We investigated whether urinary albumin could predict the development of hypertension and future increases in blood pressure in the normotensive general population.Normotensive subjects who visited our hospital for a physical checkup  were enrolled in this study. Urine samples were collected for the measurement of albumin concentration, expressed as the ratio of urinary albumin to creatinine concentrations (UACR [mg/g Cr]). After the baseline examination, subjects were followed up for a median of 1089 days with the endpoint being the development of hypertension.P < 0.0001) and the hazard ratio (lowest quartile [median UACR 1.14 mg/g Cr] as reference) was 1.53  in the highest quartile (median UACR 8.87 mg/g Cr). Multivariate Cox hazard analysis in which UACR was taken as a continuous variable identified UACR as a significant predictor of hypertension . UACR was also an independent predictor of future increases in systolic blood pressure (P < 0.01).Urinary albumin was in the normal range (UACR <30 mg/g Cr) in most subjects (97.5%). During the follow-up, hypertension developed in 1184 subjects , with more men than women affected. The incidence of hypertension was increased across the quartiles of UACR by Kaplan–Meier analysis (log-rank, Urinary albumin is an independent predictor of hypertension and increases in blood pressure in the general population even in the normal range below the threshold defined for microalbuminuria. Furthermore, more than half of cardiovascular events occurred in individuals with mild hypertension or normal blood pressure,9 despite the risk reducing with decreasing blood pressure levels. In this context, primary prevention of hypertension is an important public health aim. An intensive targeted strategy focused on identified individuals at highest risk of developing hypertension is an attractive approach for primary prevention of hypertension.Hypertension is an established risk factor of cardiovascular morbidity and mortality.13 We previously reported that glomerular filtration rate is a novel predictor of the onset of hypertension and future increases in blood pressure in the general population.14 In this earlier study, we also identified proteinuria determined by a dipstick method as a possible predictor of the onset of hypertension, although a definite conclusion could not be drawn because the urinary protein was not quantified.14 Moreover, microalbuminuria was independently associated with cardiovascular risk factors such as hypertension, and cardiovascular morbidity in previous studies.16 These observations suggested the predictive value of lower levels of urinary albumin, that is microalbuminuria, for hypertension. Indeed, microalbuminuria reflects vascular endothelium dysfunction in individuals with and without diabetes18 and endothelial dysfunction precedes the development of hypertension.19 Higher levels of urinary albumin, even within the normal range, were associated with increased risk of hypertension in the Framingham study,21 although not in other studies in premenopausal women22 or in the Multi-Ethnic Study of Atherosclerosis.23 In the light of these controversial results, the present study sought to further investigate whether increased excretion of urinary albumin within the low-grade levels (<300 mg/g creatinine) is associated with increased risk of hypertension and future elevations of blood pressure in the general population.While not the only target organ of high blood pressure, the kidney plays a central role in regulating blood pressure.This was a cohort study of participants who visited our hospital for a yearly physical checkup from July 2008 to June 2013 to assess the impact of urinary albumin on the incidence of hypertension. We undertook the study in accordance with the principles of the Declaration of Helsinki and the Ethics Committee of Enshu Hospital approved the study protocol. All participants gave written informed consent to participate prior to the start of the study and at each study visit.25The study subjects were recruited from the group of participants examined between July 2008 and June 2011 (n = 8874). First, individuals under medical treatment for hypertension (n = 1634) were excluded. Among the remaining individuals (n = 7240), the physical checkup  revealed 6212 individuals without hypertension . After further excluding those subjects with proteinuria, 6205 participants  were finally enrolled in the present study and followed up with the endpoint being the onset of hypertension  cholesterol levels <40 mg/dL, low-density lipoprotein (LDL) cholesterol ≥140 mg/dL, triglycerides ≥ 150 mg/dL, or using antidyslipidemic medications were defined as having dyslipidemia.26 Subjects with a fasting plasma glucose ≥126 mg/dL or using antidiabetic medications were defined as having diabetes mellitus. The estimated glomerular filtration rate (eGFR) was calculated using a modified formula from the Modification of Diet in Renal Disease study for the Japanese population.27Linear regression analysis was performed for each participant using a change in blood pressure or UACR as a dependent variable and follow-up period (years) as an independent variable, with the slope of the regression line considered as the yearly increase in blood pressure or UACR, respectively. In participants who started antihypertensive medication during the follow-up, changes in blood pressure or UACR were calculated using data obtained before the prescription of antihypertensive drugs. The impact of baseline UACR, changes in UACR during the follow-up period, and longitudinal changes in blood pressure during the follow-up on the onset of hypertension was investigated. Blood pressure was measured using a standard mercury sphygmomanometer with the subject in the sitting position. Three consecutive blood pressure measurements were taken at 2-minute intervals, and the mean of the second and third measurements was recorded as the blood pressure. Subjects were defined as having hypertension with a systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or if they were taking antihypertensive medications.t test, and the Mann–Whitney U-test was used to test significance of difference in follow-up periods. Yates’ corrected chi-square (χ2) test was used for comparisons between categorical data. To analyze the endpoint throughout the observation period, the significance of differences in Kaplan–Meier curves was evaluated by the log-rank test and adjusted using multivariate Cox proportional hazard regression models. Hazard ratios and 95% confidence intervals (CIs) were calculated. Furthermore, multivariate Cox proportional hazard regression models were applied to examine the relationship between UACR as a continuous variable and the onset of hypertension. In other series of analyses, multivariate linear regression analysis was performed to assess the relationships of baseline or changes in UACR as well as other baseline variables obtained from the physical checkup program to yearly changes in blood pressure. P < 0.05 was considered significant.All analyses were performed using StatView 5.0 . Data presented in the text and tables are expressed as mean ± standard deviation except for serum creatinine, UACR, and follow-up period, which are expressed as the median value and interquartile range. In addition, because the distribution of serum creatinine and UACR was skewed rightward, log-transformed creatinine and (UACR + 0.5) were used for statistical analysis. Differences between 2 means that had a normal distribution were compared by unpaired Student ,025 person-years and the median follow-up period was 1089 (range 170–1818) days. During the follow-up period, hypertension developed in 1184 subjects  with a higher incidence in men  than in women . Table Table P < 0.0001 by log-rank test; Figure P < 0.0001 by univariate analysis; 1.421, 1.235–1.635, P < 0.0001, respectively, by multivariate analysis).To evaluate the impact of the UACR on the incidence of hypertension, subjects were divided into 4 groups using the quartiles of UACR at baseline. Kaplan–Meier curve analysis demonstrated that the incidence of hypertension increased across the quartiles of UACR values . Exclusion of subjects on any medication did not alter the results (data not shown). In the subgroup of participants without diabetes, baseline UACR, but not the yearly change in UACR, significantly correlated with a yearly increase in systolic blood pressure by both univariate  and multivariate analyses after adjustment for body mass index, systolic blood pressure, heart rate, eGFR, uric acid, fasting plasma glucose, LDL-cholesterol, triglycerides, current smoking habit, and family history of hypertension (refer to model 3 in Table r = 0.055 and P < 0.0001 for baseline UACR and r = 0.031 and P = 0.02 for the yearly change in UACR). Similar results were obtained when a yearly increase in diastolic blood pressure was used as a dependent factor (data not shown).Other analyses investigated the impact of UACR levels at baseline and yearly changes in UACR during the follow-up period on systolic blood pressure progression. Univariate and multivariate regression analyses indicated that both the baseline levels and any yearly change in UACR positively correlated with a yearly increase in systolic blood pressure Table . SimilarThe present study demonstrated that any level of increased urinary albumin was closely associated with the risk for developing hypertension in the Japanese general population. The association between urinary albumin and blood pressure was further confirmed by identifying urinary albumin as a significant predictor of future increases in blood pressure.Among 6205 subjects without hypertension, Kaplan–Meier curves showed that the risk of developing hypertension increased across the quartiles of UACR, and it was significantly increased in the fourth quartile  after adjustment for possible factors that could affect the development of hypertension. These findings suggested that excretion of urinary albumin, even levels in the normal range , should be recognized as an independent predictor for hypertension in the general population, and that the concept of normal range for albuminuria should be reevaluated. The close association between urinary albumin and the development of hypertension was further supported by the finding that UACR taken as a continuous variable was a significant and independent predictor of future hypertension. Although we could not determine whether the risk of hypertension increases in a linear fashion with increasing urinary excretion of albumin or shows a threshold, there could be a threshold of urinary albumin for the development of hypertension considering similar feature of the Kaplan–Meier curves in the first to third quartiles.9 Thus, predicting the expected longitudinal increase in blood pressure would be an important clinical aid in understanding individual cardiovascular risk and for identifying suitable persons to undertake intervention programs aimed at primary prevention of hypertension. In this context, the observed close association of urinary albumin with yearly increase in blood pressure has clear clinical and pathophysiological significance.The concept that urinary albumin predicts future development of hypertension was further reinforced by the finding that not only UACR at baseline, but also a yearly increase in UACR was independently correlated with the longitudinal increase in systolic blood pressure. The definition of hypertension based on cutoff values is arbitrary due to the continuous and linear relationship between blood pressure and cardiovascular risk.28 Indeed, an inverse correlation was reported between endothelium-dependent relaxations and urinary excretion of albumin.18 Thus, increased albuminuria might reflect glomerular and/or systemic vascular endothelial dysfunction that precedes hypertension in humans.19 In previous cross-sectional studies, urinary albumin was also closely correlated with blood pressure in patients with hypertension29 as well as in the general population,16 suggesting that the increased level in the present study could be at least partially derived from an elevation of blood pressure. Blood pressure gradually increases during the development of hypertension with significant fluctuations,30 indicating that the kidney may be transiently, but frequently, exposed to high blood pressure during these earlier stages of onset. Thus, even a mild increase in urinary albumin could potentially be an early symptom of developing hypertension. Alternatively, glomerular hyperfiltration could underlie an increased urinary excretion of albumin. Reduced nephron number has been implicated as a risk factor for developing hypertension.33 In individuals with reduced nephron numbers, intraglomerular pressure and glomerular filtration of the residual glomeruli are increased to compensate for the reduced glomerular filtration rate in the kidney, with a consequent increase in urinary excretion of albumin.34 Elevated urinary excretion of albumin might therefore in turn be a sign of reduced nephron number.This observational study does not provide a causal relationship between urinary albumin and the development of hypertension. However, there are several possibilities supporting that urinary excretion of albumin predicts a new onset of hypertension. Most of the albumin filtered through glomeruli is reabsorbed in renal tubules, thus under normal circumstances there should be virtually undetectable urinary excretion of albumin. However, changes in the balance between filtration and reabsorption of albumin in the kidney could contribute, at least in part, to an increase in urinary excretion of albumin, and glomerular endothelial dysfunction could lead to an abnormally increased glomerular filtration of albumin.Several points about this study limited the data interpretation. First, only a single urine specimen was used to assess the baseline urinary excretion of albumin, despite the measurements showing day-to-day variation. Second, data on individual sodium intake were not included in the present analyses, although dietary sodium consumption influences both hypertension and the degree of albuminuria. Third, blood pressure and urinary albumin were measured only once a year during the relatively short follow-up period with a broad range, and new hypertension was ascertained using blood pressure measured at the annual physical checkup or by self-assessment when participants started antihypertensive medications. These points should be kept in mind when interpreting the data.In conclusion, urinary albumin is a novel predictor of future hypertension and increases in blood pressure in the general population. The risk of developing hypertension increases even with levels of urinary albumin near the threshold defined for microalbuminuria. This finding thus indicates that minor alterations in kidney function could be an important sign for managing blood pressure with the view to preventing hypertension onset.


