprivation therapy is associated with negative alterations in cardiovascular outcomes. Trial registry is: ACTRN12609000200280. Androgen deprivation therapy (ADT) is a commonly used treatment for prostate cancer . AlthougMetabolic implications of long-term ADT have been previously explored by Basaria et al. , who fou272 patients with prostate cancer were screened for participation in a 12-month exercise trial  from FebAll participants underwent assessment for cardiorespiratory capacity, resting metabolic rate, peripheral and central blood pressure and arterial stiffness, and markers of metabolic health.2max). A plateau in oxygen consumption was used as the criterion for achieving VO2max; if no plateau occurred, then a respiratory exchange ratio (RER) of ≥1.1 was used. If the subject achieved no plateau in oxygen consumption or a RER value < 1.1 their data were excluded. This direct assessment of peak oxygen consumption is considered the gold standard outcome of cardiorespiratory fitness or aerobic capacity [Participants performed a standardised progressive maximal walking test (Bruce Protocol) on a motorized treadmill supervised by a physician. Expired respiratory gases were collected  to determine maximal oxygen uptake  was measured via respiratory gas analysis over 20 minutes. A 5-minute period that showed an oxygen consumption with a coefficient of variation of <10% was selected for analysis . The coeBrachial blood pressure was recorded at the dominant arm in triplicate via a validated oscillometric device  . ApplanaPatients were classified as having metabolic syndrome if they met three of the following five criteria according to the Adult Panel III Criteria : (1) plaVenous blood samples (2 × 8.5 mL) were obtained from the antecubital vein with whole blood analysed for haemoglobin A1C  whilst the remaining blood was separated and analysed for testosterone, insulin, prostate specific antigen, triglycerides, LDL cholesterol, HDL cholesterol, total cholesterol, glucose, and C-reactive protein. All blood variables were analysed commercially by accredited Australian National Association of Testing Authorities laboratories .Whole body bone mineral-free lean mass and fat mass, trunk fat, and body fat percentage were assessed by dual energy X-ray absorptiometry . In addition, appendicular lean mass was calculated as the sum of upper and lower limb lean mass. The coefficient of variation for body composition measures is <1%.2max in absolute (L/min) and relative terms (mL/kg/min), and 87% for RMR in kcal/24 hr.Sample size calculations for the initial RCT  resultedt-tests, and Pearson's chi-square test for categorical variables. Potential differences between patients on <3 months or ≥3 months on ADT were undertaken based on the previous prospective work by Alibhai and colleagues [Analyses were performed using the Statistical Package for Social Sciences version 18.0 software . Normality of the data was assessed using the Kolmogorov-Smirnov test. The analyses included standard descriptive statistics, Student's independent lleagues  which shCharacteristics for all participants were age 68.6 ± 8.8 kg; height 172.4 ± 6.3 cm; and body mass 84.0 ± 13.7 kg. Mean ADT duration was 2.0 ± 0.0 and 7.1 ± 6.2 months for the shorter and longer groups, respectively. There were no significant differences in any subject characteristics  or lean 2max with no difference between groups in their ability to achieve VO2max. Maximal oxygen consumption was significantly higher in the shorter ADT duration group when presented in absolute (L/min−1) (p = 0.035) (−1) (p = 0.020) (p = 0.02). Whilst test duration was not statistically significant, shorter duration group exhibited an additional 54 seconds (p = 0.080) of walking endurance.91 (85%) of the participants were able to achieve the desired criteria for VO= 0.035)  or relat= 0.020) . Correspp = 0.005) RMR in absolute terms and relative to body mass RMR (p = 0.017) compared to the longer duration group (p = 0.079), RMR relative to lean body mass was 1.3 kcal/lean kg/24 hr higher in those with shorter ADT exposure.There was a significant difference observed in RMR with the shorter duration group recording a significantly higher .No significant differences were observed between short and longer ADT exposure in any of the blood markers analysed . Whilst p = 0.337). However, there were no significant differences observed between groups for fasting plasma glucose (p = 0.998), serum triglycerides (p = 0.874), serum HDL (p = 0.815), waist circumference (p = 0.994), or hypertension (p = 0.093).According to National Cholesterol Education Program Adult Treatment Panel III, 20.3% of the acute group and 13.5% of the chronic group were classified as having metabolic syndrome  rather than use of surrogate measures such as the 400 meters or 6 MWT as well as assessments of RMR and central blood pressure. A limitation of this study is that patients were only assessed at a single time point during their treatment; hence, we were unable to continually monitor each participant as treatment time progressed. Further, the cross-sectional nature of the study does not permit us to infer causality; however, it provides initial evidence of decline in aerobic capacity measured objectively and it could be clinically meaningful to patients but needs further validation in prospective studies. However, it should be recognised that men in this study were volunteers for an exercise trial and therefore are not representative of all men with prostate cancer undergoing ADT. Lastly, given the exploratory nature of the study, we did not adjust for multiple comparisons [The strength of this study is that we directly measured VOparisons  and, as In conclusion, we found that patients exposed to longer duration ADT had reduced cardiorespiratory capacity and RMR and these could have clinical meaningful implications. The exact mechanisms remain unclear as to why these cardiovascular parameters are further declining as the treatment time progresses and should be determined in future mechanistic studies. Intervention strategies to preserve cardiovascular capacity and RMR such as exercise medicine interventions have significant potential to counteract these forms of decline.


