Left atrial enlargement (LAE) is a risk factor for cardiovascular complications and death. In hypertensive patients, LAE is usually due to left ventricular (LV) hypertrophy and diastolic dysfunction. We aimed to identify factors associated with LAE in patients with increased and normal left ventricular mass index (LVMI) with reference to pulsatile and steady components of blood pressure (BP).The study was carried out as a cross-sectional observation. In a group of inhabitants of suburban area of Cracow, Poland, we measured office, ambulatory and central BP, carotid-femoral pulse wave velocity (PWV), as well as echocardiographic indices and gathered anthropometric data, information on habits and relevant medical history. Further, with division according to sex-stratified dichotomised LVMI, we performed correlation analysis to identify possibly significant relations between measures of left atrial volume and other studied parameters. We also fitted regression models in order to assess the respective value of steady and pulsatile BP components as factors related to measures of left atrial volume.r = 0.36, P < .001) and ratio of early diastolic mitral peak flow velocity to early diastolic mitral annulus mean velocity in tissue Doppler imaging (E/e′) .The mean age of 205 patients  was 53.6 ± 8.3 years. We found higher values of PWV, office, ambulatory and central BPs in the group of LVMI above median value. This group had also greater left atrial volume index (LAVI), which correlated with LVMI  and office measurements , but not by pulse pressure.In the group of LVMI below the median, LAVI correlated with pulsatile and steady BP components. LAVI was independently predicted by mean arterial pressure (MAP) obtained from both ambulatory (MAPLV mass and function are the main determinants of LAVI. However, in persons with lower LV mass, LAVI depends on the steady component of blood pressure, but not pulsatile one. Increased LAVI reflects early changes in response to systemic blood pressure elevation. LAVI might also be useful in the prediction of first ischemic stroke and subsequent mortality, as well as mortality in heart failure patients.Left atrial enlargement (LAE) is a risk factor for paroxysmal supraventricular arrhythmias including atrial fibrillation, systemic embolism and death.,8 Increased LA volume is mainly the result of impaired LV filling. In patients with arterial hypertension, the latter is a consequence of LV hypertrophy and remodeling. It has been suggested that LV hypertrophy is a link between hypertension and left atrium enlargement. Furthermore, LA enlargement caused by hypertension is often detected earlier than LV hypertrophy or dilatation in the course of hypertensive heart disease.,11LA volume is a marker of left ventricle (LV) diastolic dysfunction severity and duration.–14 However, it has recently been suggested that new BP parameters, including central aortic BP and carotid-femoral pulse wave velocity (PWV), should also be analyzed due to their impact on cardiovascular outcomes. The pulsatile component of BP has been demonstrated in numerous studies to be involved in the pathogenesis of atherosclerosis and to be an independent marker of cardiovascular risk.–18Epidemiological studies proved the relation between cardiovascular risk, mortality and morbidity, and the level of both systolic blood pressure (SBP) and diastolic blood pressure (DBP). A stiffened aorta is less able to adapt to the volume of blood ejected by the LV, which increases the amplitude of SBP. The early return of the reflected wave in systole, not in diastole, decreases DBP. The combined effect is a widened PP. The gold standard of large artery stiffness assessment recommended by experts is carotid-femoral pulse wave velocity (PWV). Some studies have indicated a relation of PWV with LA size in patients with hypertension.,22The pulsatile component, estimated by pulse pressure (PP), represents BP variation and is affected by heart rate, left ventricle ejection fraction (LVEF), and predominantly by large artery stiffness measured by carotid-femoral pulse wave velocity. Several other studies demonstrated a positive relation between PP and LA enlargement.–26 There is lack of sufficient data from clinical studies about the relation of MAP to LA volume or size. Therefore, we decided to identify factors associated with LA enlargement in patients with LVMI below and over the median, with particular reference to pulsatile and steady components of blood pressure.The question of which component of BP, steady represented by mean arterial pressure (MAP) or pulsatile, is a stronger predictor of LA enlargement remains unresolved. The results of the Framingham study indicate that duration of arterial hypertension and level of SBP, which reflects the pulsatile component of BP, in the general population are responsible for the rise in LA size.22.1This observational, cross-sectional study included 205 subjects . Participants were recruited from a list of 1851 Morawica and Jeziorzany inhabitants  between June 2015 and January 2016. Of 462 residents aged between 40 and 65 years, 120 refused to participate, 45 temporarily moved, and 92 were excluded from the study due to acute or chronic diseases. The exclusion criteria included: heart, liver, kidney or respiratory failure; coronary artery disease. The recruited group is representative for the population in given age range. We obtained anthropometric data, information on habits, and relevant medical history from all patients with the use of a standardized questionnaire. Diabetes was diagnosed according to World Health Organization recommendations.Arterial hypertension was diagnosed according to the 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) Guidelines.The Jagiellonian University Ethics Committee approved the study protocol (decision number: 122.6120.122.2015 issued June 25th 2015).All participants were informed of the purpose and methodology of the study and gave written consent.2.2office), diastolic blood pressure (DBPoffice), pulse pressure (PPoffice = SBPoffice–DBPoffice) and MAPoffice were determined. MAPoffice was calculated according to the formula: MAPoffice = DBPoffice + 1/3 PPoffice. Around 24 hours ambulatory blood pressure monitoring (ABPM) was performed with the use of SpaceLabs 90207 device  according to ESH expert recommendations. Measurements were performed every 15 minutes during daily activity (6:00–22:00) and every 20 minutes at night (22:00–6:00). The above-described approach allowed determining 24 hours, day and night values of systolic blood pressure , diastolic blood pressure , pulse pressure  and mean arterial pressure .We performed office blood pressure measurements twice on the nondominant arm after 10 minutes of rest using Omron M5-I device  and results were averaged. Systolic blood pressure , and central pulse pressure (cPP) by applanation tonometry method with the use of SphygmoCor device integrated with relevant analytical software . The examination was performed according to expert consensus documents- in supine position, predominantly at the right common carotid and right common femoral arteries, after patient's 10 minutes rest.2.4 LV mass and LVMI were calculated by using Devereux formula.We performed all echocardiographic measurements employing 2 independent examiners by using Vivid 7 ultrasound system  equipped with a harmonic 1.7 to 3.4 MHz variable frequency phased-array transducer. The study protocol was in agreement with ESC recommendations. Maximum LA areas, except for the confluence of pulmonary veins and the left atrial appendage, were traced in apical 2- and 4-chamber views at end systole of the LV. LAVI was calculated as LA volume/body surface area. To assess intraobserver and interobserver variabilities in LAVI measurements, 15 patients were randomly selected and measurements were taken by the main observer at 2 separate occasions and another independent observer. We computed the coefficient of variation as the ratio of the mean difference between repeat measurements to the standard deviation of the paired differences multiplied by 100. Intraobserver and interobserver variabilities were around 4% and 6%, respectively.LA volume was measured using the modified Simpson's method.E), late diastolic mitral peak flow velocity (A), and their ratio were calculated.The transmitral flow velocity was obtained from the apical long-axis view with the pulse Doppler method and the early diastolic mitral peak flow velocity (e′) at both sites and the ratio of E to e′ (E/e′) were determined.The mitral annular motion velocity was recorded at the LV lateral and septal wall sites in the apical 4-chamber view by pulsed tissue Doppler echocardiography. The means of peak early diastolic motion velocity . The results are expressed as numerical values and percentages for categorical variables and mean values ± standard deviation for continuous variables. Comparisons with unrelated groups were made using Student's 32 for women and 110 g/m2 for men). Clinical, anthropometric, and demographic characteristics of study groups are presented in Table A total of 205 persons  were included in this study and divided into 2 subgroups according to the sex-specific median LVMI value , was observed in participants with LVMI above median. Those subjects also had higher PWV, central, peripheral, and ambulatory blood pressure, and LAVI Table .The study population consisted of the subjects with a LVEF within normal range and no signs of regional LV contraction disturbances.E/e′, but not with blood pressure parameters and PWV. In the group with LVMI below median value, LAVI