Renal replacement therapies (RRTs) represent a cornerstone in the management of severe acute kidney injury. This area of intensive care and nephrology has undergone significant improvement and evolution in recent years. Continuous RRTs have been a major focus of new technological and treatment strategies. RRT is being used increasingly in the intensive care unit, not only for renal indications but also for other organ-supportive strategies. Several aspects related to RRT are now well established, but others remain controversial. In this review, we review the available RRT modalities, covering technical and clinical aspects. We discuss several controversial issues, provide some practical recommendations, and where possible suggest a research agenda for the future. Acute kidney injury (AKI) is common in critically ill patients and is associated with high mortality and morbidity . In patiThe aim of this review is to present a multidimensional update of RRT in AKI with a focus on mechanisms and modalities, anticoagulation, and extended indications. The topics of plasmapheresis and RRT during extracorporeal membrane oxygenation will not be covered in this review.Current RRT machines present multiple integrated components, including four- to five-roller pumps, three to four integrated scales, four to five pressure pods, reliable air detection, integrated pumps for heparin or citrate/calcium infusion, ultrafiltration, and various safety alarms. Considerable effort has gone into providing a user-friendly interface, limited error ranges, and possibility for data download/integration to electronic health records. New machines are often more a platform for multiple techniques than a simple dialysis monitor.Extracorporeal therapies are now exclusively delivered through double-lumen venous catheters. With few exceptions, blood flow is ensured by a peristaltic roller pump. Circuit pressures are constantly monitored in every part of the circuit . Furthermore, pressure drop and transmembrane pressures are calculated by the machine in order to monitor the filter clotting process. The most important aspect of filter patency is the process of concentration polarization, which is the accumulation of particles (mostly of protein nature) in the inner part of the hollow fiber that leads to a progressive decrease in membrane permeability and performance ,4. PossiVascular access is a particularly important determinant of the quality of RRT . A largeHemofiltration (HF) is a process that parallels what occurs in the human glomerulus . The tubFluid overload is associated with adverse outcomes in critical illness  and ofteThe timing of initiation of RRT remains controversial. It is clear that derangements of, for example, potassium, acid–base balance, pronounced azotemia, and fluid overload , early post hoc analyses [a priori at what level of fluid gain RRT should be started or the net ultrafiltration rate that should be prescribed; these factors should be tailored according to individual patient requirements.Interestingly, fluid overload may be a major outcome determinant for critically ill patients with AKI at continuous renal replacement therapy (CRRT) start ; it is panalyses , so thatThere is an even greater paucity of data on when to stop CRRT. RRT can be stopped when there is sufficient improvement in renal function, but how this can be evaluated while the patient is still receiving RRT remains unclear. Current practice suggests measuring urine output and serum creatinine levels while on a constant dose of CRRT and calculating the endogenous creatinine clearance by using both the urine and serum concentrations of creatinine. Decisions to delay or stop the next RRT session may be easier for intermittent treatments. Observational studies have shown that the most significant predictor of successful termination of CRRT is urine output . A urineIntermittent hemodialysis (IHD) was originally conceived as a treatment for acute renal failure, and CRRT was introduced as an alternative when IHD was contraindicated. Subsequently, CRRT has become a routine therapy for AKI in many countries but may not be available in some resource-limited settings. Intermittent therapy has advantages in facilitating rehabilitation and other aspects of therapy for some patients. However, when applied correctly, both continuous and intermittent modalities can achieve a satisfactory degree of metabolic control in most patients, and randomized controlled trials (RCTs) and meta-analyses have not shown a difference between modalities in terms of patient survival rates. The reasons for this lack of evidence may still lie in the selection of patients for the study populations, with many of the most severely ill patients excluded. Importantly, a systematic analysis of RRT modality and its effect on renal recovery from dialysis dependence in critically ill patients found that CRRT was associated with a higher rate of renal recovery compared with IHD , suggestVarious ‘hybrid therapies’ ,36 or ‘pThe dose of RRT is equivalent to the normalized dose of therapy delivered to the patient. In the past, RRT was largely under-dosed in critically ill patients. However, since the milestone trial by the group of Vicenza in 2000 , a dose Two large multicenter RCTs, the Randomized Evaluation of Normal versus Augmented Level of Renal Replacement (RENAL) and ATN studies ,43, showIn patients who had higher day 1 concentrations of plasma inflammatory mediators, intensive RRT was associated with reduced levels over the first week but no significant effect on renal recovery or mortality . HoweverThe increased solute clearance achieved by CRRT may cause unwanted losses of amino acids, vitamins, catecholamines, and other compounds . Severe Sufficient anticoagulation, without excessive risk of bleeding, is generally required to maintain filter and circuit patency in RRT. Although the precise definition of adequate filter patency is a matter of debate, most available membranes will have significant protein concentration polarization and pore fouling after 20 to 24 hours. Point-of-care (POC) techniques of coagulation - for example, rotational thromboelastometry and thromboelastography - are increasingly being used for rapid specific testing of hemostatic function in critically ill patients and during anesthesia with important clinical benefits . NeverthUnfractionated heparin (UFH) is still the most widely used anticoagulant . The majLow-molecular-weight heparins (LMWHs) have several advantages over UFH, including a lower incidence of HIT, less affinity for antithrombin, less platelet (and polymorphonuclear cell) activation, less inactivation by platelet factor-4, greater and more consistent bioavailability, and no metabolic side effects . HoweverThe complications associated with systemic heparin administration stimulated interest in regional anticoagulation techniques and especially regional citrate anticoagulation (RCA) -64. SodiCompared with systemic heparin, RCA has been associated with less bleeding, increased filter lifespan, and reduced transfusion rates and need for antithrombin III/platelet supplementation -67. RCA Although KDIGO  guidelines suggest that citrate be used for all patients without contraindications and heparin for other patients , some prEarly and adequate antibiotic therapy is crucial in critically ill patients with signs and symptoms of infection. AKI alters antibiotic elimination, leading to drug accumulation , and theCytokines and other inflammatory mediators contribute to the pathogenesis of septic shock and sepsis-associated AKI . Howeverex vivo experiments, animal experiments, and preliminary clinical studies [Standard filtration or dialysis membranes - even when used with high-volume HF - have demonstrated only limited effectiveness in removing cytokines, the vast majority of which are water-soluble and of mid-range molecular weight (5 to 51 kDa) . This is studies ,87. More studies . This teIt has been suggested that by separating the plasma so that cells do not come into contact with the sorbent, a system would need to be less hemocompatible but could be more effective. Coupled plasma filtration and adsorption (CPFA) separates plasma from blood by means of a plasma filter. The plasma is then passed through a synthetic resin cartridge for adsorption and returned to the blood. Unlike standard RRT, adsorption is very effective in removing large solutes. Once the blood has been reconstituted, a second blood filter can be used to remove excess fluid and small-molecular-weight toxins. CPFA and CRRT then can operate in series. A pilot clinical study using CPFA in sepsis demonstrated a marked resolution of immunoparalysis with function of circulating leukocytes restored to normal . A recenPolymyxin B hemoperfusion has been shown to decrease macrophage and monocyte activity and to inactivate circulating pro-apoptotic factors potentially involved in the pathogenic mechanisms of sepsis-associated AKI ,92. A syPatients with cardiac failure have reduced cardiac output and arterial underfilling but also venous congestion. Both of these aspects may cause AKI by reducing renal perfusion pressure ,97. Mech2 removal techniques may help to re-establish acid–base homeostasis and reduce vasopressor demands as well as ventilation pressures. Though not as effective as extracorporeal membrane oxygenation, extracorporeal CO2 removal in series with CRRT may contribute to further reduce tidal volumes (ultraprotective ventilation) or even help to avoid intubation [Respiratory failure is frequently associated with impaired renal function. Reduced cardiac output because of increased thoracic pressure results in activation of volume regulation characterized by sodium and water retention as well as reduced renal blood flow . Fluid rtubation ,106.2 production and thus brain CO2 partial pressure, with cerebral vasodilation and risk of increased ICP.AKI occurs in 8% to 23% of patients with acute brain injury and is an independent predictor of poor outcome in these patients ,108. AKICRRT should be the first option in these patients because it is associated with less increase in ICP compared with intermittent therapies . CRRT isCritically ill patients often develop multiple organ dysfunction. New extracorporeal therapies are being designed to provide supportive treatment beyond the classic renal indications. In the near future, technical developments in extracorporeal devices will lead to the creation of multiple organ support therapies, so that comprehensive replacement or at least support can be provided to multiple organs simultaneously. New machines already include multiple platforms in which different circuits and filters can be used in combination to support renal, heart, liver, and lung function. Such machines ideally will be able to automatically detect both ‘traditional’ (urea) and ‘inflammatory’ (cytokines) solutes in plasma of critically ill patients in order to automatically  tailor the therapy toward the ‘perfect blood purification’ system Figure . Along w