Background: Although data suggest that intakes of total protein and specific amino acids (AAs) reduce blood pressure, data on other cardiovascular disease risk factors are limited.Objective: We examined associations between intakes of AAs with known mechanistic links to cardiovascular health and direct measures of arterial stiffness, central blood pressure, and atherosclerosis. Methods: In a cross-sectional study of 1898 female twins aged 18–75 y from the TwinsUK registry, intakes of 7 cardioprotective AAs  were calculated from food-frequency questionnaires. Direct measures of arterial stiffness and atherosclerosis included central systolic blood pressure (cSBP), mean arterial pressure (MAP), augmentation index (AI), pulse wave velocity (PWV), and intima–media thickness (IMT). ANCOVA was used to assess the associations between endpoints of arterial stiffness and intake (per quintile), adjusting for potential confounders.Results: In multivariable analyses, higher intakes of total protein and 7 potentially cardioprotective AAs were associated with lower cSBP, MAP, and PWV. Higher intakes of glutamic acid, leucine, and tyrosine were most strongly associated with PWV, with respective differences of −0.4 ± 0.2 m/s (P-trend = 0.02), −0.4 ± 0.2 m/s (P-trend = 0.03), and −0.4 ± 0.2 m/s (P-trend = 0.03), comparing extreme quintiles. There was a significant interaction between AA intakes and protein source, and higher intakes of AAs from vegetable sources were associated with lower central blood pressure and AI. Higher intakes of glutamic acid, leucine, and tyrosine from animal sources were associated with lower PWV.Conclusions: These data provide evidence to suggest that intakes of several AAs are associated with cardiovascular benefits beyond blood pressure reduction in healthy women. The magnitude of the observed associations was similar to those previously reported for other lifestyle factors. Increasing intakes of these AAs could be an important and readily achievable way to reduce cardiovascular disease risk. Dietary protein intake has received increased attention for its role in preventing cardiovascular disease, especially in relation to blood pressure–lowering effects. A higher total protein intake has been inversely associated with both systolic and diastolic blood pressure in a number of observational studies . FurtherThe mechanisms explaining the vasoactive properties of dietary protein are likely to be dependent on the amino acid composition and the source of the protein. A number of amino acids, including glutamic acid, arginine, glycine, cysteine, and histidine, have been shown to modulate concentrations of nitric oxide, a potent vasodilator –9. In adThere is evidence to suggest that measures of central arterial function are better predictors of cardiovascular events than brachial blood pressure . ArteriaTo our knowledge, no previous cross-sectional studies have examined associations between the intakes of these 7 potentially cardioprotective amino acids and in vivo measures of arterial stiffness and atherosclerosis. Therefore, we examined associations between these 7 amino acids, which have known mechanistic links to blood pressure, and endpoints of arterial stiffness (PWV and AI), atherosclerosis (IMT), and central and peripheral blood pressure in a cohort of healthy women aged 18–75y. On the basis of previous research, it was hypothesized that participants with higher intakes of arginine, cysteine, glutamic acid, glycine, histidine, leucine, and tyrosine would have improved arterial stiffness and central blood pressure.n = 5725) who had completed both FFQs and had a clinical assessment of arterial stiffness and atherosclerosis progression between 1996 and 2000. Of the 5119 twins who completed an FFQ, 36% (n = 1857) were excluded for having an incomplete FFQ (>10 food items were left blank) or implausible energy intake [the ratio of the FFQ-derived estimate of total energy intake to estimated basal metabolic rate fell 2 SDs outside the mean ratio (<0.52 or >2.58) for this cohort] (n = 1364) did not attend a clinical session for vascular assessment, which left 1898 participants (949 twin pairs) for the current analysis. PWV and IMT were measured in a subset of 900 participants of the total population who were part of a planned longitudinal study on the heritability of arterial stiffness, of which 728 (81%) completed a valid FFQ and were included in these analyses. A power calculation related to a clinically significant association with a PWV of 0.4 m/s at an α level of 0.05 revealed 98% power to see an association with 728 participants. This population has previously been shown to be representative of the general population in terms of blood pressure and dietary intake  who were part of a study on the heritability of arterial