Predictors of Patient and Physician Assessments of Gout Control.

OBJECTIVE: To understand the clinical variables that contribute to the patient and physician assessments of gout control and which variables predict discordant assessments. METHODS: Patients (n = 223) with gout taking allopurinol ≥300 mg daily attended a standardized gout assessment visit. Participants and physicians completed questionnaires rating their assessment of current gout control using a numerical rating scale (0 = not at all controlled, 10 = fully controlled). Discordance between patients' and physicians' scores was defined as an absolute difference of >2 units. RESULTS: The mean ± SD patient gout control score was 8.09 ± 2.24, and the physician gout control score was 7.38 ± 2.63 (P < 0.001 for comparison). Absence of gout flares in the last 12 months and in the last 3 months and serum urate at the treatment target (<6 mg/dl) were associated with higher patient and physician gout control scores. Absence of tophus also predicted higher physician, but not patient, gout control scores. Discordant scores for gout control were present in 50 participants (22.3%), mostly due to lower assessment of disease control by physicians. Gout flare in the preceding 3 months (odds ratio [OR] 5.9, P < 0.001) and tophus (OR 3.1, P = 0.007) predicted discordant disease-control assessments in which physicians scored lower gout control than patients. CONCLUSION: For both patients and physicians, absence of gout flares and serum urate levels at the treatment target predict assessment of gout control. However, discordance between patients and physicians in their assessment of disease control is not uncommon, with recent gout flares and tophus predicting lower scores by physicians than patients.

Radiologic evidence of symmetric and polyarticular monosodium urate crystal deposition in gout - A cluster pattern analysis of dual-energy CT.

OBJECTIVES: To determine the clustering patterns of monosodium urate (MSU) crystal deposition and bone erosions among patients with gout requiring urate-lowering therapy (ULT) using dual-energy CT (DECT). METHODS: DECT scans of bilateral hands/wrists, feet/ankles, and knees were obtained on 153 patients with gout on allopurinol ≥300 mg daily for ≥3 months. Two radiologists assessed the images at pre-specified sites (15 in the hands/wrists, 12 in the feet/ankles, 4 in the knees). Clustering patterns of MSU crystal deposition and bone erosions were evaluated. RESULTS: Among 153 patients with gout (mean duration, 15 years) on allopurinol (mean duration, 5 years), MSU crystal deposition (67%) affected multiple sites in the hands/wrists, feet/ankles, and knees more often than would be expected by chance (p<0.001 for all 3 regions). In the feet/ankles, bone erosions were also observed in a clustered manner (p<0.001). Presence of MSU crystal deposition at a particular joint was most strongly associated with symmetric involvement of the same joint of the opposite extremity in the hands/wrists, feet/ankles, and knees (adjusted odds ratio (OR) 26.1, 46.9, and 9.9, respectively). Similarly, presence of erosions in the feet/ankles was highly symmetric (adjusted OR 91.4). Erosions were 8-fold more likely to be present in sites with MSU crystal deposition compared to those without. CONCLUSION: Among patients with longstanding gout on ULT, MSU crystal deposition and bone erosions affect multiple joints within the hands/wrists, feet/ankles, and knees in a highly symmetric manner. These radiologic data support the notion of MSU crystal deposition in gout as a symmetric polyarthropathy.

Concurrent validity of provisional remission criteria for gout: a dual-energy CT study.

BACKGROUND: Provisional gout remission criteria including five domains (serum urate, tophus, flares, pain due to gout, and patient global assessment) have been proposed. The aim of this study was to test the concurrent validity of the provisional gout remission criteria by comparing the criteria with dual-energy CT (DECT) findings. METHODS: Patients with gout on allopurinol ≥ 300 mg daily were prospectively recruited into a multicenter DECT study. Participants attended a standardized study visit which recorded gout flare frequency in the preceding 12 months, physical examination for tophus, serum urate, and patient questionnaires. DECT scans of both hands/wrists, feet/ankles/Achilles, and knees were analyzed by two DECT radiologists. The relationship between the DECT urate crystal volume and deposition with individual domains as well as the provisional remission criteria set was analyzed. RESULTS: The provisional remission criteria were fulfilled in 23 (15.1%) participants. DECT urate crystal deposition was observed less frequently in those fulfilling the provisional remission criteria (44%), compared with those not fulfilling the criteria (73.6%, odds ratio 0.28, P = 0.004). The median (range) DECT urate crystal volume was 0.00 (0.00-0.46) cm3 for those fulfilling the remission criteria, compared with 0.08 (0.00-19.53) cm3 for those not fulfilling the criteria (P = 0.002). In multivariate regression analysis, the serum urate and tophus domains were most strongly associated with DECT urate crystal deposition. CONCLUSIONS: In people with gout established on allopurinol, a state of remission as defined by the provisional remission criteria is associated with less DECT urate crystal deposition. While this study provides support for the validity of the provisional gout remission criteria, it also demonstrates that some crystal deposition may be present in people achieving these criteria.

Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study.

BACKGROUND: In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy. METHODS: Patients receiving combined lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study ("200CONT", "400CONT"), whereas those receiving only febuxostat 80 mg were randomized to lesinurad 200 or 400 mg with febuxostat ("200CROSS", "400CROSS"). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of lesinurad exposure, 800 days). RESULTS: Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT (n = 64), 200CROSS (n = 33), 400CONT (n = 65), and 400CROSS (n = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged lesinurad exposure in the extension study. CONCLUSIONS: Patients receiving lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.

Presence of monosodium urate crystal deposition by dual-energy CT in patients with gout treated with allopurinol.

OBJECTIVE: Dual-energy CT (DECT) detects and quantifies monosodium urate (MSU) crystal deposition with high precision. This DECT study assessed crystal deposition in patients with gout treated with stable-dose allopurinol, and investigated potential clinical determinants for crystal deposition. METHODS: Patients with gout treated with allopurinol ≥300 mg daily for at least 3 months were prospectively recruited from the USA and New Zealand, using monitored enrolment to include approximately 25% patients with palpable tophi and approximately 50% with serum urate (sUA) levels <6.0 mg/dL (<357µmol/L). MSU crystal deposition was measured in the hands/wrists, feet/ankles/Achilles and knees bilaterally. The presence and total volume of crystals were assessed by DECT and analysed according to sUA levels and gout characteristics. RESULTS: Among 152 patients receiving allopurinol ≥300 mg/day for 5.1 years on average, 69.1% had crystal deposition on DECT, with a median total crystal volume of 0.16 cm3 (range: 0.01-19.53 cm3). The prevalence of crystal deposition ranged from 46.9% among patients with sUA <6.0 mg/dL and no palpable tophi to 90.0% among those with sUA ≥6.0 mg/dL and tophi. Total volume of crystal deposition was positively associated with sUA ≥6.0 mg/dL, gout flares within the past 3 months and tophi. Total volume of crystal deposition correlated positively with Patient Global Impression of Disease Activity scores. CONCLUSION: A substantial proportion of patients without palpable tophi have MSU crystal deposition, despite receiving allopurinol doses ≥300 mg/day for a considerable duration. Patients with higher sUA and clinical features of severe disease have a higher frequency and greater volume of MSU crystal deposition.

Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study.

Objective: To investigate the efficacy and safety of lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods: Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with lesinurad. A total of 143 patients (65 lesinurad, 78 placebo) enrolled in the extension study. Treatment with lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with lesinurad 400 mg, lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial.

OBJECTIVE: To investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12-month phase III trial in patients with tophaceous gout. METHODS: Patients with serum urate (UA) ≥8.0 mg/dl (≥6.0 mg/dl with urate-lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of <5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data. RESULTS: Patients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of lesinurad 400 mg (76.1%; P < 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P < 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with lesinurad 400 mg. CONCLUSION: Treatment with lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with lesinurad 200 mg in patients with tophaceous gout warranting additional therapy.

Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study).

OBJECTIVES: Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. METHODS: Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. RESULTS: Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. CONCLUSION: Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. TRIAL REGISTRATION NUMBER: NCT01493531.

Lesinurad Combined With Allopurinol: A Randomized, Double-Blind, Placebo-Controlled Study in Gout Patients With an Inadequate Response to Standard-of-Care Allopurinol (a US-Based Study).