Coronary artery disease (CAD) is a leading global cause of morbidity and mortality, and improvements in the diagnosis and treatment of CAD can reduce the health and economic burden of this condition. Fractional flow reserve (FFR) is an evidence-based diagnostic test of the physiological significance of a coronary artery stenosis. Fractional flow reserve is a pressure-derived index of the maximal achievable myocardial blood flow in the presence of an epicardial coronary stenosis as a ratio to maximum achievable flow if that artery were normal. When compared with standard angiography-guided management, FFR disclosure is impactful on the decision for revascularization and clinical outcomes. In this article, we review recent developments with FFR in patients with stable CAD and recent myocardial infarction. Specifically, we review novel developments in our understanding of CAD pathophysiology, diagnostic applications, prognostic studies, clinical trials, and clinical guidelines. Some of the most important clinical trials involving patients with coronary artery disease (CAD) have assessed and confirmed the validity of FFR as a predictor of outcome. Fractional flow reserve citations in biomedical journals are increasing2 and FFR-guided management in patients with stable CAD now has Class I and Class IIa guideline recommendations.4Fractional flow reserve (FFR) is a whole cardiac cycle pressure-derived index of the maximum achievable blood flow in a coronary artery with a stenosis expressed as a ratio of maximum achievable blood flow if that artery were normal.http://www.clinicaltrials.gov, using the following key words: ‘fractional flow reserve’, ‘coronary physiology’, ‘diagnostic’, ‘stable coronary disease’, ‘acute coronary syndrome’, ‘myocardial infarction’, ‘observational study’, and ‘clinical trial’. The results include an assessment of study quality criteria6 .We consider recent studies clarifying further the role of FFR in patients with stable CAD and myocardial infarction (MI). We focus on research published from 2013 to the present, whilst also citing relevant landmark publications. We have searched databases, i.e. PUBMED and registries, i.e. 9 Invasive angiography is the reference test for the diagnosis of CAD. However, the relationship between angiographic stenosis severity and coronary blood flow is complex. Visual assessment of stenosis severity is subjective and correlates poorly with physiological significance. More objective measurements of stenosis severity using quantitative coronary analysis (QCA) are also commonly discordant with the physiological significance of the lesion, as defined by FFR (≤0.80).10Coronary artery disease is a leading global cause of morbidity and mortality.12 which itself has prognostic importance.13 The total pressure drop across a stenosis is defined by the sum of the viscous friction along the entrance of a lesion , and losses incurred by convective acceleration along the lesion . Due to flow separation and eddy formation, these pressure losses are not recovered at the stenosis exit.In the presence of an obstructive epicardial coronary stenosis, perfusion pressure is reduced leading to compensatory vasodilatation,11 Myocardial FFR (FFRmyo) is defined as the maximal blood flow to the subtended myocardium in the presence of a stenosis compared with maximal flow in the absence of a stenosis.14 Using a pressure-sensitive coronary wire, FFR is calculated from the coronary pressure distal to a stenosis (Pd) and the aortic pressure (Pa) obtained simultaneously by a haemodynamic pressure transducer, both measured under conditions of maximal hyperaemia: FFRmyo = Pd/Pa .14When coronary resistance is minimized by pharmacological vasodilatation, there is an approximately linear  relationship between perfusion pressure and blood flow within the physiological blood pressure range.Pw) during maximum hyperaemia, the contribution to myocardial blood flow from sources other than the epicardial artery  can be assessed and analysed separately.14 This is the coronary FFR (FFRcor = [Pd− Pw]/[Pa− Pw]). Myocardial FFR is normally used in practice and in most cases incorporation of Pw makes no difference to the decision for revascularization.14By measuring the coronary wedge pressure : FFRmyo = [Pd − Pv]/[Pa − Pv].14 However, pragmatically, venous pressure is not usually measured in daily clinical practice and Pv was not used for FFR calculation in the landmark clinical trials.19 This reflects the fact that Pv has minimal influence on FFR or revascularization decisions. In general, paradoxical vasoconstriction of the coronary microcirculation does not occur even in the presence of a severe stenosis.Strictly, the calculation for FFR should account for right atrial pressure  and the limits of agreement were narrow (−0.04 to −0.04). Other studies have also shown minimal FFR variation with different doses of intravenous adenosine.24The VERification of Instantaneous wave-Free ratio and fractional flow reserve for the assessment of coronary artery stenosis severity in everydaY practice (VERIFY) was a prospective study of 206 consecutive patients with an indication for an FFR measurement who were simultaneously enrolled in six European centres (4 January–10 February 2012).15 which typically occurs shortly after the onset of steady-state hyperaemia.25 Occasionally, the minimum FFR value may occur slightly before steady-state hyperaemia, implying that the Pd/Pa ratio may not equal the maximum coronary flow ratio between stenosed and normal artery.26 In this case, the steady-state FFR may be slightly higher than the minimum FFR in which case the steady-state FFR should be considered for decision-making.26Treatment decisions should be based on the minimum FFR value25 Fractional flow reserve measurements across serial lesions should be done slowly in order to reveal the minimum FFR at specific locations and repeated measurement of FFR would seem good practice.Fractional flow reserve values based on at least a 3-beat average should minimize beat-to-beat variability.et al.27 studied the influence of caffeine (an adenosine receptor antagonist) on FFR. They observed that in 28 patients with detectable blood caffeine concentrations FFR values increased with incremental doses of adenosine  compared with intra-coronary papaverine (10–20 mg) whereas the FFR results were unrelated to the dose of adenosine in 14 patients who had avoided caffeine for >24 h.Matsuomo 28 Lim et al.23 studied a cohort of patients who had an FFR evaluation with intravenous and intra-coronary adenosine in 238 lesions. They found a high degree of classification agreement  for the intravenous vs. intra-coronary routes of administration. Seto et al.25 found that peripheral and central venous routes of adenosine administration were associated with similar minimum FFR values.For intravenous adenosine, steady-state hyperaemia typically requires at least 1 min to develop meaning that the cardiologist should allow sufficient time for steady-state conditions to be established.et al.29 found that 60–100 µg of adenosine in the right coronary artery and 160–200 µg of adenosine in the left coronary artery safely induced maximum hyperaemia. The Can cONTrast Injection Better Approximate FFR compAred to Pure reSTing Physiology  study is a prospective multicentre study involving 750 patients with a clinical indication for FFR.30 A pre-specified aim of this study is to assess the equivalence between FFR measured using intra-coronary and intravenous adenosine. Given the prospective design and large sample size, this study could provide conclusive information on the utility of intra-coronary adenosine for pharmacological hyperaemia.Intra-coronary adenosine is sometimes preferred in practice as it is simpler to administer and potentially less expensive. In a recent dose–response study of intra-coronary adenosine on coronary flow velocity, Adjedj 24 and intra-coronary sodium nitroprusside,31 nicorandil,32 nitrate,33 and papaverine.34 Fractional flow reserve responses are broadly comparable for these different pharmacological vasodilator agents.23Vasodilators other than adenosine have been assessed for FFR measurement, including intravenous regadenoson (a specific A2A receptor agonist),34 A minimum lumen area (MLA) of <3.07 mm2 had moderate accuracy [area-under-the curve (AUC) = 0.65] for identifying an FFR of <0.80, and the AUC increased with increasing vessel diameter . Plaque burden had a weak positive correlation with FFR . Thin-cap fibroatheroma and calcification were associated with lower correlations between MLA and FFR. The multivariable correlates of FFR were MLA by IVUS, diameter stenosis by QCA, and left anterior descending (LAD) coronary artery (vs. right coronary artery).The FFR and Intravascular Ultrasound Relationship Study (FIRST) was a prospective, multicentre, international registry of 350 patients  that assessed the relationships between coronary lesion characteristics revealed by intravascular ultrasound (IVUS) and FFR.et al.35 found a strong inverse correlation between lesion length and FFR value. López-Palop et al.36 suggested that a length of >20 mm was the strongest morphological determinant of functional significance. Takashima et al.37 found that lesion complexity (assessed by QCA) correlated with FFR, with the hypothesis that with increasing complexity there are greater pressure losses due to flow separation and friction. In a multivariate analysis, Cho et al.38 assessed the factors associated with mismatch between FFR and QCA in 643 lesions (n = 462 patients). They observed that lesion location (LAD vs. non-LAD) predicted FFR and that QCA parameters were more likely to over-estimate stenosis severity (vs. FFR) in non-LAD lesions and short lesions. Reference vessel diameter and multi-vessel disease were associated with over- and