stiffness, PWV was calculated from sequential recordings of electrocardiogram-referenced carotid and femoral pressure waveforms obtained by tonometry with the use of the same device and transducer, as previous described  clinical laboratory. Peripheral systolic blood pressure (pSBP) and peripheral diastolic blood pressure (pDBP) were measured by a trained nurse who used an automated cuff sphygmomanometer (OMRON HEM713C) with the participant in the seated position for at least 3 min before taking 3 measurements. Measures of central blood pressure and AI were obtained with the subject in a supine position with the use of the SphygmoCor system , as described previously for this cohort °C clinic. In a suescribed .Participants completed a 131-item validated FFQ , 28. IntIntakes of energy and nutrients associated with arterial stiffness was determined from the FFQ as previously described. Height was measured to the nearest 0.5 cm with the use of a wall-mounted stadiometer, weight (light clothing only) was measured to the nearest 0.1 kg with digital scales, and BMI was calculated (kilograms per meter squared). Information on family medical history, medication use, lifestyle, and demographic variables were obtained by standardized nurse-administered questionnaire. Physical activity was classified as inactive, moderate, and active during work, home, and leisure time with the use of a questionnaire strongly correlated in this cohort with more in-depth assessment recording how much time subjects spent in moderate and vigorous nonweight-bearing and weight-bearing activity on average per week. The mean time spent in physical activity per week for each physical activity level was as follows: inactive, 16 min; light activity, 36 min; moderate activity, 102 min; and heavy activity, 199 min . Under-rP value < 0.05 was considered to be statistically significant.Statistical analyses were performed with Stata statistical software, version 11.2. The analysis focused on associations in twins as individuals, with SEs adjusted through robust regression with the use of the cluster option in Stata to take into account dependency within twin pairs. Quintiles of intake were calculated for total protein and the amino acids with known mechanistic links to outcomes associated with cardiovascular disease . There was a significant interaction between amino acid intake and protein source for PWV, so all analyses were stratified by source . ANCOVA was used to calculate adjusted means and evaluate statistical trends across these quintiles of intake. All models were adjusted for age (years); current smoking (yes or no); physical activity ; BMI (kilograms per meter squared); use of hormone replacement therapy (yes or no); use of blood pressure or statin medication (yes or no); use of vitamin supplements (yes or no); use of oral contraceptives (yes or no); menopausal status ; family history of heart disease or hypertension (yes or no); under-reporting of dietary intake (yes or no); and intake of carbohydrates (percentage of energy); SFAs, MUFAs, and PUFAs (percentage of energy); alcohol (grams); and sodium, potassium, and magnesium (milligrams). In addition, models including individual amino acids were adjusted for intakes of the other 6 amino acids and PWV was adjusted for mean arterial pressure (MAP). Unadjusted values in the text are means ± SDs (IQRs) and adjusted values are means ± SEs. A n = 1581) of participants classified as normotensive . There were no differences in BMI, energy intake, or protein intake between the study participants and those excluded from the analyses; however, the participants were younger than those excluded .The baseline characteristics of the population of 1898 female participants are presented in Total protein intake was 85.1 ± 23.4 g/d and protein contributed 16.2% to total energy intake. Of the 7 amino acids investigated, glutamic acid (3.2% energy intake) and leucine (1.3% energy intake) made the greatest contribution to total energy intake. Animal and vegetable sources contributed a similar amount to intakes of arginine , glutamic acid , and glycine , whereas intakes of histidine , tyrosine , and leucine  was predominantly from animal sources (P-trend 0.06) and glycine for pDBP (P-trend 0.11) and central diastolic blood pressure (P-trend = 0.08). The magnitude of association was greatest for tyrosine intake, with differences between quintile 5 and quintile 1 of −5.6 ± 1.3 mm Hg for pSBP (P-trend < 0.01), −5.5 ± 1.3 mm Hg for central systolic blood pressure (cSBP) (P-trend < 0.01), −2.3 ± 0.7 mm Hg for cPP (P-trend < 0.01), and −4.0 ± 1.1 mm Hg for MAP (P-trend < 0.01) (P-trend < 0.01), −5.5 ± 1.3 mm Hg (P-trend < 0.01), −2.6 ± 0.7 mm Hg (P-trend < 0.01), and −3.8 ± 1.1 mm Hg (P-trend < 0.01), respectively. For arterial stiffness, glutamic