correlated positively with blood pressure parameters, PWV, and echocardiographic parameters including LVEF, LVMI, and indices of LV diastolic function.Table office in study group according to LVMI median value is presented in Figure The relation of LAVI with MAPoffice, and MAP24h) on LAVI in patients with LVMI below and over the median value was determined by fitting univariate and multivariate linear regression models.Effect of independent factors  in Model 4 and MAP24h  in Model 1. Our analyses do not confirm any relation between LAVI and arterial stiffness index-PWV (Model 1 and Model 2) or the pulsatile component of blood pressure-cPP (Model 3 and Model 4) in participants with LVMI below, as well as above the median.The results of regression analyses are provided in Table 4In this cross-sectional study, we found that the LV mass and function are the main determinants of LAVI. However, in persons with lower LV mass, LAVI depends on mean arterial pressure, but not the pulse pressure. and the prevalence of left atrium enlargement among hypertensive subjects (over 20%), arterial hypertension is probably the most common cause of LAE.Considering arterial hypertension prevalence in the general population (reaching an average of 30%)Elevated blood pressure induces left atrial enlargement directly or via LV hypertrophy and, consequently, diastolic dysfunction. Thus, for better discrimination of these 2 mechanisms, we divided our study group into 2 subgroups below and over the LVMI median value. The group with LVMI above median value was characterized by older age, higher BMI, higher prevalence of arterial hypertension, and diabetes. All of the above-mentioned variables or clinical conditions promote the development of LV hypertrophy.,23,36,37 The consequence of differences listed above is the higher LAVI in the group close to diagnosis of LV hypertrophy than in the group with LVMI below median value.Moreover, the group with higher LVMI had higher blood pressure parameters  and indices of arterial stiffness-carotid-femoral PWV and central aortic blood pressure, comparing to the group presenting lower LVMI. Echocardiographic parameters of LV diastolic function were expectedly worse in the group with LVMI over the median value. Each cardiovascular variable listed above, including LVMI, may contribute to LA enlargement. in a group of adults with normal LV systolic function. Katayama et al suggested that elevated LV mass influences more directly left atrium through the elevation of LV filling pressure than the presence of hypertension. This conclusion is consistent with our results in the group with increased LVMI, where neither any blood pressure parameters, nor arterial stiffness correlated with LAVI. In contrary, in our group with lower LVMI blood pressure and arterial stiffness parameters remained in significant relation with LAVI. The findings might imply that at certain stage of LV hypertrophy progression, BP values are of less importance for further LAE and its pathological consequences like arrhythmia and systemic embolism, than LV hypertrophy itself. In the interim, BP parameters may influence LAVI, therefore BP control, independently of antihypertensive drug used, should prevent LA enlargement. Once LV hypertrophy develops along with its hemodynamic consequences for the LA, more attention should be paid to the antihypertensive medication choice. Priority should be given to those with evidence of cardiac hypertrophy prevention in order to counteract late LAE complications.In both groups, LAVI was in significant positive correlation to LV mass and LVMI. Similar results were obtained for the association between LA enlargement and the LV hypertrophy by Katayama and coworkers and Xu et al found significant relation between arterial stiffness  and LA diameter, while Janwanishstaporn and Boonyasirinant reported the correlation for LAVI, all in the groups of hypertensive subjects.Similarly to our results Lantelme et al,23,26,36 Some of them indicated that after inclusion of LV mass in the multivariable regression models, the relations between blood pressure variables and LA size were no longer statistically significant.Many studies confirmed the link between different blood pressure parameters and LA diameter or volume.In other studies, like the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, systolic blood pressure was an independent covariate of LA enlargement in patients with LV hypertrophy, but the odds ratio for this relation was only 1.01 (95%CI: 1.002–1.02). For comparison, the odds ratio in the relation between LV hypertrophy and LA enlargement in LIFE study was 2.46 (95%CI: 1.76–3.45).According to our results from a selected sample of the general population, we suggested that in subjects who are older, with a higher prevalence of arterial hypertension, and with increased LVMI, LV mass is crucial for LA enlargement. In younger subjects with a lower blood pressure, lower prevalence of hypertension and other comorbidities, like diabetes and consequently, lower LVMI, blood pressure and arterial stiffness parameters are more significant for LA enlargement. The last finding is of special importance when we consider LA enlargement as an early sign of hypertensive heart disease. Su et al., in a group of patients with early stages of arterial hypertension, found a 57% incidence of LA enlargement.In the group of patients where LVMI is not the predominant variable determining left atrium volume, it is a point of interest, which component of blood pressure is closer related with left atrium volume index. proved a significant correlation between LA size and BP parameters including SBP, PP, and MAP. However, after adjustment for BMI and age, only SBP and PP did have a significant contribution to LA size.Vaziri et alAmong hypertensive patients in the study of Cuspidi and coworkers in multivariate correlation analysis systolic and pulse pressure correlated positively and diastolic blood pressure negatively with left atrium size. MAP value was not included in this analysis.,25 In diabetic subjects, Zapolski and Wysokinski demonstrated a correlation between PP and LAVI and lack of correlation between LAVI and aortic DBP, which is mainly reflected the steady component of blood pressure.Similar results indicating PP as a determinant of LA enlargement were demonstrated by other investigators.office measured using Omron device and cPP measured by SphygmoCor). Different approach to regression models’ construction (including more than 1 BP variable in category) was proposed by Mulè and coworkers who presented interesting observation of BP components predicting LV hypertrophy.Contrary to the results cited above, in our group of patients with LVMI below median value, LAVI was in significant association with MAP values, but not with PP values. Regression models we fitted supported the clear distintion of relevant BP components influence on LAVI. We namely assumed introduction only 1 BP variable measured in given settings and representing steady or pulsatile BP component to eliminate multicollinearity . Both, SBP and DBP, are in strong positive association with cardiac afterload, one of the most important factors responsible for LV hypertrophy development. Thus, it is not surprising that MAP was associated positively with LV wall thickness and negatively with LV diastolic function in a large cohort in the Framingham Heart Study. In Framingham study PP was associated, similarly to MAP, with LV diameter and wall thickness, but additionally with LV systolic function.Because LAE is usually the consequence of LV hypertrophy and impaired LV filing we may expect similar stronger relation between MAP and LAVI than PP and LAVI. Calculation of LAVI in early stages of arterial hypertension, as well as in patients with low estimated cardiovascular risk, with no signs of LV hypertrophy or arterial stiffness , may provide new information about their cardiovascular risk.Of note, in the Physicians’ Health Study MAP next to SBP and DBP strongly predicted cardiovascular diseases (CVD) in younger man, whereas either average SBP or PP predicted CVD among older. Of note, 50% of study group was diagnosed for arterial hypertension. Expectedly, hypertension was more prevalent in the group with higher LVMI, however the frequency and type of antihypertensive medication used was comparable; thus we did not expect any differences in the results obtained secondary to the medication used, which was confirmed in sensitivity analysis.Our results should be considered within the context of the limitations of our study. The study group consisted of participants from a specified age range (40–65 years) which was optimal to evaluate the early signs of heart remodeling. For this reason, the results of the study should be extrapolated for the general population with caution. We used median value of LVMI to distinguish groups with or without a tendency for LV hypertrophy, which is more appropriate for the general population than using defined cut-off points recommended by guidelines for hypertensive patients.5LV mass and function are the main determinants of LAVI. However, in persons with lower LV mass, LAVI depends on the steady component of blood pressure, but not the pulsatile one. Increased LAVI reflects early changes in response to systemic blood pressure elevation.We are sincerely grateful to Mrs Elzbieta Zietara and her team for the organizational support and technical assistance with the echocardiographic examination, arterial stiffness, and ambulatory blood pressure measurements. Mr Daniel Rabczenko provided us statistical expertise, for which we thank.