OBJECTIVE: Lesinurad is a selective uric acid reabsorption inhibitor used for the treatment of gout in combination with a xanthine oxidase inhibitor. The Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) study, a 12-month, multicenter, randomized, double-blind, placebo-controlled phase III trial, was conducted to investigate daily lesinurad (200 mg or 400 mg orally) added to allopurinol versus placebo plus allopurinol in patients with serum urate (UA) levels above a target of <6.0 mg/dl. METHODS: Patients receiving ≥300 mg of allopurinol (≥200 mg in those with moderate renal impairment) who had serum UA levels ≥6.5 mg/dl at screening and ≥2 gout flares during the previous year were studied. The primary end point was the proportion of patients achieving a serum UA level of <6.0 mg/dl at month 6. Key secondary end points were the mean gout flare rate requiring treatment (months 7-12) and the proportions of patients with complete resolution of ≥1 target tophus (month 12). Safety assessments included adverse events and laboratory data. RESULTS: The study patients (n = 603) were predominantly male and had a mean ± SD age of 51.9 ± 11.3 years, a gout duration of 11.8 ± 9.4 years, a baseline serum UA level of 6.94 ± 1.27 mg/dl, and were receiving an allopurinol dosage of 306.6 ± 59.58 mg/day. Lesinurad at doses of 200 mg or 400 mg added to allopurinol therapy significantly increased the proportions of patients who achieved serum UA target levels by month 6 as compared with those receiving allopurinol alone (54.2%, 59.2%, and 27.9%, respectively, P < 0.0001). Lesinurad was not significantly superior to allopurinol alone in terms of the secondary end points: rates of gout flares and complete resolution of tophi. Lesinurad was generally well-tolerated; the safety profile of the 200-mg dose was comparable to that of allopurinol alone, except for higher incidences of predominantly reversible elevations of serum creatinine levels. CONCLUSION: Lesinurad added to allopurinol provided benefit as compared with allopurinol alone in reducing serum UA levels and represents a new treatment option for patients needing additional urate-lowering therapy.

Darbepoetin alfa once monthly corrects anaemia in patients with chronic kidney disease not on dialysis.

AIM: While darbepoetin alfa (DA) can be administered once monthly (QM) to maintain haemoglobin (Hb) concentrations in anaemic patients with chronic kidney disease not on dialysis (CKD-ND), the QM use of DA for anaemia correction has not been previously investigated. METHODS: In this randomized, double-blind, non-inferiority, active-controlled study, adult subjects with CKD-ND, Hb levels <10 g/dL, and not treated with an erythropoiesis-stimulating agent were randomized 1:1 to receive DA every 2 weeks (Q2W) or QM for 33 weeks with initial doses of 0.75 µg/kg Q2W or 1.5 µg/kg QM. Subjects were treated to target Hb levels of 10-12 g/dL and ≥1 g/dL increase from baseline. The primary end-point was Hb change between baseline and the evaluation period (weeks 29-33), with a non-inferiority margin of -0.5 g/dL. RESULTS: Three hundred and fifty-five subjects received ≥1 dose of DA. Mean (95% confidence interval [CI]) change in Hb between baseline and the evaluation period was 2.16 (1.98-2.33) g/dL for the Q2W group and 1.97 (1.80-2.14) g/dL for the QM group, the mean (95% CI) difference in Hb change being -0.19 (-0.43 to 0.05) g/dL. Most subjects (97.9% Q2W; 98.1% QM) achieved a Hb level ≥10.0 g/dL and ≥1.0 g/dL increase in Hb from baseline. Mean DA (SD) weekly equivalent doses over the evaluation period were 0.20 (0.23) and 0.27 (0.31) µg/kg per week for the Q2W and QM groups, respectively. Safety profiles were similar between groups. CONCLUSION: In subjects with CKD-ND, QM dosing was non-inferior to Q2W dosing for anaemia correction and had a similar safety profile.

Human heart rate: heritability of resting and stress values in twin pairs, and influence of genetic variation in the adrenergic pathway at a microribonucleic acid (microrna) motif in the 3'-UTR of cytochrome b561 [corrected].