acid, leucine, and tyrosine intakes were significantly inversely associated with PWV (after adjustment for MAP) with respective differences of −0.4 ± 0.2 m/s (P-trend = 0.01), −0.4 ± 0.2 m/s (P-trend = 0.04) and −0.4 ± 0.2 m/s (P-trend = 0.02), comparing extremes of intake. Sensitivity analysis showed that the magnitude of associations with PWV were not markedly changed when protein was residually adjusted for energy intake , when amino acids were expressed as a percentage of protein , or when potential under-reporters of energy intake were excluded from the analyses .In multivariable analyses, higher intakes of total protein and the 7 individual amino acids examined were significantly associated with lower peripheral and central blood pressure ( < 0.01) . A higheNo significant associations were observed between intake of total protein or the individual amino acids assessed and either AI or IMT (data not shown). The results were not altered after exclusion of the low proportion (11%) of participants who reported taking blood pressure or statin medication (data not shown).P-trend < 0.05)  (P-trend = 0.04) and MAP . In relation to intakes of amino acids from animal sources, significant inverse associations were observed between glutamic acid, leucine, and tyrosine intakes and PWV, with respective differences of −0.3 ± 0.2 m/s (P-trend = 0.03), −0.3 ± 0.2 m/s (P-trend = 0.02), and −0.4 ± 0.2 m/s (P-trend = 0.02) between extreme quintiles of intake. Total vegetable protein intake and total animal protein intake were not associated with any of the outcomes assessed , and there were no significant associations for IMT (data not shown).Higher intakes of amino acids from vegetable sources were inversely associated with cSBP and AI. Intakes of arginine, glycine, histidine, leucine and tyrosine were significantly associated with −2.0 to −2.4 mm Hg lower cSBP values and intake of cysteine, glutamic acid, lysine, and tyrosine with −3.5% to −5.7% lower AI, comparing extreme quintiles of intake  . FurtherTo our knowledge, this is the first cross-sectional study to examine associations between amino acids that have known mechanistic links to cardiovascular disease and a range of in vivo measures of arterial stiffness and central blood pressure associated with cardiovascular disease risk. We showed that higher intakes of all 7 of the amino acids examined  were significantly associated with improved measures of peripheral and central blood pressure. Higher intakes of glutamic acid, leucine, and tyrosine were also associated with lower PWV. These associations were significant after adjustment for a number of important covariates known to be associated with vascular health, including lifestyle factors, medication use, and other nutrients. The magnitude of the inverse associations ranged from −2.8 to −5.5 mm Hg for systolic blood pressure, −1.5 to −3.2 mm Hg for central diastolic blood pressure, and −0.40 to −0.45 m/s for PWV.It was previously estimated that a modest reduction in systolic blood pressure of 5 mm Hg would potentially lead to an overall reduction in mortality from stroke, coronary heart disease, or all-cause mortality . IntakesOur results provide further insights into the vascular effects of these amino acids and a potential explanation to support the reduction in blood pressure observed with higher protein intake in a recent meta-analysis . Our finThese current results, however, do not support the findings of the INTERMAP , which showed that higher glycine intake was associated with an increase in blood pressure, and those of the Rotterdam study, which found no significant associations between intakes of glutamic acid, arginine, and cysteine and blood pressure or risk of hypertension , 17. A nr = 0.89, P < 0.01) remains unclear.Because of the strong interrelations previously reported between blood pressure and protein source, and because we observed a significant interaction in the current analyses, we further examined the relation between amino acid intake and arterial stiffness according to protein source. Protein from vegetable sources, but not animal sources, has previously been shown to be associated with a −1.1 mm Hg reduction in pSBP and 15% reduction in risk of hypertension , 4. We fThe findings of the current study reflect intakes of amino acids that are readily achievable in the habitual diet. The difference in PWV of 0.4 m/s shown between extreme quintiles of intakes of glutamic acid, leucine, and tyrosine equates to a 3.53 g, 1.64 g, and 0.76 g difference in intake, respectively. This intake can be incorporated into the diet by consuming approximately one-half of a medium steak (74 g), a medium salmon fillet (100 g), or a 500 mL glass of skimmed milk.Strengths of the current study include the large sample of well-characterized