Chronic venous insufficiency (CVI) is a common pathology of the circulatory system and is associated with a high morbidity for the patients and causes high costs for the healthcare systems. Arterial stiffness has been shown to be a predictor of cardiovascular events and mortality. The relationship between CVI and arterial stiffness using pulse wave velocity (PWV) and augmentation index (Aix) was evaluated in this study. Sixty-two patients with the stage of C3-C5 chronic venous disease (CVD) and 48 healthy subjects were enrolled in the study. To assess arterial stiffness, all cases were evaluated with I.E.M. Mobil-O-Graph brand ambulatory blood pressure monitor device. PWV and Aix were used to assess arterial stiffness in this study. The mean age was 61.9±11.05 years and 54 % of the patient population was females. PWV and Aix were significantly higher in CVI patients than controls  and also positive linear correlation was observed between CVI and all measured arterial stiffness parameters . A PWV value of > 9.2 has 88.9 % sensitivity and 71.4 % specificity to predict the presence of CVI. PWV and Aix are the most commonly used, easy, reproducible, reliable methods in the clinic to assess arterial stiffness. Logistic regression analysis showed that PWV and Aix were the independent predictors of CVI. PWV has the sensitivity of 88.9 % and specificity of 71.4 % to detect the presence of CVI. Chronic venous disease (CVD) is a common pathology of the circulatory system that has high prevalence, high cost of diagnosis and treatment, significant loss in manpower, and adverse effects on the quality of life of the patients , 2. ThisCVD includes the full spectrum of signs and symptoms associated with classes C0 to C6 of the Clinical–Etiology–Anatomy–Pathophysiology (CEAP) classification and Chronic Venous Insufficiency (CVI) is a severe form of the disease.Arterial stiffness is a strong predictor of cardiovascular (CV) events and all-cause mortality –5. VarioTraditionally, arterial stiffness has been assessed by pulse wave velocity (PWV), a noninvasive parameter which has been shown to predict cardiovascular mortality –10. In aVenous pathology develops when venous pressure increases and blood return is insufficient. Continuous venous hypertension leads to some histological changes known as “venous hypertensive microangiopathy” in capillary networks. These changes are capillary network curl, expansion, and increase on the endothelial surface. It is inevitable that the changes in the venous system due to the continuity of vascular structure also affect the arterial system. Arterial stiffness in CVI may be affected due to the continuity of vascular structure. Although arterial stiffness is known in coronary heart diseases and arterial pathologies, there is no sufficient information about venous diseases. As a result, we aimed to evaluate the arterial stiffness in CVI patients with PWV and Aix.Sixty-two patients with the stage of C3-C5 CVD and 48 age/sex and body mass index (BMI) matched healthy subjects were enrolled into the study between November 2015 and April 2016. CVD was evaluated according to CEAP classification. Patients fulfilling CEAP class 3, 4, and 5 were included in this study. The exclusion criteria were history of myocardial infarction, percutaneous coronary intervention (PCI) and coronary bypass grafting, cardiac pacemaker, heart failure, cardiomyopathy, valvular heart diseases, arrhythmia, LVEF < 55%, thyroid dysfunction, chronic renal failure , peripheral artery disease , connective tissue disorders, malignancy and use of cardiotoxic medication, uncontrolled hypertension, congenital heart disease, chronic obstructive lung disease, congenital CVD, secondary CVD, and active leg ulcers (CEAP class C6). The study was approved by the local ethics committee. All of the patients in the study signed an informed consent form.Body mass index  was calculated by dividing body weight in kilograms by the square of body height in meters. Transthoracic echocardiography assessment  was performed in patients according to the echocardiography guidelines. All images were accrued from patients in the left lateral decubitus position and connected to ECG.Diabetes mellitus (DM) was defined as fasting plasma glucose ≥ 126mg/dl or plasma glucose level ≥ 200mg/dl 2 hours after the 75mg oral glucose tolerance test or HbA1C ≥ 6.5% or patients using antidiabetic medications. Hypertension (HT) was defined by a previous diagnosis of hypertension or the presence of SBP ≥140 mmHg or DBP ≥ 90mmHg. Hyperlipidemia (HLP) was defined as total cholesterol >190mg/dl or previous diagnosis of dyslipidemia. Cigarette smoking was defined as smoking ≥1 cigarettes a day for at least 1 year, without an attempt to quit.I.E.M. Mobil-O-Graph ambulatory blood pressure monitor device, which automatically measure pulse wave velocity (PWV), central blood pressure (cBP), augmentation index (Aix), and central pulse pressure (cPP), was used to evaluate arterial stiffness. Ambulatory blood pressure measuring device recorded data from patients for 24 hours. PWV, Aix, and cBP from these parameters were used in this study.SPSS 25.0  program was used to analyze the variables. Quantitative variables were expressed as mean ± SD (standard deviation) and median range (Maximum-Minimum) according to the normal distribution of the variable, and categorical variables were expressed as numbers and percentages. The normal distribution of the data was evaluated by the Shapiro-Wilk test and the variance homogeneity was evaluated by the Levene test. The Independent-Samples T test was used with the Bootstrap results when comparing two independent groups with one according to the quantitative data, and the Mann–Whitney U test was used together with the Monte Carlo results. To compare categorical variables, Pearson Chi-Square and Fisher Exact tests were tested using exact results. The odds ratio was used to determine the most important risk factor from categorical significant risk factors. Binary logistic regression analysis and Receiver operator characteristic curves (ROCs) were used to analyze the sensitivities of PWV and Aix to predict the presence of CVI. Variables were examined at 95% confidence level (Cl) and p <0.05 was considered to indicate a statistically significant difference.The mean age was 61.9±11.05 years and 54 % of the patient population was female. Baseline characteristics of study groups were compared in There were not any significant differences between groups for age, gender, HT, DM, HLP, LVEF, BMI, and smoking . Also thTG was significantly higher in patients with CVI than controls  .PWV and Aix were significantly higher in CVI patients than controls   and alsoPWV  =5.36, 95% Confidence interval (C.I.) =2.35–12.26), Aix , and TG  were the independent predictors of CVI .ROC analyses were performed to find out ideal arterial stiffness cut off values to predict the presence of CVI. A PWV value of > 9.2 has 88.9 % sensitivity and 71.4 % specificity and an Aix value of > 18.4 has 81.9 % sensitivity and 54.2 % specificity to detect the presence of CVI (AUC 0.826 (p<0.001) and AUC 0.795 (p<0.001), respectively) Figures .CVD is a progressive medical condition that results from venous hypertension. It is already a major and growing global medical problem, with a high economic burden. Chronic inflammation and “venous hypertensive microangiopathy” are the principal basis behind the pathophysiological mechanisms that potentiate disease progression and produce the signs and symptoms of CVD. Brought on by chronic venous hypertension, the accumulating leukocytes and damaged venous endothelium initiate inflammatory cascades in the distended veins, which then propagate into the microvasculature and surrounding tissues. This chronic inflammation further degrades venous integrity and function, resulting in diminished venous return, fluid accumulation, tissue fibrosis, atrophy, and ulceration in severe cases .An injury or dysfunction in a part of vascular tree may affect all vascular system. Atherosclerosis, arteriolosclerosis, and CVD share common risk factors and mediators. Therefore, CVD may be an accepted form of vascular sclerosis and vascular system should be evaluated in continuum. Arterial stiffness in CVI may be affected due to this continuity of vascular structure. Therefore, arterial stiffness using PWV and Aix in CVI patients was investigated in this study. The present study showed that PWV and Aix were significantly increased in patients with CVI compared to controls. Logistic regression analysis showed that PWV, Aix, and TG were the independent predictors of CVI.Ozpelit et al. reported that among the arterial stiffness parameters, central aortic pressure, Aix, and PWV were slightly higher in patient with CVD . SimilarAykan AC et al. showed that cardioankle vascular index (CAVI) is independently increased in CVI patients and a CAVI value of > 7.9 had a sensitivity of 64.4% and a specificity of 94.7% for predicting the presence of CVI . HoweverSimilarly, in terms of dyslipidemic condition, we showed that TG was significantly increased in CVI patients. It may be attributed to the roles of HDL and TG in chronic inflammation and atherosclerosis.Weber T et al. investigated the relationship between left ventricular mass and brachial office as well as brachial and central ambulatory systolic blood pressure. They founded that in younger participants, central ambulatory systolic pressure was superior to both other measurements. Central ambulatory systolic pressure, measured with an oscillometric cuff, shows a strong trend toward a closer association with left ventricular mass and hypertrophy than brachial office/ambulatory systolic pressure . In the Association between symptoms of CVD in the lower extremities and cardiovascular risk factors was evaluated by Auzky O et al. and they showed that CVD symptoms were strongly associated with a higher prevalence of pathological values of ankle/brachial systolic blood pressure index (ABI) and several other manageable cardiovascular risk factors . These fIn conclusion, arterial stiffness is increased in patients with CVI. PWV and Aix are the most commonly used, easy, reproducible, reliable methods in the clinic to assess arterial stiffness. Logistic regression analysis showed that PWV and Aix were the independent predictors of CVI. PWV has the sensitivity of 88.9 % and specificity of 71.4 % to detect the presence of CVI.The main limitation of our study is a small patient population (110 patients) and cross-sectional study design. Since there is no follow-up in our study, it is not possible to determine the importance of this result in daily practice. Further studies are needed to determine the real diagnostic and prognostic role of these abnormalities in the clinical management of CVI patients.