OBJECTIVES: The goal of this study was to understand the role of genetic variation in the catecholamine biosynthetic pathway for control of human heart rate (HR). BACKGROUND: Human HR is an integrated cardiovascular trait predictive of morbidity and survival. Because the autonomic pathway exerts rapid control over the heart, we probed the role of heredity in the control of HR, focusing on a component of the autonomic sympathetic pathway already predictive of outflow responses: cytochrome b561 (CYB561), the electron shuttle in catecholamine vesicle membranes for transmitter biosynthesis. METHODS: We studied hereditary control of HR with the twin pair design, at rest and during environmental (cold) stress. Single nucleotide polymorphism disruption of a microribonucleic acid (microRNA) recognition motif in the human CYB561 3'-UTR was identified computationally, and its differential effect on gene expression was demonstrated in a transfected luciferase reporter/3'-UTR variant. We exposed stem cell-derived human embryoid bodies to the microRNA mimic or antagomir oligonucleotides, and we observed the effects on contraction rate in proto-hearts. RESULTS: Substantial heritability (h(2)) was demonstrated by using twin pair variance components for both basal/resting HR (h(2) 50.9 ± 6.4% of trait variation, p = 2.47 × 10(-10)) and stress-augmented HR (h(2) 55.1 ± 5.9%, p = 8.79 × 10(-13)), and the 2 HR traits shared genetic determination (genetic covariance ρG 0.747 ± 0.058, p = 2.85 × 10(-9)). CYB561 displayed 1 common genetic variant in the transcript region: A+1485G (rs3087776), in the 3'-UTR, 1485 bp downstream of the termination codon, in a conserved region, with the A-allele ancestral in primates. In a twin/sibling sample (n = 576), A+1485G influenced HR, both at rest (p = 0.010) and after environmental stress (p = 0.002), with the minor (A) allele displaying a recessive effect with lower HR. The effect of A+1485G on HR was extended by meta-analysis into 2 additional population samples (total n = 2,579), and the influence remained directionally consistent and significant (p = 0.007). A+1485G disrupted a microRNA (human microribonucleic acid-1294 [hsa-miR-1294]) recognition motif in the 3'-UTR, as demonstrated by a transfected luciferase reporter/human 3'-UTR variant system in 2 different neuronal/neuroendocrine cell types. The microRNA effect was further documented by cotransfection of an hsa-miR-1294 mimic, yielding an exaggerated decline in expression of the A-allele (better match) reporter (p = 4.3 × 10(-5)). Similar findings of differential 3'-UTR allelic susceptibility to hsa-miR-1294 were noted during expression of the full-length human CYB561 messenger ribonucleic acid with its cognate 3'-UTR. Finally, exposure of stem cell-derived human embryoid bodies to hsa-miR-1294 mimic or antagomir oligonucleotides yielded directionally opposite effects on contraction rate in proto-hearts. CONCLUSIONS: HR is a substantially heritable trait, with genetic influence by variation in the adrenergic pathway, here shown for messenger ribonucleic acid translational control at the CYB561 step of transmitter formation. The results have implications for potentially modifiable autonomic pathways that influence this risk trait in the population.

Total sleep time and other sleep characteristics measured by actigraphy do not predict incident hypertension in a cohort of community-dwelling older men.

STUDY OBJECTIVE: To evaluate whether actigraphy-measured total sleep time and other sleep characteristics predict incident hypertension in older men. METHODS: Study subjects were community-dwelling participants in the ancillary sleep study of the Osteoporotic Fractures in Men Study (MrOS) who were normotensive at the time of actigraphy (based on self-report, lack of antihypertensive medication use, and with systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg). In 853 community-dwelling men 67 years and older (mean 75.1 years), sleep measures (total sleep time [TST]), percent sleep [%-sleep], latency, and wake after sleep onset [WASO]) were obtained using validated wrist actigraphy with data collected over a mean duration of 5.2 consecutive 24-h periods. We evaluated incident hypertension (based on self-report, use of antihypertensive medication, or measured systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg) at a follow-up visit an average of 3.4 years later. Baseline prehypertension was defined as a systolic blood pressure 120 to < 140 mm Hg or diastolic blood pressure 80 to < 90 mm Hg. RESULTS: At follow-up, 31% of initially normotensive men were hypertensive (264 of 853). Those with incident hypertension had higher baseline body mass index (BMI; kg/m(2)) and were more likely to have had prehypertension at the sleep visit than those men who remained normotensive. However, neither TST (reference 6 to < 8 h; < 6 h OR 0.96 [95% CI 0.7, 1.3] and ≥ 8 h OR 0.93 [0.5, 1.7]) nor the other actigraphic-measured sleep variables, including % -sleep (reference > 85%; < 70% OR 1.17 [0.66, 2.08]) and 70% to ≤ 85% OR 1.23 (0.9, 1.68), sleep latency (reference < 30 min; ≥ 30 min OR 1.29 [0.94, 1.76]), or WASO (reference < 30 min; 30 to < 60 min OR 0.7 [0.43, 1.14] and ≥ 60 min OR 0.92 [0.58, 1.47]) differed in those community-dwelling men who developed incident hypertension compared to those who remained normotensive. CONCLUSION: TST and other sleep parameters determined by wrist actigraphy were not associated with incident hypertension in community-dwelling older men.