underestimation of the physiological significance, respectively. Leone et al.39 found an inverse correlation between the amount of subtended myocardium and the FFR value. Quantitative coronary analysis cannot accurately predict FFR as it does not account for the volume of distribution of the coronary artery nor for the function of the microcirculation within that coronary territory. In summary, morphological parameters of stenosis severity influence FFR but are not a reliable substitute for physiological assessment.Iguchi post hoc analysis of the FAME trial participants, Lim et al.40 observed that the mean FFR value obtained in older patients (>65 years) was higher than that in patients <65 years , and that for any given angiographic stenosis severity the FFR value was more likely to be higher in older subjects. However, FFR-guided percutaneous coronary intervention (PCI) was equally beneficial regardless of age,40 reflecting similar potential for flow-augmentation after PCI.12 Ageing was also a multivariable associate of overestimation of disease severity in the analysis by Cho et al.38Fractional flow reserve measured in a coronary artery without atherosclerosis approximates 1.0 irrespective of age or sex, whereas this may not be the case in flow-derived indices such as coronary flow reserve (CFR) or hyperaemic stenosis resistance (HSR). Age-related changes in cardiac structure  and coronary disease (e.g. microvascular dysfunction) may influence FFR. In a 41 Li et al.42 reported a similar finding in a retrospective study of 1090 patients. The potential explanations for this discrepancy include an increased prevalence of microvascular disease in females and a lower body surface area and myocardial mass resulting in a smaller subtended myocardial territory for a given stenosis compared with males.The IRIS FFR-DEFER registry of 700 patients reported that for the same degree of angiographic stenosis severity women were more likely to have higher FFR values.46 As IMR is measured during hyperaemia, it is less dependent on haemodynamic variations and has better repeatability than CFR. Index of microvascular resistance is calculated from distal coronary pressure (Pd) multiplied by the mean transit time (Tmn) of a 3 mL bolus of room temperature saline during hyperaemia induced by intravenous adenosine, where IMR = Pd × Tmn. An IMR < 25 is considered normal, with values greater than this consistent with microvascular dysfunction.The index of microvascular resistance (IMR) is a guidewire-based quantitative measure of microvascular resistance.Figure 2). This approach may be particularly relevant in a subset of patients presenting with angina, non-invasive evidence of ischaemia, but no significant epicardial CAD (FFR > 0.80).50 In patients with non-obstructive atheroma (FFR > 0.8), an impaired CFR and an increased IMR indicates the presence of coronary microvascular disease. In contrast, in patients without obstructive epicardial CAD (by angiography or FFR), an impaired CFR and a normal IMR, diffuse atherosclerotic CAD may cause ‘low-flow’ ischaemia.47 In this situation, increasing atherosclerotic plaque burden is offset by vessel remodelling which preserves the vessel lumen diameter. With no focal stenosis, there is a lack of convective acceleration through the vessel and thus distal pressure loss is limited (FFR > 0.8) even if CFR is significantly impaired.48 The discordance between FFR and CFR  may be prognostically important.51 The Distal Evaluation of Functional Performance With Intravascular Sensors to Assess the Narrowing Effect – Combined Pressure and Doppler FLOW Velocity Measurements (DEFINE-FLOW) study will prospectively examine a management strategy that combines FFR and CFR to inform treatment decisions in 500 patients with CAD. In this study, patients with a reduced FFR but preserved CFR (>2.0) will be treated medically and PCI will only be performed when FFR and CFR are reduced.52Combining FFR with CFR and IMR measurements in daily clinical practice can give clinicians instantaneous and complementary diagnostic information on epicardial CAD and microvascular function in the catheter laboratory  that may have induced sub-maximal hyperaemia.53 Further validation of HSR has been undertaken involving post hoc ROC analyses.54 Wider adoption of Doppler-based indices is limited by reproducibility55 and pressure-flow diagnostic wires are more expensive than pressure-only wires.Hyperaemic stenosis resistance is derived from coronary pressure and Doppler flow measurements.Pd/Pa measured during contrast-induced hyperaemia is already <0.80, then pharmacological vasodilation might be obviated. Leone et al.56 assessed 104 coronary stenoses in 80 consecutive patients. They found that Pd/Pa derived from contrast media was slightly higher than FFR derived from intravenous adenosine. The correlation between these two parameters was strong  and at a cut-off of ≤0.83 contrast Pd/Pa had high diagnostic accuracy for FFR ≤ 0.80 [AUC = 0.97 ]. The primary outcome of the CONTRAST study30 is the improvement in agreement from resting indexes (rest Pd/Pa and iFR™) to contrast Pd/Pa, using FFR ≤ 0.8 as the binary reference standard.Radiographic contrast media have vasodilator properties and, if Pd/Pa may fluctuate. Focusing on the inherent variability in coronary pressure recordings, Johnson et al.57 demonstrated that despite fluctuating haemodynamics the minimum measured FFR value is highly repeatable. They have developed a novel ‘smart minimum’ algorithm to select out the highest quality FFR data within a recording, which should help cardiologists to identify the minimum FFR value for decision-making. The algorithm is generic and not commercially restricted.During a continuous recording with the pressure sensor at a fixed position in a coronary artery 59 In a post hoc analysis of the VERIFY study, we found near equivalent diagnostic accuracy for whole-cycle and dFFR with an AUC of 98% in an ROC analysis for diastolic FFR predicting FFR ≤ 0.80 . In reality, full-cycle FFR and dFFR have similar diagnostic value.Coronary blood flow is predominantly in diastole and segmentation of FFR to diastole (dFFR) might have higher diagnostic accuracy for the detection of ischaemia.60 The larger HEARTFLOW-NXT trial incorporated further developments with the FFR-CT technology and in a stringent protocol involving a selected patient population diagnostic accuracy for FFR-CT was further improved.61Fractional flow reserve can now be estimated non-invasively from high-quality computed tomography (CT) coronary angiograms. The DISCOVER-FLOW study examined the relationships between non-invasive FFR (FFR-CT) vs. FFR measured invasively in 159 arteries in 103 patients and reported that adoption of FFR-CT markedly improved the diagnostic accuracy of the CT scan.62 and also from rotational angiography images alone [virtual FFR (vFFR)63]. These promising developments should undergo further studies in larger unselected patient populations.Fractional flow reserve can be estimated using 3-D angiography, TIMI frame count (FFR-QCA),et al.64 originally described the relationships between resting and hyperaemic pressure measurements in 528 pressure wire recordings obtained in 483 patients. They found that for an FFR ischaemic threshold (≤0.75), a whole-cycle Pd/Pa cut-off of ≤0.85 had a positive predictive value of 95% and Pd/Pa of ≥0.93 had a negative predictive value of 95.7%. One other study reported near 100% diagnostic accuracy with a Pd/Pa adenosine zone of 0.87–0.99.65Mamas 66 More recently this cut-off value has been revised upwards to 0.89–0.9067 and a hybrid strategy is also proposed.68 The VERIFY22 and RESOLVE69 studies called into question the diagnostic accuracy of resting pressure indices vs. FFR stimulating further investigations,75 including head-to-head comparisons of iFR™ vs. FFR-guided management in clinical trials designed to assess health outcomes.75iFR™ involves estimation of the trans-stenotic pressure gradient at rest during a time interval starting 25% into diastole and ending 5 ms before the onset of systole using a trademarked algorithm. iFR™ was originally described in 2011 by the ADVISE investigators who proposed that an iFR™ cut-off value of 0.83 was equivalent to an FFR value of 0.80.et al.76 reported data from the large single-centre ASAN PCI registry in which 2699 patients had PCI performed before FFR was in routine use and 2398 after it became the standard of care. Fractional flow reserve was used in lesions with diameter stenosis severity between 50 and 80% when there was no prior evidence of ischaemia. Percutaneous coronary intervention was undertaken if the FFR is <0.75 and deferred if FFR is >0.8. ‘Grey zone’ results were left to the operator's discretion. The primary endpoint of the study was a combination of death from any cause, MI, and repeat revascularization at 1 year. In a propensity-matched analysis, compared with the angiography-guided population, the primary endpoint was lower in the FFR-guided population  with a hazard ratio of 0.55 . This result was mainly attributed to less peri-procedural MI and repeat revascularization, despite a lower use of stents.Park et al.77 analysed the London PCI registry (2004–2011) in which FFR was used according to operator discretion. The FFR group had an unadjusted all-cause mortality benefit  though there was no association with mortality when the data were adjusted for confounders. A propensity-matched analysis of FFR vs. angiography-alone (919 pairs) showed no difference in mortality (P = 0.32) but with a lower mean stent number in the FFR group . The publication lacked information on medically managed patients.Frohlich et al.78 reported follow-up results of a similar analysis of 7050 patients from the Mayo Clinic registry (2002–2009). They found lower MACE with FFR guidance compared with angiographic guidance . Fractional flow reserve-guided revascularization in patients with bypass grafts is also associated with a better outcome and lower costs.79Li et al.81 retrospectively analysed the outcomes of 720 (881 intermediate lesions) patients in whom PCI was deferred following FFR measurement between 2002 and 2010. Lesions were divided into three groups according to FFR: grey zone ; borderline , and non-borderline . One hundred and fifty-seven (18%) patients required deferred lesion intervention during 4.5 ± 2.1 years follow-up. Of these, 117 had PCI and 40 had coronary artery