Efficient and effective strategies for treating chronic health conditions such as hypertension are particularly needed for under-resourced clinics such as Urban Indian Health Organizations (UIHOs).The objective of the Controlling Blood Pressure Trial is to assess the impact of an interactive voice response and text message (IVR-T) intervention compared with usual care among individuals with hypertension receiving care at a UIHO in Albuquerque, New Mexico. This manuscript presents the baseline characteristics of individuals enrolled in the trial and compares their characteristics with those in the hypertension registry who did not enroll in the trial.A hypertension registry developed from the clinic’s electronic health record was used for recruitment. Potentially eligible participants were contacted by letter and then by phone. Those who expressed interest completed an in-person baseline visit that included a baseline survey and blood pressure measurement using standardized procedures. Individuals randomized to the intervention group could opt to receive either automated text messages or automated phone calls in either English or Spanish. The messages include reminders of upcoming appointments at First Nations Community HealthSource, requests to reschedule recently missed appointments, monthly reminders to refill medications, and weekly motivational messages to encourage self-care, appointment keeping, and medication taking for hypertension. Individuals in the IVR-T arm could opt to nominate a care partner to also receive notices of upcoming and missed appointments. Individuals in the IVR-T arm were also offered a home blood pressure monitor. Follow-up visits will be conducted at 6 months and 12 months.P=.04 for systolic blood pressure and P=.01 for diastolic blood pressure), were more likely to self-pay for their care , and had a more recent primary care visit . The enrolled cohort reported a high prevalence of poor health, low socioeconomic status, and high levels of basic material needs.Over a 9.5-month period from April 2017 to January 2018, 295 participants were enrolled from a recruitment list of 1497 individuals. The enrolled cohort had a mean age of 53 years, was 25.1% (74/295) American Indian or Alaska Native and 51.9% (153/295) Hispanic, and 39.0% (115/295) had a baseline blood pressure greater than or equal to 140/90 mmHg. Overall, the differences between those enrolled in the trial and patients with hypertension who were ineligible, those who could not be reached, or those who chose not to enroll were minimal. Enrolled individuals had a slightly lower blood pressure DERR1-10.2196/11794 American Indians and Alaska Natives (AI/ANs) face pervasive health disparities in comparison with other racial and ethnic groups in the United States. Although disparities in diabetes have received national attention, cardiovascular disease (CVD) remains the primary cause of mortality in AI/ANs as in other groups . InterveTreatment of hypertension is a pillar of CVD prevention. Hypertension is the most common chronic health condition in the United States . UncontrInteractive Voice Response and Text Message (IVR-T) technology can be used to send targeted voice messages to landlines and voice or text messages to cell phones. IVR-T tools could improve hypertension care by sending reminders about appointments or medication refills, recalling individuals who have missed appointments, and providing educational and motivational messages . ExistinThe specific aim of the Controlling Blood Pressure Trial is to assess the impact of an IVR-T intervention compared with usual care among individuals with hypertension receiving care at a UIHO in Albuquerque, New Mexico. The primary study endpoint is change in mean systolic blood pressure between baseline and 12 months. Secondary endpoints include change in diastolic blood pressure, self-reported adherence, and the proportion of missed clinic appointments between intervention and control groups.This pragmatic clinical trial is taking place at First Nations Community HealthSource (FNCH), a nonprofit, urban Indian community-based health and human services organization incorporated in 1972. The health center is authorized through Title V of P.L. 94-437, and subsequent amendments, of the Indian Health Care Improvement Act to improve the health of urban Indians. FNCH has expanded its mission to serve the greater community, without losing its fundamental basis for existence, and now provides primary medical care to urban AI/ANs and other socially disadvantaged residents of the Albuquerque, New Mexico area. In 1997, the center was designated as a Federally Qualified Health Center, and it is an Accreditation Association for Ambulatory Health Care (AAAHC)-Accredited Health Center and Medical Home. Approximately 40% of FNCH clients are AI/AN; Diné (Navajo) is the most common tribal affiliation. Many other clients served by FNCH are undocumented immigrants. Housing insecurity and homelessness are common. Most clients speak either English or Spanish as their primary language. FNCH has 3 campuses in close geographic proximity in southeastern Albuquerque. The medical clinic is staffed by physicians, nurse practitioners, and physician assistants with extensive support staff including public health nurses, diabetes educators, patient navigators, and on-site behavioral health clinicians. FNCH provides comprehensive primary medical, dental, behavioral health, and traditional healing and a range of preventive support services to address the health disparities experienced by its target population. Its mission is to provide a culturally competent, comprehensive health service delivery system integrating traditional values to enhance the physical, spiritual, emotional, and mental well-being of American Indian families and other underserved populations residing in Albuquerque and on tribal reservations.The study team established an Advisory Council consisting of FNCH staff from pharmacy, public health nursing, and social services and 2 patients and their caregivers. The Advisory Council actively collaborated in designing the trial, including participant eligibility criteria, recruitment materials, incentives for participation, operationalization of the intervention, participant survey materials, and the timing and content of the IVR-T messages. The Advisory Council met 3 times before starting the study and has met at least twice annually during the study itself.Consistent with principles of a pragmatic trial, study inclusion criteria are broad, to demonstrate the impact of the intervention in a “real world” setting . IndividBefore the initiation of the trial, the study team developed a hypertension registry using information extracted from FNCH’s electronic medical record, eClinicalWorks . FNCH began using eClinicalWorks in 2012. The registry was built using SAS version 9.4 . This registry had several purposes, including characterization of the FNCH population, assessment of baseline blood pressure control, and recruitment for the randomized trial. Hypertension was identified using diagnosis codes , orders for antihypertensive medication, and elevated blood pressures (≥140/90). We considered individuals to have hypertension if any 1 of the following criteria was met: (1) having 2 visits with a hypertension diagnosis on different days, (2) having 1 visit with a hypertension diagnosis and 1 medication order, (3) having 1 visit with a hypertension diagnosis and 1 elevated blood pressure, or (4) having 2 consecutive elevated blood pressures on different days . For stuExclusion criteria include the following: another preferred site of primary care, significant impairment of vision and hearing, life-limiting illnesses such as advanced cancer, renal dialysis, receipt of home health care with blood pressure monitoring and/or assistance with administration of medications, hospice services or residence in a nursing home, dementia, pregnancy at the time of recruitment, current homelessness, no landline or cellular phone access, or inability to understand English or Spanish.Potentially eligible participants were contacted by letter and then by phone. Those who expressed interest completed an in-person baseline visit that included the informed consent process, a baseline survey, and blood pressure measurement using standardized procedures. They were then randomized to either the IVR-T intervention or usual care.Individuals were randomized 1:1 to IVR-T intervention or usual care using block randomization with blocks of 4. A randomization table was generated by the study statistician (SX) using SAS software. The study coordinators were blinded to the randomization sequence.Since 2005, the Institute for Health Research at Kaiser Permanente Colorado has developed and managed an IVR-T system that initiates telephone calls to landlines or cellular phones and text messages to cellular phones. The system uses a commercial database to distinguish between cellular phones and landlines and to determine whether a cellular phone is text-enabled . For thiParticipants complete in-person baseline, 6-month, and 12-month visits. At each visit, blood pressure measurements are collected and participants complete a survey. Blood pressure is measured in a standardized fashion during the research visits, using an Omron HEM 907XL IntelliSense Professional Digital Blood Pressure Monitor (an automated sphygmomanometer) . After aIn addition to information from the baseline survey, we also collected demographic characteristics, hypertension characteristics, comorbidities, and geographic variables using information from the FNCH electronic health record (EHR). Race and ethnicity were categorized using the following hierarchical categories: AI/AN, Hispanic, non-Hispanic white, non-Hispanic African American, non-Hispanic other, and missing. Individuals with missing ethnicity information were assumed to be non-Hispanic.2 using the CKD-EPI estimating equation [Comorbidities such as diabetes, cardiovascular disease, and depression were defined as the presence of at least one ICD-9 or ICD-10 diagnosis code within the previous 2 years see . Chronicequation .Ever homeless was defined using EHR visit types specific to homeless services and include information on visits since the inception of the FNCH EHR in 2012. The multiple insurance payers for FNCH clients were categorized into 5 groups . We then defined the dominant payer by determining which insurance category predominated over the previous 2 years. When 2 encounters had different insurance categories, we assumed that the insurance change occurred at the midpoint between the 2 encounters. We geocoded addresses and created maps to determine those in and out of the Albuquerque city limits and Bernalillo County limits using ArcMap 10.3.1.  