Central hemodynamics in prehypertension: effect of the ß-adrenergic antagonist nebivolol.

The aim of the current study was to characterize the effects of the novel ß-adrenergic antagonist nebivolol on central aortic blood pressures, arterial properties, and nitroxidergic activity in individuals with prehypertension. Prehypertension is emerging as a major risk factor for several adverse cardiovascular consequences. Increased pulse wave velocity, aortic augmentation index, and aortic blood pressures have been linked with augmented risk of cardiovascular disease and mortality. While the effects of antihypertensive drugs on these parameters in hypertensive patients have been studied, there are limited data so far in prehypertension. Fifty individuals with prehypertension were randomized to either nebivolol (5 mg per day) or placebo in a double-blind clinical trial. Patients underwent measurement of pulse wave velocity as well as aortic blood pressure and aortic augmentation index via pulse wave analysis at baseline and 8 weeks. Patients also had blood and urine biochemistries done at each visit. Nebivolol achieved significant reductions in central aortic systolic (P=.011), diastolic (P=.009), and mean arterial blood pressure (P=.002). Pulse wave velocity trended toward improvement but did not achieve significance (P=.088). Nitric oxide production, measured as urinary nitrite/nitrite excretion, also rose substantially in the nebivolol group (by approximately 60%, P=.030). Central blood pressures can be effectively lowered by ß-blockade while patients are still in the prehypertension phase, and the effects may be coupled to improve nitric oxide release by the drug.

Heritable influence of DBH on adrenergic and renal function: twin and disease studies.

BACKGROUND: Elevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits. METHODS: We evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance-components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation on renal disease was tested in the NIDDK-AASK cohort. RESULTS: Norepinephrine secretion rose across eGFR tertiles while eGFR fell (p<0.0001). eGFR was heritable, at h(2) = 67.3±4.7% (p = 3.0E-18), as were secretion of norepinephrine (h(2) = 66.5±5.0%, p = 3.2E-16) and dopamine (h(2) = 56.5±5.6%, p = 1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (ρG = -0.557±0.088, p = 1.11E-08) as well as dopamine (ρG = -0.223±0.101, p = 2.3E-02). Since dopamine ß-hydroxylase (DBH) catalyzes conversion of dopamine to norepinephrine, we studied functional variation at DBH; DBH promoter haplotypes predicted transcriptional activity (p<0.001), plasma DBH (p<0.0001) and norepinephrine (p = 0.0297) secretion; transcriptional activity was inversely (p<0.0001) associated with basal eGFR. Meta-analysis validated DBH haplotype effects on eGFR across 3 samples. In NIDDK-AASK, we established a role for DBH promoter variation in long-term renal decline rate (GFR slope, p = 0.003). CONCLUSIONS: The heritable GFR trait shares genetic determination with catecholamines, suggesting new pathophysiologic, diagnostic and therapeutic approaches towards disorders of GFR as well as CKD. Adrenergic activity may play a role in progressive renal decline, and genetic variation at DBH may assist in profiling subjects for rational preventive treatment.

Neuropeptide Y (NPY): genetic variation in the human promoter alters glucocorticoid signaling, yielding increased NPY secretion and stress responses.