bypass graft surgery (CABG). Overall, one in four stenoses with a borderline FFR (0.81–0.85) required intervention during the study follow-up period. The rate of subsequent MI following deferral based on FFR was 11% and the deferred lesion was the culprit in 38%.Depta et al.13 measured FFR and coronary flow velocity reserve (CFVR) in one intermediate stenosis in 157 patients in whom revascularization was deferred. During 10 years of follow-up, a normal FFR with abnormal CFVR was associated with more MACE regardless of whether an FFR cut-off of 0.75 or 0.80 was used. One explanation for this discordance is that whilst successful revascularization should negate the prognostic impact of a lesion with an ischaemic FFR, this effect may be attenuated if post-PCI CFR remains abnormal. The DEFINE-FLOW study will focus on this question.52Van de Hoef 82 Two hundred patients with stable angina were enrolled in 10 UK centres. The main result was that the management plan  changed in 26% of the population. The results of the Registre Français de la FFR (R3F) in 1075 consecutive patients enrolled in 20 centres83 were consistent with those of RIPCORD in that reclassification of management with FFR was common . In addition, clinical outcomes at 1 year were not compromised by deciding the treatment plan based on FFR.The RIPCORD study was designed to assess whether routine FFR measurement during diagnostic coronary angiography would impact the management of patients when compared with angiographic assessment.n = 9173) and individual patient-level (n = 6961) data by Johnson et al.84 has provided new information on the prognostic importance of individual FFR values. Put simply, clinical events increased as FFR decreased and FFR measured post-PCI had an inverse relationship with prognosis . Fractional flow reserve-guided management reduced MACE  and angina. This analysis affirms the prognostic importance of the FFR value  and indicates that patients who have a low-normal FFR value, i.e. 0.81–0.85, have a higher likelihood of future adverse cardiac events compared with patients with a near-normal FFR value, i.e. 0.96–1.0. Although evidence from randomized trials is lacking, a pragmatic clinical approach would be to prescribe more intensive preventative therapy in patients with lower FFR values, including after PCI.81The meta-analysis of study-level  in whom PCI was intended were randomized to either PCI with optimal medical therapy (OMT) or OMT alone. Drug-eluting stents were used almost exclusively. The study was stopped prematurely by the Data Safety Monitoring Board due to a statistically significant reduction in hospital re-admission for urgent revascularization in the PCI group. Clinical outcomes in the PCI patients were similar to those in the registry patients who had no ischaemia in the first place (FFR > 0.80) . The FAME-2 design involved unblinded treatment assignment thus participants in the OMT group and their clinicians were aware that PCI had been cancelled by protocol. The definition of urgent coronary revascularization for the primary outcome required both an urgent unplanned hospital admission with persistent or increasing symptoms (with or without ECG changes or elevated biomarker levels) and that the revascularization be performed within 24 h of admission. Cardiologists blinded to the treatment group assignment adjudicated this outcome. The 2-year primary outcome results reaffirmed the initial results.19The FAME-2 trial enrolled 1220 patients with stable CAD.n = 8000).85In patients with moderate–severe ischaemia revealed by non-invasive testing, the impact of invasive management with OMT vs. medical therapy alone on cardiovascular death and non-fatal MI is currently being assessed in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial  antegrade flow is usually preserved.The diagnostic validity of FFR is less certain in ACS patients partly because of concerns that the response to pharmacological vasodilatation may be reduced due to culprit artery microvascular obstruction leading to false-negative FFR values. Accordingly, FFR is not valid in the culprit artery of STEMI patients.88 Three hundred and fifty medically stabilized patients with an NSTEMI were randomized and an initial treatment decision was made following the coronary angiogram and before FFR measurement. Where feasible, FFR was performed in each artery containing at least one lesion of ≥30% diameter stenosis by visual estimation but in the patients randomized to angiographic guidance, the FFR results remained blinded. The primary outcome was the between-group difference in the proportion of patients allocated to medical management. A higher proportion of patients were treated with medical therapy only in the FFR group compared with the angiography-guided group  . In other words, the use of FFR reduced revascularization. As in FAME,17 there was marked discordance between the visual assessment of stenosis severity and functional significance defined by FFR.The FAMOUS-NSTEMI trial (NCT01764334) was the first multicentre, randomized trial of routine FFR-guided management vs. standard invasive management in ACS patients.n = 706 lesions), an FFR result was obtained in 100% of the participants and only two coronary dissections occurred due to the pressure wire, indicating routine FFR measurement was feasible and safe. There were no adverse events relating to intravenous adenosine. There was no difference in MACE between the groups and other health and economic outcomes were similar.Of 350 patients  were possible, FFR was recorded but not disclosed in the angiography-guided group, and the stenosis cut-off value for enrolment in FAMOUS was ≥30% whereas in FAME it was ≥50%. The purpose of adopting this wider range of stenosis severities in FAMOUS-NSTEMI was to provide data on the relationship between ‘mild’ lesions and FFR. A 3.0 Tesla stress perfusion magnetic resonance imaging sub-study in FAMOUS has recently provided evidence that FFR retains diagnostic validity in medically stabilized NSTEMI patients.89 A large trial of FFR-guided management in NSTEMI patients that is designed and powered to assess health and economic outcomes now seems warranted.FAMOUS-NSTEMI3 and myocardial revascularization4 reaffirm the diagnostic value of FFR and that FFR-guided PCI with medical therapy is evidence-based to decrease the need for urgent revascularization compared with OMT alone. The guidelines state that deferral of PCI or CABG based on an FFR >0.80 appears safe. The adoption of FFR has a Class I (Level of Evidence A) recommendation when prior evidence of ischaemia is not available. Fractional flow reserve-guided PCI has a Class IIa (Level of Evidence B) recommendation in patients with multi-vessel coronary disease. The guidelines for stable CAD3 recommend consideration of direct referral of patients with severe angina or a high pre-test probability of CAD (>85% likelihood) for early invasive coronary angiography, and since information on inducible ischaemia may then be lacking treatment decisions in the catheter laboratory should be informed by measurement of FFR where appropriate . Coronary angiography with FFR should also be considered for risk stratification in patients with an inconclusive diagnosis on non-invasive testing or when conflicting results arise from different test modalities . Revascularization of angiographically intermediate lesions without ischaemia or without an FFR < 0.80 is not recommended . The guidelines also mention that non-invasive FFR requires further validation before its clinical use may be justified.4The current guidelines for stable CADThese guidelines are evidence-based recommendations, but they are not presented as binding requirements. The FFR threshold of 0.80 represents the upper limit of a transition zone for flow-limiting coronary disease, and as mentioned above, patient-specific factors influence the FFR value. Good clinical practice should take into account all relevant information when making a revascularization decision.90 FFR is described as useful in patients with intermediate lesions >5 days after the index event. Fractional flow reserve may be helpful to decide upon the treatment strategy, and in patients with multi-vessel disease, FFR may help to assess non-culprit lesions as part of a sequential management approach involving the ‘Heart Team’. The STEMI guidelines91 state that FFR may be used to assess non-infarct arteries as part of a staged revascularization approach planned for days or weeks after the initial primary PCI.In the guidelines for the management of patients presenting without persistent ST-segment elevation,File S1Supplementary material online, . The potential clinical utility of an FFR-guided management in STEMI patients with multi-vessel CAD is being studied in DANAMI-3-PRIMULTI,92 COMPARE-ACUTE,93 and COMPLETE.94The current trials of FFR-guided strategies are highlighted in File S1Supplementary material online, ) indicates that retrospective analyses in selected patient cohorts involving comparisons of diagnostic indices without masking (blinding) and/or independent analysis are common. The quality of diagnostic studies in the future must improve.As the FFR evidence-base evolves, so will the rationale for functional testing of CAD severity. An assessment of published studies using quality criteria (Emerging developments with diagnostic coronary guidewires include a diagnostic rapid exchange FFR microcatheter (ACIST NAVVUS™), and solid-state pressure wires with optical technology with the potential to overcome pressure drift , and potentially measurement of absolute coronary flow may become possible.European Heart Journal online.Supplementary material is available at All of the authors contributed to the literature review, manuscript drafts, and reviewed and approved the final manuscript.British Heart Foundation (BHF) Clinical Research Training Fellowship (FS/14/15/30661). B.H. is supported by a BHF project grant (PG/14/97/31263). Funding to pay the Open Access publication charges for this article was provided by the University of Glasgow.D.C. is supported by a Conflict of interest: The University of Glasgow holds contracts with St Jude Medical for consultancy and research conducted by C.B. K.G.O. has received consultant and speaker fees from St. Jude Medical and Volcano Corporation which manufacture pressure wires. None of the other authors have any potential conflicts of interest.