on a secure system. We also mapped the addresses onto census tracks and reported median household incomes and educational levels, using census track information from the 2010 US census. We assessed diet quality using the diet metric from the American Heart Association Simple 7 score and physical activity using American Heart Association recommendations .The primary outcome of the trial is the change in systolic blood pressure between baseline and 12-month research visits, comparing participants receiving the IVR-T intervention with those in usual care. Secondary outcomes are change in diastolic blood pressure between baseline and 12 months, self-reported adherence, and the proportion of missed clinic appointments.The primary medication adherence measure is the self-reported Voils instruments administered at baseline and during both follow-up surveys ,40-42. TThe measure of visit adherence is the proportion of scheduled appointments that are kept, missed, or canceled. This measure is assessed using the FNCH EHR and calculated as a proportion of all visits scheduled during the period from enrollment to the end of follow-up. This is a standard measure in interventional trials to improve appointment keeping . All 3 vInformation from the hypertension registry and the randomization table was loaded into REDCap electronic data capture tools hosted at Kaiser Permanente Colorado. REDCap was then used for study data collection, data management, and completion of the study visit questionnaires. REDCap is a secure, Web-based app designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry, (2) audit trails for tracking data manipulation and export procedures, (3) automated export procedures for seamless data downloads to common statistical packages, and (4) procedures for importing data from external sources .The primary analytic strategy will be intention to treat. As secondary analyses, we will also perform per protocol and as-treated analyses. Linear mixed models will be used to analyze repeated measures of systolic blood pressure (the primary outcome variable) and diastolic blood pressure (a secondary outcome variable) as continuous variables . For eacWe anticipate that some outcomes will be missing because of missed appointments or attrition. By default, the linear mixed models accommodate missing data by assuming that data are missing at random (MAR). We will explore different ways to examine the assumption of MAR . When tht test was used to compare with Mann-Whitney P values as a check, and the results were similar except for distance to clinic. Due to outliers for distance to clinic, we report the medians. To compare agreement between the EHR and the study survey for specific comorbidities, we used the prevalence and bias adjusted kappa [In our analyses of the baseline data, we compared individuals in the recruitment pool who did and did not enroll in the trial using SAS version 9.4. Statistical significance was computed using Fisher exact test for categorical variables and Mann-Whitney for discrete ordinal variables and continuous variables. A ed kappa .Our initial target sample size for this study was 512, based on the following assumptions: (1) 1800 individuals in the FNCH hypertension registry, (2) 36% of eligible FNCH clients would agree to enter the study, and (3) 80% of those would complete the trial. This would have yielded 80% statistical power to detect a 5 mmHg reduction in systolic blood pressure with a Cronbach alpha of .05 and estimated SD in systolic blood pressure of 18 mmHg [This study was approved by the Kaiser Permanente Colorado Institutional Review Board (KPCO IRB). The Colorado Multiple Institutional Review Board, which governs research activities at the University of Colorado Anschutz Medical Campus, ceded to the KPCO IRB. The National Indian Health Service Institutional Review Board determined that it did not have oversight of the study and deferred to local authorities. The study was registered at clinicaltrials.gov (#NCT03135405) on April 27, 2017.Recruitment for the study took place from April 12, 2017, to January 31, 2018. Out of a recruitment list of 1497, a total of 295 eligible individuals completed the informed consent process and were randomized. An additional 6 individuals were randomized but were then found to be ineligible, as they had not had a qualifying visit at FNCH in the previous 2 years. These individuals will be excluded from all analyses. Individuals were not enrolled because of the following reasons: could not be contacted (n=508 or 35.0%), declined to participate (n=496 or 33.1%), were ineligible (n=106 or 7.1%), or never completed a baseline visit . The study cohort was 25.1% (74/295) AI/AN and 51.9% (153/295) Hispanic. Among the AI/AN participants, 8 (10.8%) also identified as Hispanic. Almost all participants reported having hypertension (94.5%), whereas 79.8% reported taking blood pressure medication. Only 17.4% had a home blood pressure monitor. Nearly all individuals in the intervention group  opted to receive a blood pressure monitor as part of the study intervention. Over one-third (39.0%) had a baseline blood pressure greater than or equal to 140/90 mmHg. Our self-reported medication adherence rate was 36.4%. Concordance between the medical record and the survey was relatively good for most chronic health conditions, with prevalence and bias adjusted kappa for diabetes, CVD, chronic kidney disease, and depression of 0.81, 0.71, 0.73, and 0.55, respectively.Over three-quarters of the sample reported a poor diet. Our study cohort reported poor general health, with only 46% reporting good or better health. Self-reported socioeconomic status was low. Over one-third of participants had less than a high school education, and over one-quarter of individuals were unemployed or unable to work. Over one-third of participants reported annual household incomes of less than US $10,000, with a mean annual household income of US $17,170 and median household income of US $12,500. Basic resource needs were very common. High percentages of participants reported they did not always have enough money to buy food, health care, or utilities.Individuals who did not answer or who chose the “does not apply” option were included in the denominator as not having that particular social need; this number varied widely between the different options .Our recruitment pool from the FNCH hypertension registry was 17% smaller than originally estimated (1497 instead of 1800). We successfully recruited 295 individuals or 20%. Improving the health of underserved populations requires effective, low-resource interventions. The Controlling Blood Pressure Trial will evaluate the effectiveness of an IVR-T intervention to improve blood pressure, medication adherence, and visit keeping among individuals with hypertension who receive care at a UIHO. The study has enrolled 295 individuals with hypertension. Important design features of this trial include (1) registry-based recruitment, which allows the assessment of generalizability to the source population, and (2) a pragmatic design that minimizes exclusions.A recent review of the representativeness of major cardiology randomized clinical trials found that “real-world” cardiology patients tend to have higher risk characteristics, to be older, to be more likely to be female, to have clinical impairments and comorbidity disease, and to be treated less frequently with guidelines-recommended therapy, compared with individuals enrolled in cardiology RCTs. In many studies, over 50% of “real-world” patients would be ineligible for trials . HoweverThe study is designed to be pragmatic , with inWe did observe some discrepancies in baseline data between the 2 data sources (self-report vs EHR). For example, the race data showed 90.2% agreement between the data sources. For the main trial analysis, self-reported race will be used as the gold standard. The proportions of those reporting having hypertension and taking blood pressure medications  were similar to those found from the EHR data . Differences may be due to a number of factors, including incomplete medical coding, individuals not taking medications that have been prescribed, blood pressure medications that have other indications, and individuals not understanding the indications for all their medications.The trial is being conducted in a clinic with a population that is largely underserved, without substantial additional resources from the clinic itself. On the baseline survey, we confirmed that the study population is a group with high medication nonadherence, poor self-reported health, low socioeconomic status, and high social needs. Other characteristics such as health literacy, health numeracy, and diet are similar to populations in other safety-net health systems. To put our self-reported medication adherence rate of 36.4% in perspective, Weidenbacher et al found an adherence rate of 63% among US veterans taking antihypertensive medications, using the same adherence scale . Our perOur finding that over three-quarters of the sample reported a poor diet score is similar to other studies. National Health and Nutrition Examination Survey (NHANES) 2005-2006 found that 76% of adults reported a poor diet, 24% an intermediate diet, and <0.5% an ideal diet . In the We found a baseline level of blood pressure control (blood pressure <140/90) of 61.0%, which compares favorably with the national NHANES 2011 to 2014 estimates of 54.4% . IncludiHypertension is the most common chronic disease in the United States, and treatment of hypertension is crucial to CVD prevention. Although the Controlling Blood Pressure Trial is set in a UIHO, it could potentially be adapted to other under-resourced clinical environments. It, therefore, has implications for other populations with low socioeconomic status and high social needs. Results from the trial should be available in early 2019.


Clinical factors that influence distribution of FDG into the arterial wall and other tissues have not been characterized in LVV. Understanding these factors will inform analytic strategies to quantify vascular PET activity. Patients with LVV (n = 69) underwent 141 paired FDG-PET imaging studies at one and two hours per a delayed image acquisition protocol. Arterial uptake was quantified as standardized uptake values (SUVMax). SUVMean values were obtained for background tissues . Target-to-background ratios (TBRs) were calculated for each background tissue. Mixed model multivariable linear regression was used to identify time-dependent associations between FDG uptake and selected clinical features. Clinical factors associated with FDG distribution differed in a tissue- and time-dependent manner. Age, body mass index, and C-reactive protein were significantly associated with arterial FDG uptake at both time points. Clearance factors (e.g. glomerular filtration rate) were significantly associated with FDG uptake in background tissues at one hour but were weakly or not associated at two hours. TBRs using liver or blood pool at two hours were most strongly associated with vasculitis-related factors. These findings inform standardization of FDG-PET protocols and analytic approaches in LVV. FDG-PET is useful to detect and potentially monitor treatment response in LVV7. Currently, most studies in LVV use qualitative analytical approaches to measure arterial FDG uptake which depends on the expertise of the reader and may lack precision due to categorized resultant metrics . In comparison, semiquantitative analysis may be preferred to limit the effect of reader bias, increase reproducibility, and optimize precision. To date, few studies have used semiquantitative analysis to assess the utility of FDG-PET in LVV9. These studies employed a variety of approaches, including direct measurement of arterial FDG uptake10 and measurement of arterial FDG uptake normalized to a background tissue using target-to-background ratios (TBR)12. Moreover, different background tissues  have been used to normalize FDG uptake and image acquisition time can vary from one study to the next, making study comparisons difficult.Giant cell arteritis (GCA) and Takayasu’s arteritis (TAK) are the two major forms of large-vessel vasculitis (LVV) defined by immune-mediated inflammation of the large arteries leading to stenoses, occlusions, and aneurysms8. Most evidence supporting these recommendations was based on studies in atherosclerosis rather than LVV15. Recommendations included normalization of arterial FDG uptake to blood pool and acquisition of images at a minimum of 60 minutes after radiotracer injection. In studies of atherosclerosis, delayed imaging (i.e. 90 minutes or more) may be advantageous to allow for more FDG uptake into the arterial wall and clearance from the blood pool18. Ultimately the guidelines indicated that further research