participants and the rigorous assessment of a range of in vivo measures of arterial stiffness and central blood pressure. It is well established that aortic stiffness, as assessed by PWV, is able to predict future cardiovascular events and all-cause mortality . The pubThe limitations of the current study include the cross-sectional design that meant we were unable to infer causality Numerous hypothesis-driven comparisons were made in our analysis that we felt were justified, given the novel and exploratory nature of the analyses. The inclusion of twin pairs within the same sample may introduce bias, but this was reduced by accounting for the clustering within twin pairs in all statistical analyses and with the use of a sample shown to be representative of the general population in terms of outcome variables and dietary intake. Validated biomarkers, such as 24 h urine nitrogen, are available for total protein intake, but they were not measured in the current study and may have reduced potential measurement error . FurtherIn conclusion, these novel data suggest that intakes of selected amino acids is associated with arterial stiffness and central blood pressure, with significant associations observed for PWV and cSBP similar in magnitude to established lifestyle risk factors for hypertension, such as physical activity, not smoking, and reduced intakes of sodium and alcohol , 38. The


Patients with mean pulmonary artery pressures (mPAP) of 21 to 24 mm Hg have a so-called borderline elevation of mPAP (BoPAP)—a condition thought to represent early-stage pulmonary arterial vasculopathy. Based on the DETECT study, this post-hoc analysis examined patient characteristics of systemic sclerosis (SSc) patients with normal mPAP, BoPAP and elevated mPAP, fulfilling pulmonary arterial hypertension (PAH) criteria.Adult patients with a duration of SSc more than 3 years, a diffusing capacity of the lung for carbon monoxide less than 60% predicted, and no previous diagnosis of any form of pulmonary hypertension (PH) underwent screening tests followed by right heart catheterization. Subjects were divided into three groups: normal mPAP, BoPAP, and PAH. Exploratory comparative and binary logistic regression analyses were performed for the BoPAP versus normal mPAP and PAH versus BoPAP groups., and 60 (25%) had definite PAH. Univariable logistic regression (ULR) showed the mean tricuspid regurgitation velocity in patients with BoPAP to be intermediate between normal mPAP and PAH. In the ULR analyses BoPAP versus normal mPAP and PAH versus BoPAP, the statistically significant predictors were, amongst others: demographic, clinical, pulmonary function, echocardiographic and hemodynamic variables.Of 244 patients evaluated, 148 (60%) had normal mPAP, 36 (15%) had BoPAPIn this exploratory post-hoc analysis of the DETECT study population patients with BoPAP could be distinguished from patients with normal mPAP and PAH, and it appears that BoPAP may be an intermediate stage on the continuum between normal PA pressures and PAH.The online version of this article (doi:10.1186/s13075-014-0493-1) contains supplementary material, which is available to authorized users. Systemic sclerosis  is an autoimmune connective tissue disorder characterized by inflammation, fibrosis and vasculopathy. Pulmonary arterial hypertension (PAH) is a leading cause of death in SSc ,2. BasedThe DETECT study was a multi-center study that systematically evaluated 466 SSc patients at increased risk for development of SSc-PAH . DETECT post-hoc analysis was to compare the demographics and clinical features of patients with normal PAP, borderline mPAP (BoPAP), and elevated PAP (PAH) in a large international cohort of patients with SSc who participated in the DETECT study. The identification of characteristics specific to SSc patients with BoPAP would facilitate future investigations into the natural history of this condition, and provide insights into the proportion of patients who develop PAH.Measurements in healthy individuals show a normal mean pulmonary arterial pressure (mPAP) to be 14 ± 3.3 mmHg , with 2 Our study was conducted in accordance with the Declaration of Helsinki and its amendments, followed the International Conference on Harmonization Guideline for Good Clinical Practice, and was approved by local institutional review boards/ethics committees  a pulmonary artery wedge pressure (PAWP) ≤15 mmHg by RHC; 2) no significant interstitial lung disease ; 3) no systemic hypertension (stage-I hypertension defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90) ; and 4) The DETECT study collected 112 variables, collated into four groups: 1) demographic and clinical parameters (68 variables); 2) serum tests (13 variables); 3) electrocardiography (ECG) (3 variables); and 4) echocardiography (28 variables). In the present study, variables were selected for further analysis based on a review of numerical descriptive differences between the three groups, as well as input from the authors on feasibility of the variables and their clinical relevance to PAH. Two additional variables were computed: 1) the transpulmonary gradient (TPG) which is the difference between mPAP and left atrial pressure (estimated by the PAWP); and 2) the diastolic wedge gradient (DWG) which is the difference between diastolic PAP and left atrial pressure (estimated by the PAWP). The selected variables were described using summary statistics: sample size, mean, SD, median, upper and lower quartiles, minimum and maximum for quantitative data and frequencies (counts and percentages) for qualitative and categorical data. The distributions of the variables were compared using non-parametric tests: Wilcoxon rank-sum and chi-square/Fisher’s exact test for continuous and categorical data, respectively. Univariable logistic regression (ULR) analysis was performed using BoPAP versus normal mPAP and PAH versus BoPAP as binary outcomes in separate models. The odds ratio (OR) and 95% CI for each variable was calculated and statistical significance was examined by the Wald chi-square test. A Forest plot was constructed to display the odds ratios and the 95% CI for 13 variables in the BoPAP versus normal mPAP and PAH versus BoPAP groups. Variables were selected for the plot if they met the statistical significance criteria or had potential clinical utility as screening tests for BoPAP and PAH. RHC hemodynamics were used for exploratory purposes only, as they were part of the group definitions.Among the 244 SSc patients included in the PAP analysis set, 60% n = 148) had a normal mPAP, 15% (n = 36) had BoPAP and 25% (n = 60) had an elevated mPAP (PAH) , serum urate (PAH versus BoPAP), left atrium diameter  and TR velocity  (PAH versus BoPAP), presence of peripheral edema , presence of telangiectasias (PAH versus BoPAP), ratio of FVC percent predicted/DLCO percent predicted (PAH versus BoPAP), TLC percent predicted , presence of anti-centromere antibodies (PAH versus BoPAP), logP <0.05): older age, presence of peripheral edema, a higher log10 NT-proBNP, greater left atrium diameter, and greater tricuspid regurgitation (TR) velocity. Of note, 6-minute walk distance was not statistically different.As shown in Table The RHC variables PAWP, TPG and PVR (which defined the groups) were all statistically significant, though DWG was not.P <0.05) predictors of PAH: higher WHO FC (III or IV), diffuse versus limited disease subtype, the presence of telangiectasias, higher FVC percent predicted/DLCO percent predicted ratio, presence of anti-centromere antibodies, higher serum urate, a lower TAPSE and a higher TR velocity. As was the case with the BoPAP versus normal PAP analysis, 6-minute walk distance was not statistically different. As expected, the PAH group had a higher TPG, a higher DWG, and a higher PVR  and lower mean percent predicted peak oxygen consumption (VO2) values  [P-value not significant) 14.92 ± 9.23 and 12.19 ± 6.82 months after the first RHC, respectively [P <0.001). Within the borderline mPAP group, 18.5%  developed PAH within 3 years, and 27.1%  developed PAH within 5 years [A number of recent studies have shown an association between BoPAP and worse clinical outcomes. One small study compared SSc patients with mPAPs >17 but <25 mmHg (group mean of 20 ± 2 mmHg) to those with mPAPs ≤17 mmHg (group mean 14 ± 2 mmHg), and found the former group to be associated with both shorter mean 6-minute walk distances  . After eectively . Within  5 years .In the current study we identified significant differences in clinical, serologic, echocardiographic and hemodynamic parameters useful in differentiating BoPAP from normal PAP and PAH from BoPAP groups. Across both comparisons, TR velocity was the variable most strongly associated with BoPAP  and PAH (versus BoPAP).Our analysis also identified additional variables capable of differentiating BoPAP from the PAH group: WHO functional class, SSc subtype, presence of telangiectasias, ratio of % predicted FVC/percent predicted DLCO, anti-centromere antibodies, and serum urate concentration. Some of these variables   are beliIn the present study we excluded patients with overt pulmonary venous hypertension based upon the finding of a PAWP >15 mmHg by RHC. It is important to acknowledge that occult pulmonary venous hypertension (OPVH) due to left heart disease may have been present in a proportion of patients who underwent a RHC while in a state of volume depletion, and were thus found to have underestimated left-heart filling pressures . One stuOur study has significant strengths. Ours is the first BoPAP study to mandate