Hypertension is a complex trait that often co-occurs with other conditions such as obesity and is affected by genetic and environmental factors. Aggregate indices such as principal components among these variables and their responses to environmental interventions may represent novel information that is potentially useful for genetic studies.In this study of families participating in the Genetic Epidemiology Network of Salt Sensitivity  Study, blood pressure (BP) responses to dietary sodium interventions are explored. Independent component analysis (ICA) was applied to 20 variables indexing obesity and BP measured at baseline and during low sodium, high sodium and high sodium plus potassium dietary intervention periods. A “heat map” protocol that classifies subjects based on risk for hypertension is used to interpret the extracted components. ICA and heat map suggest four components best describe the data: (1) systolic hypertension, (2) general hypertension, (3) response to sodium intervention and (4) obesity. The largest heritabilities are for the systolic (64 %) and general hypertension (56 %) components. There is a pattern of higher heritability for the component response to intervention (40–42 %) as compared to those for the traditional intervention responses computed as delta scores (24 %–40 %).In summary, the present study provides intermediate phenotypes that are heritable. Using these derived components may prove useful in gene discovery applications.The online version of this article (doi:10.1186/s12863-015-0226-8) contains supplementary material, which is available to authorized users. Hypertension is a major risk factor for many cardiovascular diseases. , 2 MoreoTraditionally, principal component analysis (PCA)  is used The purpose of this report is to construct endophenotypes using ICA analysis of several obesity and BP measures during a sodium intervention test in the GenSalt study, and assess their utility using heritability analysis. GenSalt is a dietary sodium/potassium intervention study on blood pressure levels in rural Chinese families . After bby design. The rational for this study design (omitting probands parents from the intervention) was that the siblings of the probands would provide the most useful information [The GenSalt study was designed to identify genes related to variation in BP responses to dietary sodium . The stuormation . IsolateThis study protocol was approved by the Institutional Review Boards at all participating institutions, including Washington University in St. Louis and Tulane University, and all participants gave their informed consent.In the first 3-day baseline observation phase participants consumed their usual diet. Then, participants received a low sodium diet (51.3 mmol of sodium per day) for 1 week, followed by a high sodium diet (307.8 mmol of sodium per day) for 1 week, and finally a high sodium diet plus a potassium supplement (60 mmol potassium) for 1 week, see  for furtA variety of demographic, pedigree, medical history, lifestyle risk factor, anthropometric, blood and urine data was collected on all study participants. For the current analysis, a total of 20 phenotypes (plus age) are used  separately by gender groups after exploring distributional properties. First, sparse outliers  were temporarily set aside. A given phenotype was regressed on a polynomial in age retaining only significant terms. Age effects in the residual variance (heteroscedasticity) were also examined. A given analysis phenotype was the standardized residual from this regression. Skewness and kurtosis of these standardized variables was also explored to ensure each variable was normally distributed.The anthropometric and hemodynamic variables are adjusted for a polynomial in age , BMI and waist circumference (N = 2 variables), and the SBP and DBP responses to adjacent intervention weeks . The software R (fastICA) [Independent components analysis (ICA) is used to identify independent components using correlated variables. The 20 correlated variables include: SBP, DBP and PP, each measured at baseline and during each of the 3 intervention periods (fastICA)  is used The optimal number of components will be determined using the screen criteria. A preliminary principal components analysis  , 26 is pSeveral methods are used to define the component traits. First, loadings of each component on the original phenotypes are used to identify enriched representation of any particular phenotypic groups. Second, clinical characteristics of each component are classified using a heat map . The heat map depicts the means of the original 20 phenotypes separately for two groups, with high risk values shown in red and low risk values in green. The brightness of the colors is determined by within-variable comparisons across groups where more intense colors represent the extremes of the variable range.Heritability of the adjusted and standardized variables is computed using maximum likelihood methods under a variance components model as parameterized in the computer program QTDT . In thisThe descriptive statistics for the variables are presented in Table Table A comparison of the loadings for this factor  loadings on the eight SBP and DBP measures. However, there are additional moderate contributions from other variables for two of the factors. ICA22 has additional moderate contributions from the adiposity variables and delta BP responses, ICA33 shows moderate additional contributions from the adiposity variables, and ICA43 has little additional contributions. Thus, as the number of extracted factors increases from 2 through 4, there is a pattern of increasing homogeneity among the variables. This component represents “generalized hypertension” whose precise interpretation depends on the number of factors extracted.This factor was detected only when 3 and 4 components were extracted. Both the factor loadings and the heat map suggest this factor primarily reflects the six delta response variables. It is interesting that the contrasting directions of the loadings for the response variables in this component are consistent with their effects on blood pressure. That is, the loadings for variables that tend to increase BP (LH_) are in one direction while those that tend to lower BP (BL_ and HK_) are in the other. Both factor loadings and heat map show additional moderate contributions from the high-sodium BP variables (B_ and H_). The group with the more extreme responses also has somewhat higher baseline and high-sodium BP levels. Thus, this construct represents a “response to sodium intervention”.Finally, one factor (ICA44) was detected only when 4 components were extracted. The factor loadings Fig.  and heatHeritabilities of the individual BP traits and ICA components are shown in Tables In this study, ICA was used to explore the factor structure underlying the BP responses to a longitudinal sodium intervention study. Factors representing four basic underlying constructs were derived and were relatively stable across 2-, 3- and 4-factor solutions. Heritability analysis revealed that familial factors accounted for 40 % to 60 % of the variance in the component factors. Thus, these new endophenotypes have the potential to provide novel information about genetic architecture underlying sodium-dependent variability in hypertension, and may enhance gene discovery efforts.ICA was chosen over PCA to extract factors since any departures from multivariate normality would result in factors that, although uncorrelated, may not be independent. This would yield factors that would be difficult to interpret clinically and less likely to represent endophenotypes that would be useful in genetic applications. The component constructs arising from this study appeared to be clinically relevant and were consistent across the alternative 2-, 3-, and 4-factor solutions. Clinical interpretation of each factor was aided by the results from the heat map which discriminated among individuals based on the means of the extracted factor value.The first derived factor was labeled systolic hypertension and provided the strongest contrasts for SBP and PP means, across all background sodium levels. Clinically, systolic hypertension is characterized by elevated SBP (i.e. > 140), and is further classified as isolated systolic hypertension if DBP is normal (i.e. < 90) . As reviThe second construct was generalized hypertension . The heat map shows that this factor primarily discriminates among individuals based on SBP and DBP means, although additional variables also had moderate loadings depending on the number of factors extracted. For example, when only 2 factors were extracted (ICA22) there were additional moderate loadings for both adiposity and delta responses to the intervention. When 3 factors were extracted (ICA33), the delta response variables were removed from the hypertension factor and formed a third factor. Similarly, the addition of a 4th factor (ICA43) removed the adiposity variables to a new factor, leaving the hypertension factor a more homogeneous construct reflecting only SBP and DBP traits.As reviewed by Delles et al. , while hThe third construct is a response to the sodium intervention. This factor was stable across both the 3- and 4-factor solutions but did not appear in the 2-factor solution. The positive versus negative means in the heat map and factor loadings is consistent with the direction of effects on BP in the intervention. That is, loadings and means for the responses that lower sodium (HK_ and BL_) are opposite to those that increase sodium levels (LH_). Moreover, the group with the larger (positive or negative) responses also has somewhat higher SBP and DBP means. This suggests that individuals who are more sensitive to the sodium intervention also have higher pressures on high sodium diets, as may be expected. Genetic factors underlying this endophenotype account for over 42 % of the variance, suggesting it should be investigated to isolate the causal genes.The final construct in this study was labeled adiposity. Both the body mass index and the waist circumference measures loaded heavily on this factor. However, the factor also includes smaller loadings for most of the BP traits and the delta responses. The heritability for this construct is 49 %, as compared to heritabilities of 60 % for BMI and 52 % for the waist circumference. As recently reviewed , the herHeritabilities for the baseline BP traits in GenSalt 23 % to 25 %) are within range of those reported in the literature. For example, previous family studies from various ethnic backgrounds –37, incl % are wiIt is also noteworthy that the BP heritabilities, standardized for the background levels of sodium , were nearly doubled as compared to those for the unstandardized BPs (at baseline). This pattern was strongest for SBP (increased from 23 % to as high as 53 %) and DBP (from 25 % to 48 %), but was also noted for PP (43 % to over 60 %). As previously indicated , the envThere are limitations in this study. First, while PCA analysis always extracts as the first factor the one that accounts for the most variance among the inter-correlated traits, ICA does not order the extracted components. The ICA also does not provide statistics for determining the optimal number of components to extract. However, a priori clinical knowledge about the specific disease under study can assist in making a meaningful selection of traits and in providing information about the optimal number of factors. The preliminary use of exploratory PCA also yields information about the optimal number of factors. In general, ICA may be preferred when there are uncertainties about departures from multivariate normality and to ensure appropriate clinical interpretation of independent factors.Second, although GenSalt probands have high blood pressure, they did not meet the definition of hypertensive. Thus, some of the conclusions relating to hypertension remain to be tested in samples of hypertensive individuals. However, the fact that none of the individuals in the GenSalt were being treated for hypertension obviates other problems such as those related to the effects of medication use on blood pressure levels.Third, in general, when using nuclear family data (i.e. parents and offspring only), the heritability estimate includes both shared genes and shared environmental (lifestyle) factors provided the latter exist. Thus, the “heritability” computed using a nuclear family design may be an overestimate of the genetic effect to the extent there are shared environments or lifestyle factors that affect BP levels. However, in the current study, our family structures are extended pedigrees consisting of up to three generations (probands and their siblings as well as the spouse and offspring of the proband). Using this extended pedigree design the heritability may be less biased as compared to a more simple design of nuclear families alone .Finally, the specific results regarding the components arising from the ICA analysis may not be easily applied to other populations since our study was based on a very specific design. However, the applicability of this study is that we have found evidence of an underlying biological genetic cause for a blood pressure response to sodium. Further, this represents a “generalized” response to sodium since it includes concurrent responses to high and low sodium levels as well as to a potassium supplement. Thus, it is likely to capture genes that are common to each of these mechanisms. The identification of the genetic variants leading to this response will be investigated in follow-up studies. As reviewed in the introduction, blood pressure levels are affected by sodium intake in many populations. Whether the genetic variants identified in this Chinese sample are applicable to the general population will be investigated once the variants are identified.In summary, the present study used ICA as a robust method to extract several novel components which may enhance our ability to find the underlying genes for sodium-dependent hypertension. Certainly, as compared to the individual variables that contributed to the factors, heritabilities are higher for components indexing systolic hypertension, generalized hypertension, and BP responses to the sodium intervention. These results validate the use of these factors as novel endophenotypes in future genetic association studies.The data are available from the authors upon request to and approval from the GenSalt steering committee.