is needed to inform recommendations on semiquantitative analytic approaches in LVV.Recent consensus guidelines on the role of FDG-PET in LVV offered few evidence-based recommendations about the use of semiquantitative analysis to measure vascular FDG uptake19. The clinical factors associated with FDG distribution into the arterial wall and background tissues have not been comprehensively assessed in LVV. Understanding to what extent factors related and not related to vasculitis are associated with arterial FDG uptake may provide insight into the underlying pathophysiology of vascular PET activity and will inform the development of PET-based outcome measures of vascular inflammation. This study employed a unique design; whereby, sequential FDG-PET images were obtained in the same patients one and two hours after a single injection of FDG. This sequential imaging protocol enabled evaluation of time-dependent factors associated with FDG distribution in patients with LVV.Previous studies have shown that various factors can influence the distribution of FDG into specific tissues, including the arterial wall and tissues used for normalization of arterial FDG uptakeA total of 69 patients  were recruited into the study. A total of 141 paired one-hour and two-hour FDG-PET scans were included . Baseline demographics of the study population are shown in Table Inter- and intra-rater reliability was excellent for contouring of the arterial wall  and all background tissues: blood pool , liver , and spleen   between the one and two-hour imaging times as shown in Table BMI and UT were associated with FDG distribution in the blood pool at both time points  . Additionally, GFR was negatively associated with FDG distribution in the blood pool at one-hour imaging , but this association did not persist during two-hour imaging . Increased hematocrit was associated with decreased FDG uptake in the blood pool at one-hour imaging , while age  and female sex  were positively associated with FDG uptake in the blood pool only during two-hour imaging. Apart from hematocrit during one-hour imaging there were no other vasculitis-related variables associated with FDG uptake in blood pool. Normalized beta-estimates indicated the three factors most strongly associated with FDG uptake in the blood pool were UT, GFR, and BMI at one-hour and age, BMI, and sex at two-hour imaging . Although not statistically significant, patients with higher GFR had decreased FDG uptake in the liver at one-hour . These associations did not persist during two-hour imaging . Although no vasculitis-related variables were significantly associated with FDG uptake at either time point, patients taking immunosuppressant medications had on average greater FDG uptake in the liver during one-hour imaging . Normalized beta-estimates indicated the three factors most strongly associated with FDG uptake in the liver were BMI, UT, and GFR at one-hour and BMI, age, and sex at two-hour imaging  and two-hour imaging . While not significant, there was a negative association with PGA  and a positive association with CRP  observed during one-hour imaging. Normalized beta-estimates indicated the three factors most strongly associated with FDG uptake in the spleen were BMI, PGA, and hematocrit at one-hour and BMI, age, and Total WBC at two-hour imaging  and two-hour imaging . Fasting glucose level was negatively associated with arterial FDG uptake only during two-hour imaging . Treatment with immunosuppressant medications was associated with decreased arterial FDG uptake during two-hour  but not one-hour imaging . Clinical assessment of disease activity was not associated with arterial FDG uptake at either time point . Complete results from the mixed multivariable linear regression models at both time points are shown in Table Blood pool at two hours, but the strength of association was reduced compared to the association of age and arterial FDG uptake without normalization . CRP also remained associated with all TBRs, with the exception of TBRSpleen during two-hour imaging. While SUVSum was not associated with any imaging-related factors during one-hour imaging, TBRBlood pool was significantly associated with UT  and GFR  at that time point. Use of immunosuppressant medication was negatively associated with TBRLiver  during one-hour time imaging. Complete results from the mixed multivariable linear regression models for all TBRs are shown in Supplementary Tables Blood pool were age, CRP, and UT at one-hour and CRP, age, and fasting glucose at two-hour imaging  except for TBRA summary of all significant factors in each of the mixed multivariable linear regression model is shown in Table 20. This study is unique in that factors associated with FDG distribution were studied in a time-dependent and tissue-specific manner in a cohort of patients with LVV. Consistent with prior reports, delayed imaging from one to two hours was associated with increased FDG uptake in the arterial wall and other tissues, with decreased FDG uptake in the blood pool14. Clinical factors and strength of association with FDG uptake in the artery and background tissues differed during one-hour versus and two-hour imaging and were dependent on whether SUV metrics or TBRs were used to quantify FDG uptake. While the objective of this study was not to derive an optimal semiquantitative metric to diagnose or monitor vascular PET activity in LVV, this work should inform the future development of PET-based outcome measures by providing a deeper understanding of the strengths and limitations of different TBRs at specific imaging time points.Quantification of FDG uptake in the arterial wall can be affected by many factors. Previous studies in atherosclerosis have examined how multiple clinical factors influence FDG distribution in the arterial wall and other tissues21. Our findings align with data from previous studies in atherosclerosis that show delayed imaging increases the sensitivity to detect FDG uptake in the arterial wall23. In LVV, delayed imaging increases the vascular-to-blood pool ratio of FDG. The average uptake of FDG increased by 40.5% in the arterial wall between one-hour to two-hour imaging, while FDG uptake in the blood pool decreased by 9.6% over a similar time frame. Additionally, time-dependent associations between arterial FDG uptake and clinical factors related and unrelated to vasculitis were identified. At the later time point, CRP levels were more strongly associated with arterial FDG uptake, indicating that delayed imaging may increase the sensitivity to detect vascular inflammation. However, significant associations between arterial FDG uptake and factors not directly related to vasculitis, such as BMI and age, were also stronger at the two-hour compared to one-hour time point.This study provides evidence in support of delayed image acquisition in LVV. Delayed image acquisition influences subjective interpretation of FDG-PET scans in vasculitis, as scans performed at later time points are more likely to be interpreted as active vasculitis11. Most patients included in the cohort were studied later in the course of disease rather than at diagnosis. This may explain why clinical assessment of disease activity was not associated with arterial FDG uptake, as a significant burden of vascular PET activity has been observed during periods of clinical remission in patients with LVV24. Similarly, many patients in the cohort were taking glucocorticoids or other immunosuppressant medications, which likely reduced the overall burden of vascular PET activity25. Given the relatively modest sample sizes, use of immunosuppressant medications was studied as a composite variable, and studying the effect of specific medications may be more informative. Similarly, cumulative glucocorticoid exposure in the immediate period prior to imaging rather than daily prednisone dose may be better linked to FDG activity. Ultimately, quantification of arterial FDG uptake may be a better biomarker of vascular inflammation in longitudinal studies that assess the effect of a given treatment on individual patients rather than across populations.Interestingly, there were few vasculitis related factors associated with arterial FDG uptake. These findings are consistent with cross-sectional analyses that demonstrate weak differences in FDG uptake between patients with LVV and controls by semiquantitative analysis19. Potential differences in age and BMI could bias studies that compare arterial SUVs if these factors are imbalanced between study groups. Using TBRs can lessen the impact of BMI but may introduce other potential confounding variables. This is illustrated by the potential impact of clearance-related factors on TBRBlood pool during one-hour imaging. UT and GFR were not associated with FDG uptake in the artery at one hour but were associated with FDG uptake in blood pool. When arterial uptake was normalized to blood pool at one-hour imaging, clearance-related factors were strongly associated with the resultant TBR metric due to associations with background rather than target tissue. At two hours, GFR was no longer associated with blood pool activity and the strength of association with UT was markedly reduced. Consequently, clearance-related factors were no longer associated with the resultant TBRBlood Pool metric at two-hour time imaging. Recent guidelines on FDG-PET imaging in LVV have recommended a minimum of 60 minutes between intravenous FDG injection and image acquisition and have recommended the use of TBR, normalizing to venous blood pool, instead of SUV for the quantification of arterial wall FDG uptake8. Findings from this study show that normalization of arterial wall uptake to venous blood pool activity may provide a good reference for assessing vascular imaging; however, delayed two-hour imaging would be preferable to reduce the potential impact of clearance-related factors. FDG-PET-based imaging studies that use one-hour image acquisition should be mindful of potential imbalances of clearance-related factors between study groups that could bias results.Understanding the time-dependent factors associated with FDG distribution in arteries and background tissues may enable investigators to account for potential confounding variables when developing outcome measures for arterial FDG uptake. Age, in particular, was strongly associated with vascular FDG uptake, consistent with prior studiesLiver or TBRBlood pool and not TBRSpleen. Further, the highest coefficient of variation of FDG uptake was observed in spleen compared to liver and blood pool. For these reasons, liver and blood pool may be preferable over spleen as a background tissue; however, future longitudinal studies of vascular PET activity in LVV should further explore the utility of different background tissues, being mindful of tissue-specific and time-dependent potential confounding variables.Findings from this study suggest that imaging time point, rather than a specific background tissue, is more important for studying normalized arterial FDG uptake. At one hour, there were many potential confounding variables associated with FDG uptake in each of the background tissues. At two hours, there were fewer associated potential confounding variables and no vasculitis-related variables significantly associated with FDG uptake in any of those tissues. Vasculitis-related variables were only associated with TBR27, a global summary score of quantitative vascular PET uptake throughout the aorta and branch arteries was used as an outcome measure to study the clinical factors associated with arterial FDG uptake in LVV. This summation approach parallels qualitative summary scores previously employed by our group and others to measure global arterial PET activity28. Imaging studies were performed prospectively in all patients