OBJECTIVES: This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells. BACKGROUND: The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15. METHODS: Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population. RESULTS: Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇-880Δ (2-bp TG/-, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h(2)) stress traits: higher NPY secretion (h(2) = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇-880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele -880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter -880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same -880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes. CONCLUSIONS: We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇-880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.

Autonomic and hemodynamic origins of pre-hypertension: central role of heredity.

OBJECTIVES: The purpose of this study is to better understand the origins and progression of pre-hypertension. BACKGROUND: Pre-hypertension is a risk factor for progression to hypertension, cardiovascular disease, and increased mortality. We used a cross-sectional twin study design to examine the role of heredity in likely pathophysiological events (autonomic or hemodynamic) in pre-hypertension. METHODS: Eight hundred twelve individuals (337 normotensive, 340 pre-hypertensive, 135 hypertensive) were evaluated in a sample of twin pairs, their siblings, and other family members. They underwent noninvasive hemodynamic, autonomic, and biochemical testing, as well as estimates of trait heritability (the percentage of trait variance accounted for by heredity) and pleiotropy (the genetic covariance or shared genetic determination of traits) by variance components. RESULTS: In the hemodynamic realm, an elevation of cardiac contractility prompted increased stroke volume, in turn increasing cardiac output, which elevated blood pressure into the pre-hypertension range. Autonomic monitoring detected an elevation of norepinephrine secretion plus a decline in cardiac parasympathetic tone. Twin pair variance components documented substantial heritability as well as joint genetic determination for blood pressure and the contributory autonomic and hemodynamic traits. Genetic variation at a pathway locus also indicated pleiotropic effects on contractility and blood pressure. CONCLUSIONS: Elevated blood pressure in pre-hypertension results from increased cardiac output, driven by contractility as well as heart rate, which may reflect both diminished parasympathetic and increased sympathetic tone. In the face of increased cardiac output, systemic vascular resistance fails to decline homeostatically. Such traits display substantial heritability and shared genetic determination, although by loci not yet elucidated. These findings clarify the role of heredity in the origin of pre-hypertension and its autonomic and hemodynamic pathogenesis. The results also establish pathways that suggest new therapeutic targets for pre-hypertension, or approaches to its prevention.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC).

BACKGROUND: Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. METHODS: We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ∼4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ∼4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. RESULTS: In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. CONCLUSION: We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association.

Genetic variation within a metabolic motif in the chromogranin a promoter: pleiotropic influence on cardiometabolic risk traits in twins.

BACKGROUND: The cardiometabolic syndrome comprised of multiple correlated traits, but its origin is incompletely understood. Chromogranin A (CHGA) is required for formation of the catecholamine secretory pathway in sympathochromaffin cells. In twin pair studies, we found that CHGA traits aggregated with body mass index (BMI), as well as its biochemical determinant leptin. METHODS Here we used the twin method to probe the role of heredity in generating such risk traits, and then investigated the role of risk-trait-associated CHGA promoter genetic variation in transfected chromaffin cells. Trait heritability (h(2)) and shared genetic determination among traits (pleiotropy, genetic covariance, ρ(G)) were estimated by variance components in twin pairs. RESULTS: CHGA, BMI, and leptin each displayed substantial h(2), and the traits also aggregated with several features of the metabolic syndrome (e.g., insulin resistance, blood pressure (BP), hypertension, catecholamines, and C-reactive protein (CRP)). Twin studies demonstrated genetic covariance (pleiotropy, ρ(G)) for CHGA, BMI, and leptin with other metabolic traits (insulin resistance, BP, and CRP). We therefore investigated the CHGA locus for mechanisms of codetermination with such metabolic traits. A common functional variant in the human CHGA promoter (G-462A, rs9658634, minor allele frequency ~21%) was associated with leptin and CRP secretion, as well as BMI, especially in women; marker-on-trait effects on BMI were replicated across twin populations on two continents. In CHGA promoter/luciferase reporter plasmids transfected into chromaffin cells, G-462A alleles differed markedly in reporter expression. The G-462A variant disrupted predicted transcriptional control by a PPARγ/RXRα motif and costimulation by PPARγ/RXRα and their cognate ligands, differentially activated the two alleles. During chromatin immunoprecipitation, endogenous PPARγ bound the motif. CONCLUSIONS: Multiple features of the metabolic syndrome are thus under joint (pleiotropic) genetic determination, with CHGA as one such contributory locus: a common polymorphism in the promoter (G-462A) of CHGA predicts such heritable metabolic traits as BMI and leptin. CHGA promoter variant G-462A was not only associated with such metabolic traits but also disrupted a PPARγ/RXRα motif and responded differentially to characteristic trans-activators of that motif. The results suggest novel links between the catecholaminergic system and risk for the metabolic syndrome as well as systemic hypertension.