Epidemiological research has long observed a varying prevalence of hypertension across socioeconomic strata. However, patterns of association and underlying causal mechanisms are poorly understood in sub-Saharan Africa. Using education and income as indicators, we investigated the extent to which socioeconomic status is linked to blood pressure in the first wave of the National Income Dynamics Study — a South African longitudinal study of more than 15000 adults – and whether bio-behavioural risk factors mediate the association.In a cross-sectional analysis, structural equation modelling was employed to estimate the effect of socioeconomic status on systolic and diastolic blood pressure and to assess the role of a set of bio-behavioural risk factors in explaining the observed relationships.After adjustment for age, race and antihypertensive treatment, higher education and income were independently associated with higher diastolic blood pressure in men. In women higher education predicted lower values of both diastolic and systolic blood pressure while higher income predicted lower systolic blood pressure. In both genders, body mass index was a strong mediator of an adverse indirect effect of socioeconomic status on blood pressure. Together with physical exercise, alcohol use, smoking and resting heart rate, body mass index therefore contributed substantially to mediation of the observed relationships in men. By contrast, in women unmeasured factors played a greater role.In countries undergoing epidemiological transition, effects of socioeconomic status on blood pressure may vary by gender. In women, factors other than those listed above may have substantial role in mediating the association and merit investigation. Socioeconomic disparities in the prevalence of hypertension have long been observed in high income countries, where sound epidemiological evidence associates higher socioeconomic status (SES) with a lower prevalence of high blood pressure and cardiovascular disease, an association that is consistent across a variety of indicators of social position,2.By contrast, the pattern of association appears diverse in sub-Saharan Africa (sSA), where a mix of positive and negative gradients has been found across studies, in some distinct by gender-6.Inconsistencies in SES measurements, sample heterogeneity and different degrees of economic development have been argued as possible explanations of these conflicting results. HoweverModifiable bio-behavioural factors affecting blood pressure levels and risk of hypertension include body mass index (BMI) and other measures of body shape such as waist circumference, as well as resting heart rate, alcohol consumption, exercise, and smoking. A positive association between BMI and blood pressure has been consistently observed in a large number of studies, including in sSA,8-10. SiThese biological and behavioural factors are often unevenly distributed across socioeconomic strata, making them suitable candidates as mediators of the observed effects of socioeconomic variables on blood pressure. Two recRecently, the National Income Dynamics Study (NIDS) made avaThe aim of the present study was (1) to assess the independent association of education and income, as SES indicators, with blood pressure in the adult population of South Africa, and (2) to examine the extent to which differences in body mass, resting heart rate, smoking and alcohol use explain these relationships.This study analyses the adults subsample  of the first wave of the NIDS. The NIDS survey method is described in detail by Woolard et al.. It was a. Education was measured in years of completed schooling, and individual monthly income was calculated as the summation of a wide array of sources, which is considered a more reliable method than the use of single questions[Age in years was treated as a continuous variable, and race self-defined by participants according to the historical “population group” categorization used in South Africauestions. Missinguestions.Supine blood pressure and heart rate were measured twice by trained field workers in the left arm after a 5 minute rest period, using an automated blood pressure monitor . Measurements were retained if systolic blood pressure (SBP) was between 80 and 240 mm Hg, diastolic blood pressure (DBP) ≥ 30 mm Hg, and their difference was ≥ 15 mm Hg. Heart rate measurements were retained if ≥ 30 bpm and < 150 bpm.Use of antihypertensives was assessed by asking subjects if they were currently taking medication for high blood pressure.BMI, smoking, alcohol use, physical exercise and resting heart rate were considered as possible mediators of the association between SES and blood pressure.Duplicate measures of weight and height were recorded, with a third measure taken if their difference was greater than 0.5 Kg and 0.5 cm, respectively. Excluding measures with implausible values , the average of the available readings was used to calculate BMI. Current smoking status, alcohol use and physical exercise were represented by ordinal variables, as shown in TableSample characteristics were described as median and interquartile range for continuous variables and frequency for categorical measures.Based on epidemiological and biological evidence,27-31, wStructural equation modelling was used to evaluate the extent to which the hypothesised causal structure was able to explain the observed associations between variables, and to estimate the magnitude of the postulated effects. To minimise the bias due to measurement error, blood pressure and heart rate were introduced as latent variables, with the observed multiple readings as indicators.Estimated model coefficients were used to decompose total effects of SES on blood pressure (i.e. the change in blood pressure per unit increase in each of the SES indicators) into mediated and unexplained effects. Mediated effects  are represented in FigureModel coefficients were estimated adjusting for age, race and hypertensive medication. In view of previous evidence that relationships might differ by gender, models were fitted separately for women and men.α=0.05 when the confidence interval excluded the null value.To relax the assumption of multivariate normality underlying the estimation of standard errors with the usual formulae – rarely satisfied in multiple mediators models – 95% confidence intervals for mediated and unexplained effects were bootstrapped, and effects considered statistically significant at probability level Analyses were carried out using Stata®; 12 and Mplus®; 6,34, takiFurther details on modelling assumption and estimation procedure are reported in Additional fileUnweighted sample characteristics are described in TableTableThe structural models showed an excellent fit with the data , but inverse (or null) associations among women (protective effect). The relative size of the coefficients and the width of their confidence intervals suggest also that SES is more strongly associated with DBP than SBP in men, while the opposite holds for women.Overall then, the findings show an inconsistent relationships between SES indicators and blood pressure across gender. Education and income have positive (or null) associations with blood pressure levels among men  and a 0.019 mm Hg increase per income doubling (95% CI: 0.005 to 0.044). The corresponding values for DBP were 0.035 (95% CI: 0.014 to 0.063) and 0.015 (95% CI: 0.005 to 0.034).Smoking, exercise frequency and heart rate were also involved in significant relationships in men, some of them (involving exercise and smoking through BMI and HR) representing protective effects, opposite to the total effect. However, their overall role was modest compared to that of BMI. The only statistically significant direct path (representative of an unexplained harmful effect) connected income to DBP.As among men, BMI in women mediated statistically significant harmful effects, despite the overall protective role of higher SES on blood pressure. Effects mediated by BMI accounted for a 0.028 mm Hg increase in SBP per year of education (95% CI: 0.014 to 0.056) and a 0.019 mm Hg per income doubling (95% CI: 0.010 to 0.034) as well as a 0.028 mm Hg increase in DBP per year of education (95% CI: 0.014 to 0.056), and a 0.019 mm Hg per income doubling (95% CI: 0.005 to 0.034).Independently of its effect on BMI, alcohol use in women accounted for a 0.024 mm Hg increase in DBP per income doubling (95% CI: 0.010 to 0.053). The mediating role of the remaining risk factors was similar to that of men, both in magnitude and direction. Except for the effect of income on DBP, all direct paths in women were statistically significant and accounted for a sizable share of the overall association between SES and blood pressure, which remained therefore largely unexplained by the mediators hypothesised in our model.Relationships between SES and blood pressure with gender specific patterns consistent with our results (i.e. a protective effect of SES among women and a harmful effect among men) have been previously found in South Africa and otheIncreased awareness of hypertension, accessibility of and adherence to medical treatment, less chronic stress, and, recently, more favourable neighbourhood characteristics, have been indicated in the literature as possible mediators of a protective effect of higher SES on raised blood pressure, and may contribute to the share of effect among women which is unexplained in our model. The reason why a protective effect of the same magnitude is not observed in men might be related to the lower levels of awareness and control consistently observed in men than in women, and to the lower sensitivity to the adverse effect of unfavourable neighbourhood characteristics on blood pressure that recent studies suggest,18,41-44Salt intake, whose causal relationship with blood pressure levels is supported by results of experimental studies in South Africa, has alsBeyond differences in relative magnitude and statistical significance, the overall patterns of association of physical exercise, alcohol use, smoking and heart rate with both SES and blood pressure are consistent with those found in high income countries,19. HoweA separate analysis for the 5% of the total sample with the highest income offers some support for this hypothesis. In that subsample the associations between SES indicators and BMI become inverse also in men, albeit not statistically significant owing to the small sample size . This heterogeneity is not accounted for by the modest differences in the association between mediators and SBP or DBP, and calls for consideration of other variables. Among those, stress and dietary patterns (e.g. vegetable consumption) have been shown to be selectively associated with SBP and DBP, thus representing suitable targets for further mediation studies,49.Strengths of the present study include the use of a large sample and an analytical approach allowing for simultaneous testing of multiple mediation pathways  and for the explicit consideration of measurement error in physiological variables. Moreover, this study is the first, to our knowledge, to perform mediation analysis in a large sample modelling simultaneously for both SBP and DBP.The major limitations of this study are the intrinsic lack of temporal information in our cross-sectional dataset – which limits the interpretation of the temporal sequence of the relationships – and the possibility that important unmeasured confounding variables (e.g. undernutrition in infancy which could be associated with income and is a known risk factor for high blood pressure later in life) have intLow reliability of self-report data, including those on physical exercise, alcohol and tobacco use is a well known problem in population-based surveys, which usually results in observed associations biased towards the null. More prOther than for age – a strong predictor of blood pressure which is associated with many of the variables in our model – our analyses were adjusted for racial group and antihypertensive medication. Despite the fact that statistical control for race and medication is common in the literature , Besides income and education, racial group assignment may indirectly capture differences in household wealth, genetic ancestry, social stress  and dietary intake, possible confounders of the association between income and blood pressure not otherwise captured in our analyses-57. ThesSimilarly, we cannot rule out that being on medication for high blood pressure  lies on a causal pathway between SES and blood pressure . In this case, adjustment for a mediator would bias the observed association between SES and blood pressure towards the null.However, restricting our analyses to the Black subsample or omitting adjustment for antihypertensive medication did not produce appreciable changes in the overall pattern of association between variables. All model coefficients maintained the same sign with negligible to moderate changes in magnitude  effects of SES on blood pressure may vary by gender; and (2) factors other than those listed above may have a greater role in mediating the association in women.The worsening in blood pressure with upward mobility observed in men can be viewed as a significant public health cost of socio-economic development, while understanding the causes of the opposite effect in women may inform action to reduce the growing cardiovascular health burden in developing countries.a Under apartheid, South Africans were categorised into one of four socially defined groups: Asian (or Indian), Black (or African), Coloured (wide grouping of people of mixed ancestry) and White (or European). Race in this sense is closely and enduringly correlated with socioeconomic status in South Africa.The authors declare that they have no competing interests.AC performed the analysis and drafted the manuscript. RE conceived the study and contributed to the drafting of the manuscript. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/14/414/prepubStatistical analyses and further results. Methodological details on statistical analyses. Further results.Click here for file