a diagnostic RHC in all subjects, allowing us to assign individuals into groups  based on rigorous, objective criteria. Standardization of the study protocol and centralization of serum laboratory testing and data management assured homogeneity. In addition, it is the largest, most complete cohort of patients evaluated for SSc-PAH, providing us a sufficient sample size to conduct our analyses.Our study has important limitations. Results are cross-sectional, so longitudinal follow up to determine the incidence of PAH in the BoPAP group over time was not determined. Our inclusion criteria included a DLCO <60% to enrich for a higher likelihood of PAH. Thus, the groups analyzed in our study represent a high-risk SSc group, and may not be representative of the general SSc population. Future studies are needed in order to expand our findings into the general SSc population. Our study was not designed to compare and model relationships involving the BoPAP sub-group; thus, multivariable logistic regression for this post-hoc sub-analysis could be misleading, and was not performed. In addition, the three sub-groups analyzed  were defined using mPAP (a continuous variable). Various pairwise sub-groups using binary logistic regression may provide a different set of predictive covariables for each multiple regression model that may be inaccurate.In conclusion, our study identifies clinical, echocardiographic, hemodynamic, pulmonary function, and serologic variables that allow SSc patients with BoPAP to be differentiated from SSc patients with normal mPAPs and PAH. Future longitudinal studies designed to reassess patients with BoPAP at pre-designated time points would be the ideal means of validating the prognostic value of our findings. Such studies would allow further characterization of the natural history of BoPAP, including the rate and frequency of conversion to pre-capillary or post-capillary PH. Our exploratory analyses of hemodynamic data suggest that the TPG and DWG should continue to be evaluated as potential predictors for the development of PAH in the SSc population.


Patients with diabetes mellitus (DM) are known to have microvascular coronary artery disease (CAD), in the absence of hypertension and flow limiting stenoses on epicardial coronary arteries. Microvascular coronary dysfunction can be detected on CMR using adenosine stress perfusion imaging.Native T1 values can detect tissue water content of intra/extracellular or intra/extravascular origin. We hypothesised that increased myocardial blood volume in the intravascular space under adenosine vasodilator stress will have a measurable effect on T1 values. Therefore, we compared adenosine stress T1 response and myocardial perfusion reserve in patients with type-2 DM (T2DM) without macrovascular CAD against controls.27 patients with T2DM  and 24 matched controls  were studied. Patients were on oral antidiabetic therapies (mean HBA1c 7.44±1.26%) with no known diabetic complications. Obstructive CAD (defined as >50% lumen diameter reduction) was excluded in patients by CT coronary angiography. CMR included cine, rest and adenosine stress native T1-mapping, perfusion imaging (at rest and adenosine stress), late gadolinium enhancement, post-contrast T1-mapping, all performed at 3.0 T. At rest, a mid-ventricular short-axis T1 map was acquired using the Shortened Modified Look-Locker Inversion recovery (ShMOLLI) sequence. Adenosine (140 μg/kg/min) was infused intravenously for 3-6 minutes, and the same mid SA T1 map was acquired at peak stress. followed by first-pass perfusion imaging (0.03 mmol/kg gadoderic acid-Dotarem®). After 20min break rest perfusion imaging was performed. A single mid-ventricular short axis slice was acquired for post-contrast T1 maps 15 minutes after administration of contrast.Left ventricular ejection fraction (LVEF) and mass (LVM) were similar in patients with T2DM and controls. During adenosine stress, increases in rate pressure product were similar in patients and controls . Myocardial perfusion reserve index (MPRI) was reduced in patients  in keeping with microvascular disease. Stress T1 response to adenosine was blunted in patients . There was no difference in rest native T1 values , or extracellular volume (ECV) measurements  between groups, suggesting absence of diffuse myocardial fibrosis.In patients with T2DM but no significant flow limiting CAD, T1 response under adenosine stress is blunted, likely due to microvascular CAD as suggested by the reduced myocardial perfusion reserve. Adenosine stress native T1 mapping allows the assessment of vascular reactivity, and may be useful particularly for the assessment of patients with contraindications to contrast.The National Institute for Health Research Oxford Biomedical Research Council supported this work.