within the cohort, minimizing the selection bias issues commonly encountered in retrospective studies of FDG-PET in LVV.This study has several unique strengths. Serial imaging by FDG-PET at two time-points on the same day enabled identification of time-dependent clinical factors associated with FDG distribution. All patients underwent a standardized imaging protocol using the same set of scanners with a centralized reader to generate semiquantitative metrics of FDG uptake per a specific contouring approach. Reliability analyses demonstrated excellent reproducibility of the imaging contouring procedure. Since arterial FDG distribution in LVV is typically diffuse throughout the large arteriesThere are several potential study limitations to consider. Patients underwent serial imaging on two different imaging platforms: PET-MR at one-hour and PET-CT at two-hours. Scanner specific differences will likely contribute to differences in the strength of associations observed at the different imaging time points. Although Takayasu’s arteritis can affect young populations, children were excluded from multiple PET acquisitions on the same day to minimize radiation exposure. Moreover, this study does not provide information about how vascular imaging should be used in clinical practice, where potential risks, such as repetitive radiation exposure in younger populations, must be considered. While this study identified many time-dependent factors associated with FDG distribution into tissues, unmeasured confounders likely exist that also impact the distribution of FDG in patients with LVV. Specifically, limited information was recorded about atherosclerosis-related risk variables including lipid levels or information related to cardiovascular risk modification. Finally, while this study employed TBR calculations to quantify vascular FDG uptake, alternative analytic methods, such as measurement of total lesion glycolysis could be considered.17; however, TBR outcome measures are susceptible to confounding effects of factors that are associated with FDG distribution in both the artery and the background tissue. While FDG-PET may be useful to monitor vascular inflammation in LVV, the development and validation of disease-specific semiquantitative metrics of vascular PET activity is prerequisite to unlock the utility of imaging-based outcome measures in these diseases.In conclusion, this study highlights the complexities of semiquantitative assessment of arterial PET activity in LVV and provides data that can inform standardization of imaging acquisition protocols and analytical approaches in LVV. Delayed imaging at two hours compared to one hour appears to be preferable in vascular FDG-PET imaging to allow more time for FDG to distribute into the arterial wall and clear from the blood pool. Specific factors are associated with the distribution of FDG in a tissue-specific time-dependent manner. Carefully designed studies that minimize imbalances of these factors are required to compare arterial FDG uptake among different populations. Normalization of arterial FDG uptake to a background tissue is advantageous to minimize the potential effects of body weight and radiotracer injection dose from one study to the next29 or modified 1990 ACR Criteria for giant cell arteritis31. Patients could be enrolled at any point in the disease course.Patients ≥18 years of age with LVV were recruited into a prospective, observational cohort at the National Institutes of Health (NIH) in Bethesda, Maryland, USA. All patients with LVV fulfilled the 1990 American College of Rheumatology (ACR) Classification Criteria for Takayasu’s arteritisAll participants underwent clinical and laboratory assessments at the NIH clinical center within 24 hours of imaging acquisition. When feasible, patients underwent repeat assessments at 6-month intervals.32, exact time in minutes from radiotracer injection to image acquisition , and fasting glucose at the time of injection.All clinical and laboratory assessments were collected blinded to imaging results. Clinical and laboratory assessment factors were divided into three groups; demographic, vasculitis-related, imaging-related. Demographic variables included body mass index (BMI), age, and sex. Vasculitis-related variables included clinical assessment of disease activity, c-reactive protein (CRP), total white blood cell count (WBC), hematocrit, daily prednisone dose, and use of additional immunosuppressive medications other than glucocorticoids (yes vs no). As there are no validated disease activity indices for both TAK and GCA, clinical assessment of disease activity was measured using the Physician Global Assessment (PGA) scale which was scored from 0 (remission) to 10 (severe disease). Imaging-related variables included glomerular filtration rate (GFR)2 and/or a fasting glucose above 7.1 mmol/L were excluded from the study. All patients received a single, fixed dose of 10 mCi FDG.Patients were instructed to consume a carbohydrate-sparse meal the day prior to imaging, and fast on the day of imaging. Patients with a GFR lower than 30 mL/min per 1.73 mPatients underwent simultaneous PET-MR  approximately one hour after injection per a standardized imaging protocol: axial 2D free breathing, ECG-gated turbo spin echo double inversion recovery pulse sequence (TSE-DIR) with spectral attenuated inversion recovery (SPAIR). Acquisition parameters included automatically selected (Ti) by ECG, two R-to-R intervals employed resulting in repetition times (Tr) between 1,000–1,300 mSec. The echo time (Te) was set to 27 mSec. Slice thickness was set to 5 mm, matrix was 187 × 384 with a receiver bandwidth (Rbw) of 766 hertz per pixel (hz/px), flip angle was set to 160 degrees, and the echo-train length (ETL) was set to 11. Parallel imaging  was used to reduce overall scan time by a factor of 2. 2D axial TSE-STIR (turbo-spin echo short tau inversion recovery) images were obtained. The Ti was 220 mSec, Tr 4,500 mSec, and Te was 73 mSec. Slice thickness was set to 8 mm, matrix 284 × 448, and Rbw of 302 hz/pz, flip angle 120 degrees, and ETL was set to 11. GRAPPA parallel imaging was also used. Reconstruction of PET-MR images employed MR-based attenuation correction and iterative reconstruction . Following PET-MR, patients also underwent FDG-PET-CT  of the torso approximately two hours after injection. Image reconstruction employed CT attenuation correction and iterative reconstruction  for each arterial region. The mean SUVMax for each of the nine arterial territories were then averaged together to produce a global summary metric of FDG uptake (SUVSum) for the entire aorta and branch arteries of interest.Arterial FDG uptake was quantified by manually drawing regions of interest (ROI) in OsiriX DICOM Viewer , with attention to both CT anatomic location and co-registered PET activity. In an axial view, ROIs that encompassed both the arterial wall and lumen were drawn around five segments of the aorta , and four branch arteries (right and left common carotid and subclavian arteries) Fig. . This prMean) was also measured in three background reference tissues . Mean liver activity was measured within the right lobe of the liver. Mean venous blood pool activity was evaluated by placing ROIs within the right jugular, superior vena cava, and the inferior vena cava with care to avoid non-venous activity . A volume of interest for mean spleen activity was placed with attention to potential respiratory PET and CT mis-registration artifact and non-splenic activity. Further details of ROI placement can be found in Supplementary Table Sum of the arteries was divided by SUVMean in background tissue to generate three TBR metrics: TBRLiver, TBRBlood Pool, and TBRSpleen.Average SUV  were contoured a second time to determine intra-rater reliability and were contoured by a second reader to determine interrater-reliability, assessed by Pearson correlation.Ratios of change between the one-hour and two-hour time points were calculated for tissue-specific FDG distribution. Coefficients of variation  were calculated for all tissue types at each time point to determine the amount of variability across the study population. An ideal background tissue would have a low coefficient of variation.lmer function of the lme4 package in R with patient identifier as the random effect to account for patients who had multiple study visits. Dependent variables for these models were the global arterial SUVSum, Liver SUVMean, Blood Pool SUVMean, Spleen SUVMean, TBRLiver, TBRBlood Pool, and TBRSpleen. Independent variables included in the mixed models were: 1) demographic variables: age, gender, body mass index (BMI); 2) vasculitis-related variables: total white blood cell count (WBC), c-reactive protein (CRP) (nmol/L), immunosuppressant treatment (yes/no), prednisone daily dose (mg), physician global assessment (PGA), hematocrit; and 3) imaging-related variables: uptake time (in minutes), glomerular filtration rate (GFR)32 (mL/min per 1.73 m2), and fasting glucose (mmol/L). PGA was scored on a scale of 0  to 10 (severely active disease). All independent variables were included in each mixed model regression analysis to facilitate comparisons among the different outcome measures. Normalized beta estimates were calculated using the std beta function of the sjstats package in R to facilitate comparison of effect size across the independent variables within each model. The Anova function of the car package in R was used to calculate p-values for the models. A p-value < 0.05 was considered statistically significant in all models.Associations between clinical factors and FDG uptake in the arterial wall, background tissues, and arterial wall normalized to background were studied separately at the one and two-hour imaging time points using mixed model multivariable linear regression. Since this was a longitudinal study, patients could undergo the serial delayed imaging acquisition protocol at successive study visits. Mixed model multivariable linear regression was performed using the All study participants signed written informed consent. The National Institute of Arthritis and Musculoskeletal and Skin Diseases ethics board and the National Institutes of Health Radiation Safety Committee approved the protocol. The research was conducted in accordance with the Declaration of Helsinki.Supplementary Material