Decreased slow wave sleep increases risk of developing hypertension in elderly men.

The importance of sleep to health and cardiovascular disease has become increasingly apparent. Sleep-disordered breathing, sleep duration, and sleep architecture may all influence metabolism and neurohormonal systems, yet no previous study has evaluated these sleep characteristics concurrently in relation to incident hypertension. Our objective was to determine whether incident hypertension is associated with polysomnography measures of sleep-disordered breathing, sleep duration, and sleep architecture in older men. Participants were 784 community-dwelling, ambulatory men ≥65 years of age (mean age: 75.1±4.9 years) from the Outcomes of Sleep Disorders in Older Men Study who did not have hypertension at the time of their in-home polysomnography sleep studies (2003-2005) and who returned for follow-up (2007-2009). Of 784 older men included in this report, 243 met criteria for incident hypertension after a mean follow-up of 3.4 years. In unadjusted analyses, incident hypertension was associated with increased hypoxemia, increased sleep stages N1 and N2, and decreased stage N3 (slow wave sleep [SWS]). After adjustment for age, nonwhite race, study site, and body mass index, the only sleep index to remain significantly associated with incident hypertension was SWS percentage (odds ratio for lowest to highest quartile of SWS: 1.83 [95% CI: 1.18 to 2.85]). No attenuation of this association was seen after accounting for sleep duration, sleep fragmentation, and indices of sleep-disordered breathing. Percentage time in SWS was inversely associated with incident hypertension, independent of sleep duration and fragmentation, and sleep-disordered breathing. Selective deprivation of SWS may contribute to adverse blood pressure in older men.

A cross-sectional and 10-year prospective study of postmenopausal estrogen therapy and blood pressure, renal function, and albuminuria: the Rancho Bernardo Study.

OBJECTIVE: Blood pressure, urine albumin-to-creatinine ratio, and estimated glomerular filtration rate (GFR) are highly correlated conditions. The longitudinal effect of exposure to postmenopausal estrogen therapy on these traits studied together has not been reported. METHODS: This was a cross-sectional study of 1,044 older postmenopausal community-dwelling women from the Rancho Bernardo Study (1992-1996); 443 women were reevaluated ∼ 10 years later (2002-2005). We determined the cross-sectional and prospective association of baseline postmenopausal estrogen therapy and blood pressure, urine albumin-to-creatinine ratio, GFR, and the odds of categorical hypertension (physician diagnosis, medication, or blood pressure ≥ 140/≥ 90 mm Hg), chronic kidney disease (GFR ≤ 60 mL/min per 1.73 m2), and albuminuria (urine albumin-to-creatinine ratio ≥ 25 mg/g). RESULTS: At baseline, the mean age was 68.3 years for current estrogen users, 75.4 years for past users, and 74.3 years for never users. In the cross-sectional analyses, current users had lower diastolic blood pressure and lower odds of having chronic kidney disease, independent of covariates. In the ∼ 10-year follow-up, comparisons between never, past, and current estrogen use (91% continuous use since baseline), the mean diastolic blood pressure declined over time in current users, whereas systolic blood pressure increased among never users. Urine albumin-to-creatinine ratio also increased in never users and decreased in current users; GFR did not differ by estrogen use. CONCLUSIONS: In cross-sectional analyses, estrogen users had better GFR and blood pressure than nonusers did, but the 10-year follow-up showed improved blood pressure and decreased urine albumin-to-creatinine ratio among mostly long-term current users, without differences in GFR by estrogen use. This study suggests no association of GFR with 10 years of continuous estrogen use and an inverse association with albuminuria.