Higher left ventricular mass (LV) strongly predicts cardiovascular mortality in hemodialysis patients. Although several parameters of preload and afterload have been associated with higher LV mass, whether these parameters independently predict LV mass, remains unclear.This study examined a cohort of 391 adults with incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study. The main exposures were systolic and diastolic blood pressure (BP), pulse pressure, arterial stiffness by pulse wave velocity (PWV), volume status estimated by pulmonary pressures using echocardiogram and intradialytic weight gain. The primary outcome was baseline left ventricular mass index (LVMI).Each systolic, diastolic blood, and pulse pressure measurement was significantly associated with LVMI by linear regression regardless of dialysis unit BP or non-dialysis day BP measurements. Adjusting for cardiovascular confounders, every 10 mmHg increase in systolic or diastolic BP was significantly associated with higher LVMI , and increased pulse pressure was also associated with higher LVMI . Intradialytic weight gain was also associated with higher LVMI but attenuated effects after adjustment . PWV and pulmonary pressures were not associated with LVMI after multivariable adjustment . Simultaneously adjusting for all main exposures demonstrated that higher BP was independently associated with higher LVMI .Among a younger and incident hemodialysis population, higher systolic, diastolic, or pulse pressure, regardless of timing with dialysis, is most associated with higher LV mass. Future studies should consider the use of various BP measures in examining the impact of BP on LVM and cardiovascular disease. Findings from such studies could suggest that high BP should be more aggressively treated to promote LVH regression in incident hemodialysis patients.The online version of this article (doi:10.1186/s12882-015-0131-4) contains supplementary material, which is available to authorized users. Left ventricular hypertrophy (LVH) is the most frequently observed cardiac abnormality in end-stage renal disease (ESRD), and strongly predicts cardiovascular mortality in hemodialysis patients . DespiteHypertension is a major risk factor for LVH, and the role of blood pressure (BP) in the progression of LVM and mortality of patients receiving hemodialysis has been well documented . The timOther factors associated with LVH are arterial stiffness and volume overload. Aortic pulse wave velocity (PWV) predicts cardiovascular disease and mortality in patients with hypertension and ESRD –11, and These parameters of arterial compliance and ventricular volume , 15, preWe conducted cross-sectional analyses using data from participants enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, which enrolled 402 adult incident hemodialysis patients who completed a baseline cardiovascular study visit. The methods of the PACE study have been described in detail previously . BrieflyThe study protocol was approved by the institutional review board of the Johns Hopkins School of Medicine, MedStar Health Systems, and by the medical director of each dialysis unit. All participants provided informed written consent.Data were collected by self-report from standardized questionnaires and also during study visits at the Johns Hopkins Institute for Clinical and Translational Research (ICTR). All participants underwent a study visit with detailed cardiovascular evaluations by trained technologists or study staff including echocardiogram, PWV and BP assessments on non-dialysis days to ensure uniformity across the study population. Based on the studies of myocardial stunning during dialysis and at the end of dialysis treatments with many shifts in fluids and electrolytes, the study visit was set to a non-dialysis day in order to standardize the study visits for all dialysis patients and asses their cardiac status at a steady state. Data on all hemodialysis treatment parameters and available laboratory tests during outpatient dialysis therapy were also provided by Davita Clinical Research and MedStar Health Systems.The echocardiograms  were performed by three trained technologists at baseline, to determine left ventricular (LV) stroke volume, LV ejection fraction, and LVMI with 4 chamber views and standard calculations for LVM. The M-mode by the parasternal short axis view was used to estimate LVM, as the long axis view can result in the improper alignment and overestimate LV dimensions and mass . All carThe exposure variables of interest included measures of volume (pulmonary artery pressures and IDWG), and vascular and arterial measurements. Vascular measurements included SBP and diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure, PWV, and augmentation index. Four different measurements of SBP or DBP and pulse pressure at various time points were included. Predialysis BP measures taken at the dialysis units were examined as (1) a three-month average of the predialysis measurements taken using automated BP measurements prior to the study visit and (2) a single measurement closest to the study visit. Non-dialysis BP measures taken at the study vist on a non-dialysis day were examined as: (1) an average of three standardized BP measures conducted using the Omron HEM-907 BP measuring device  in a seated and (2) an average of three BP measures collected using the same method in a supine position. Volume status was estimated by pulmonary artery pressure based on TR from the echocardiogram –21, as tThe primary endpoint was LVMI calculated by Devereux’s formula , as reco2 in males and LVMI greater than 104 g/m2 in females.LVH was defined as LVMI greater than 116 g/mAdditional variables included self-reported age at enrollment, sex, and ethnicity. Body-mass index (BMI) and waist to hip ratio (WHR) were determined during the ICTR visits. Comorbidities were identified by detailed chart review of medical records and included history of hypertension, hypercholesterolemia, smoking status, diabetes mellitus, coronary artery disease (CAD), congestive heart failure (CHF) and peripheral vascular disease (PVD), dialysis frequency, cause of ESRD, time since first nephrology visit, antihypertensive medications, and the Charlson Comorbidity Index (CCI). Medications were determined at baseline by medical record review from dialysis electronic patient records and participant questionnaire during the study visit. Medications were also brought in for review by the study team. As a result, adherence to medication treatment was not specifically assessed. Antihypertensive medications were grouped into the following categories: (1) Renin-angiotensin-aldosterone system (RAAS) blockade (angiotensin-converting-enzyme inhibitor [ACEi] or angiotensin II receptor blocker [ARB]), (2) β-blocker or α- and β-blocker, (3) α-blocker, vasodilator, or calcium channel blocker, (4) centrally acting agent, and (5) other. Dietary sodium intake was calculated from a 24-h diet recall at the baseline study visit. Dialysis unit hemoglobin data were included as a 3 month average prior to the study visit.For categorical variables, frequencies and percentages with 95 % confidence intervals (CI) were used; for continuous variables, means with standard deviations (± SD) were used for normally distributed data and median with interquartile range for skewed distributed data.Multiple analyses were used to examine the association of BP, arterial stiffness, and volume with LVMI. To assess the associations of each vascular, arterial and volume measurement with LVMI, a multivariable linear regression for each vascular, arterial or volume measure was conducted. To assess the independent association of each main explanatory measure with LVMI, all vascular, arterial, and volume measures were simultaneously adjusted for in the final multivariable linear regression model. Each vascular measure was modeled in a separate multivariable model due to the high correlation between the vascular measurements. The multivariable models were constructed using the forward selection model building approach, and included age, sex, ethnicity, BMI, history of hypercholesterolemia, smoking, diabetes mellitus, coronary heart disease, congestive heart failure, cause of end-stage renal disease, time since first nephrology visit, beta blocker and RAAS blockade use, number of antihypertensive medication, and dietary sodium intake. To ensure the consistency and the validity of the final model, all omitted variables were included back into the final model and this indicated that there were no significant changes in the main estimates. Correlation and variance inflation factor tests indicated a low degree of multicollinearity among all factors. Tests of non-linearity indicated that there were no significant non-linear effects. Patients with missing antihypertensive medication data (14 %) were grouped into a separate category. All other missing values for covariates were imputed using the multiple imputation by chained equations method . The impGiven the high proportion of African American patients in this study, we tested for an interaction between the exposure variables and ethnicity (African Americans vs. non-African Americans) in stratified models. We also stratified the results from the multivariable regression models using pre-identified groups of IDWG , by β-blocker medication status , and by P value of < 0.05 was considered statistically significant. All analyses were performed using Stata/SE 12.0 .A two-tailed 2 and are predominantly male and African American. Cardiovascular risk factors are common: 57 % with diabetes, 33 % with CAD, 41 % with CHF, 20 % with PVD, and 62 % has a history of smoking. The vast majority is on two to three antihypertensive medications with approximately 62 % taking a beta-blocker and 39 % on any RAAS blockade. A total of 306 patients (78 %) have demonstrable LVH.Of the 402 participants who completed the study visits with an echocardiogram, 11 were excluded due to poor echocardiographic windows for measurement of LVMI. The final study cohort comprised of 391 patients. Table Figure The associations of vascular and volume measures with LVMI are examined and shown in Table Table Given the high proportion of African American patients, we first examined the interaction between ethnicity and the exposure variables, and then stratified the results from the adjusted model  study, which examines changes in LV structure and function in patients transitioning from CKD to ESRD but could not examine the role of clinical factors associated with LV disease . We are Despite the findings of previous studies, evidence to guide BP management in dialysis patients still remains sparse . The guiOther controversies regarding the BP management in dialysis patients include the effect of BP-lowering medications, such as RAAS inhibitors, β-blockers, and calcium channel blockers, on the reduction of LVMI in hypertensive patients , 38. TheContrary to past studies, we do not find that vascular stiffness was significantly associated with LVMI . ArteriaLastly, IDWG is associated with LVMI, however, the association is attenuated after adjustment for other confounders. Another surrogate measure of volume status, pulmonary pressure, is not significantly associated with higher LVMI. In our study population of younger and diverse ethnicities, adjusting for dietary sodium intake does not modify any associations. The results of our study likely differ based on the change in residual kidney function of dialysis patients over years. Most of our cohort is studied within the first 6 months from diagnosis. This suggests that during the transition from reaching ESRD to receiving dialysis, IDWG management may not be a significant contributor until there is loss of residual function.A few limitations of this study include the cross-sectional study design, which does not provide evidence of a temporal relationship and would require a trial to demonstrate normalization of blood pressure. Other measures of volume status and pulmonary pressure and preload should also be considered in future studies, as tricuspid regurgitation by echocardiography alone may not be as accurate as newer methods such as ultrasounds to detect lung congestion , and TR Despite the limitations, this well characterized cohort of incident hemodialysis patients has been assessed in a consistent manner on non-dialysis days with standardized questions, adjudicated comorbidities and methods for cardiovascular assessment, as well as extensive dialysis unit BP and IDWG data. Moreover, our study cohort is predominantly African American (72.6 %), often underrepresented in many studies or trials, despite comprising 10.4 % of the Medicare end stage renal disease population. Understanding cardiovascular risk in this high risk population is important .Among a younger and incident hemodialysis population, afterload as measured by BP using either predialysis or interdialytic measures, is most associated with higher LVMI. This suggests that future studies should consider the use of various BP measures in examining the impact of BP on LVM and cardiovascular disease. Findings from such studies could suggest that high BP should be more aggressively treated to promote LVH regression in incident hemodialysis patients.