Laparoscopic partial nephrectomy, which minimizes renal function loss due to its nephron sparing nature, has become a standard technique among many experienced centers worldwide for surgical treatment of localized kidney tumors. Although partial nephrectomy will remain the gold standard, we need to improve perioperative management and surgical method to prevent postoperative acute kidney injury.To demonstrate the frequency of the development of postoperative acute kidney injury following laparoscopic partial nephrectomy in patients with healthy contralateral kidney and determine the early predictive effects of serum neutrophil gelatinase-associated lipocalin on ischemia-reperfusion injury and its association with warm ischemia time.Cross-sectional study.nd hour, and on postoperative days 1 and 2. We used receiver operating characteristic curve for determining the cut-off point of neutrophil gelatinase-associated lipocalin to detect postoperative acute kidney injury. Correlation analysis was performed using Spearman’s test.Eighty patients were included. We analyzed tumor size, operating time, duration of anesthesia, and warm ischemia time. Serum samples were obtained for measurement of serum creatinine, estimated glomerular filtration rate, and neutrophil gelatinase-associated lipocalin level preoperatively, at the postoperative 2nd hour in the acute kidney injury group (p=0.048). For a cut-off of 129.375 ng/mL neutrophil gelatinase-associated lipocalin, the test showed 70.0% sensitivity and 68.3% specificity for the detection of acute kidney injury at the postoperative 2nd hour. For a cut-off of 184.300 ng/mL neutrophil gelatinase-associated lipocalin, the test exhibited 73.3% sensitivity and 63.3% specificity for the detection of acute kidney injury on postoperative day 1. A significant correlation was found between warm ischemia time and neutrophil gelatinase-associated lipocalin level at the postoperative 2nd hour . The creatinine values were significantly higher and the estimated glomerular filtration rates were significantly lower on postoperative days 1 and 2 in the acute kidney injury group compared with those in the non-acute kidney injury group (p<0.001).Twenty-seven patients developed acute kidney injury on postoperative day 2, and the neutrophil gelatinase-associated lipocalin level increased significantly at the postoperative 2The neutrophil gelatinase-associated lipocalin may be used as an alternative biomarker to serum creatinine in differentiation of ischemic damage in patients undergoing laparoscopic partial nephrectomy. Laparoscopic partial nephrectomy (LPN), which minimizes renal function loss due to its nephron sparing nature, has become a standard technique among many experienced centers worldwide for surgical treatment of localized kidney tumors . Renal aAcute kidney injury (AKI) is the deterioration of kidney functions within hours and is more directly associated with morbidity and mortality than expected in perioperative period. AKI, a significant risk factor for long-term chronic kidney dysfunction, is associated with the development of perioperative increased incidence of sepsis, anemia, coagulopathy, and extended mechanical ventilation and induces the occurrence of injuries in different organs ,9,10,11.nd hour.In this study, we aimed to demonstrate the frequency of the development of AKI following LPN in patients with healthy contralateral kidney and determine the early predictive effects of serum NGAL levels on ischemia–reperfusion injury and its association with WIT. Our primary hypothesis is that serum NGAL levels would increase in patients with AKI at the postoperative 2This study sought the ethics committee approval and obtained written informed consent from the participants. Eighty patients classified with physical status I–III based on the American Society of Anesthesiologists, aged between 40 and 70 years, and scheduled for elective LPN were enrolled in this prospective cross-sectional study between September 2013 and February 2015. Patients were excluded if they had pre-existing renal insufficiency [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73], congestive heart failure, and peripheral vascular disease and if they used nephrotoxic drugs, such as aminoglycosides, amphotericin, and ciclosporin.2). Subsequently, 5 mL/kg/h ringer lactate intravenous infusion was initiated. General anesthesia was induced using 0.03 mg/kg midazolam, 2 mg/kg propofol, 0.6 μg/kg rocuronium, and 0.2 μg/kg remifentanil. Mechanical ventilation was achieved with tidal volume of 8 mL/kg, respiratory rate of 10-12/minute, and positive end-expiratory pressure of 4 cm of H2O after the insertion of an endotracheal intubation tube. The patients were positioned at 45°-60° modified flank position with minimal elevation of the kidney bridge. Anesthesia was maintained with 4%-6% desflurane in a mixture of 40% oxygen and 60% air and 0.1 μg/kg/min remifentanil infusion to maintain the intraoperative blood pressure within 20% of the preoperative values. Volume replacement and 5 mg incremental ephedrine were administered to the patients in incidents of hypotension. Bradycardia (heart rate <50 beats/min) was treated using 0.01 mg/kg atropine. At the end of the surgery, the patients were extubated and transported to the postanesthesia care unit.The preoperative preparations and anesthesia techniques were performed similarly among all patients. Routine monitorization was conducted using electrocardiogram, non-invasive blood pressure, and pulse oximetry . The renal artery was unclamped following the completion of renorrhaphy, and the specimen was retrieved with a laparoscopic entrapment bag.nd hour), and on postoperative days 1 and 2. eGFRs were calculated using the “chronic kidney disease epidemiology” formula  were recorded. The levels of sCr, eGFR, and NGAL were evaluated before the surgery (preoperative), 2 hours after completion of the surgery . NGAL detection kits were labeled for research use and incorporated in assays based on sandwich enzyme-linked immunosorbent assay technology. Absorbance was recorded with a microtiter plate reader at 450 nm. Each sample was tested in duplicate, and the coefficient of intraassay variation among the duplicates was <10%. NGAL concentration was calculated from the standard curves by linear regression analysis.2 test for categorical data. Differences among all parameters at different time points were assessed by repeated measures ANOVA for quantitative variables. Correlation analysis was performed using Spearman’s test. Factors potentially influencing variations in NGAL level were evaluated in univariate analysis. The threshold value of NGAL level in accordance with AKI classification was investigated using receiver operating characteristic. Sensitivity, specificity, positive predictive level, negative predictive level, and accuracy rate were evaluated in accordance with the specified threshold levels. The significance value was regarded as p<0.05.Statistical analysis was performed using the Statistical Package for the Social Sciences version 21.0. The creatinine level was 1.01±0.4 mg/dL on postoperative day 2 in patients with AKI in our pilot study. A minimum of 70 patients would be required to obtain a 0.28 difference with a standard deviation of 0.4, with α and β errors of 0.05 and 0.2, respectively. Therefore, 80 patients were selected in case of drop outs. eGFR was calculated by “chronic kidney disease epidemiology” formula. Kolmogorov–Smirnov test was performed to assess deviation from normal distribution. Quantitative variables were summarized as mean and standard deviation or as median. The different patient groups (AKI group vs non-AKI group) were compared using Student’s t-test and Mann-Whitney U test for quantitative variables and Xnd hour and on postoperative day 1 compared with the preoperative values (p<0.001)  (nd hour in the AKI group compared with those in the non-AKI group (p=0.048). However, on postoperative day 1, no significant difference was found between AKI and non-AKI groups (p>0.05)  . We analp=0.003) . Howeverp=0.003) . Twenty-(p>0.05) . The sCr(p>0.05) . Twenty-nd hour and on postoperative day 1  at the postoperative 2nd hour : 0.494-0.759, p=0.042]; at a cut-off value of 129.375 ng/mL NGAL at the postoperative 22nd hour .The area under the curve was 0.623 ; and at a cut-off value of 184.300 ng/mL NGAL on day 1, the sensitivity and specificity were 73.3% and 63.3%, respectively. The receiver operating characteristic curve analysis confirmed the positive value of NGAL for prediction of AKI (53.3%) on postoperative day 1 .nd hour in patients with AKI compared with those in patients without AKI. A positive correlation was detected between WIT and serum NGAL levels at the postoperative 2nd hour. In addition, the sCr and NGAL levels were significantly higher in the postoperative period than in the preoperative period. We suggested that the rate of postoperative development of AKI might be higher than the estimated rate in such cases and that NGAL could a significant biomarker in early diagnosis of kidney damage.In this prospective clinical study, we observed that the serum NGAL levels significantly increased at the postoperative 2In partial nephrectomy, the primary goal is to control cancer while preserving the maximal renal function and obtaining minimal morbidity in the perioperative period. We found a decrease in kidney functions by about 20% in solitary operated kidney and by 10% in global function in partial nephrectomies. Progressive chronic kidney failure may also develop in acute period in addition to severe kidney damage that required dialysis in 1% of patients .nd hour was positively correlated with WIT.The development of severe AKI is associated with conditions, such as the need for intensive care and dialysis, which increases hospital stay . The mosHemodynamic changes, particularly mean arterial pressure, in the intraoperative period have a significant role in kidney perfusion. Even the short-period hypotension attacks in this period may cause ischemia in the kidney. Walsh et al.  reportedEnergy stocks are wasted due to decrease in enabling oxygen to the tissues after ischemia because of various causes in the kidney; this phenomenon results in cell necrosis and accumulation of toxic metabolites. The products developed after the reperfusion of ischemic tissue activate the mast cells and neutrophils; the local cell damage causes systemic inflammatory reaction and secretion of cytokine and inflammatory mediators that cause multi organ failure . TherefoNGAL, a member of the lipocalin family, is secreted from kidney proximal tubuli after ischemic damage. Ischemia causes an increase in the urine and serum levels of NGAL. However, NGAL was not routinely used in the clinics but has been employed in cardiovascular surgery, intensive care, and transplant surgery; NGAL increased within 2 hours immediately after the development of damage ,29. Woodst hour following the cold ischemia in nephron sparing open partial nephrectomies of a small number of patients. Sprenkle found no significant increase in the NGAL levels in the urine after open partial nephrectomy in individuals with healthy kidney functions and did not accept NGAL as a diagnostic factor. The detection of less damage in their study might be due to several factors, such as performing cold ischemia, which has a better kidney protection effect, in most patients during the renal artery clamping, and infusion of intraoperative mannitol (To date, few clinical studies have demonstrated the importance of NGAL in diagnosis of possible AKI in partial nephrectomies. However, Abbasi et al.  reportedmannitol .We conducted tumor resection using laparoscopic method and under the warm ischemia in all patients. Pneumoperitoneum during laparoscopy increases the intraabdominal pressure, which might contribute to the deterioration of kidney perfusion. Similar to our study, the results of the study of Koo et al.  showed iIn this study, the diagnostic value of serum NGAL level was measured using the receiver operating characteristic curve. The receiver operating characteristic curve analysis showed that serum NGAL level has a valuable diagnostic performance. As evidenced by the area under the curve of 0.67, the biomarker NGAL has a good ability to predict AKI in the first 2 hours after partial nephrectomy.nd hour compared with the preoperative values. The postoperative sCr level was also significantly higher compared with the preoperative values. In addition, AKI developed in 36% of the patients on day 2, and their NGAL levels in the early period were significantly higher. Due to the lack of information about long-term patient follow-up, the rate of permanent renal damage is difficult to predict. This aspect can be regarded as a limitation of our study.In our study, the serum NGAL level was significantly higher at the 2nd hour post LPN are predictive of increased risk of AKI. Early diagnosis of renal injury may prevent the side effects of this undesirable condition. Despite that it is more expensive than sCr, NGAL is an alternative biomarker of AKI in the early postoperative period especially in patients with long WIT.In conclusion, this study showed that increased serum NGAL levels at the 2