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Aims: In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy., Methods: The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo., Conclusion: VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF., (© 2024 Bayer AG, Merck Sharp & Dohme LLC and The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF., Methods and Results: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all p interaction  > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years)., Conclusions: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses., (© 2024 European Society of Cardiology.)

Background: We examined whether the primary composite outcome (cardiovascular death or heart failure hospitalization) was related to differences in background use and dosing of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction enrolled in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), a randomized trial of vericiguat versus placebo., Methods: We evaluated the adherence to guideline use of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. We assessed basic adherence; indication-corrected adherence accounting for guideline indications and contraindications; and dose-corrected adherence (indication-corrected adherence+≥50% of drug dose target). Associations between study treatment and the primary composite outcome according to the adherence to guidelines were assessed using multivariable adjustment; adjusted hazard ratios with 95% CIs and P interaction are reported., Results: Of 5050 patients, 5040 (99.8%) had medication data at baseline. For angiotensin-converting enzyme inhibitor, angiotensin-receptor blockers, and angiotensin receptor-neprilysin inhibitors, basic adherence to guidelines was 87.4%, indication-corrected was 95.7%, and dose-corrected was 50.9%. For beta-blockers, basic adherence was 93.1%, indication-corrected was 96.2%, and dose-corrected was 45.4%. For mineralocorticoid receptor antagonists, basic adherence was 70.3%, indication-corrected was 87.1%, and dose-corrected was 82.2%. For triple therapy (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin receptor-neprilysin inhibitors+beta-blocker+mineralocorticoid receptor antagonist), basic adherence was 59.7%, indication-corrected was 83.3%, and dose-corrected was 25.5%. Using basic or dose-corrected adherence, the treatment effect of vericiguat was consistent across adherence to guidelines groups, with or without multivariable adjustment with no treatment heterogeneity., Conclusions: Patients in VICTORIA were well treated with heart failure with reduced ejection fraction medications. The efficacy of vericiguat was consistent across background therapy with very high adherence to guidelines accounting for patient-level indications, contraindications, and tolerance., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02861534., Competing Interests: Disclosures Dr Ezekowitz: Research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics; consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr McMullan: Employee of Merck. Dr Westerhout: Consulting fees from Bayer Canada. Dr Piña: Advisory Board member of Relypsa and Vifor. Dr Lopez-Sendon: Grants and personal fees from Bayer, Pfizer, Sanofi, and Boehringer Ingelheim; personal fees from Menarini; grants from Merck and Amgen. Dr Anstrom: Research grants from Merck and the National Institutes of Health. Dr Hernandez: Research grants and personal fees from Merck, AstraZeneca, Novartis, and Boehringer Ingelheim; grants from American Regent; personal fees from Bayer, Amgen, and Boston Scientific. Dr Lam: Grants and personal fees from Merck and Bayer; grants from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; personal fees from Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, and WebMD Global LLC; has a patent to PCT/SG2016/050217 pending and a patent to 16/216,929 issued; and is cofounder and nonexecutive director of Us2.ai. Dr O’Connor: Research funding from Merck and consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. Dr Pieske: Personal fees from Merck, Bayer Healthcare, Novartis, Astra Zeneca, BMS, and Servier. Dr Ponikowski: Research grants from Vifor Pharma Ltd and Servier; consulting fees from MSD, Novartis, Vifor Pharma Ltd, Servier, BMS, Boehringer Ingelheim, Respicardia, AstraZencea, Cibiem, RenalGuardSolution, and Berlin Chemie. Dr Roessig: Employee of Bayer AG. Dr Voors: Research grants from Boehringer Ingelheim and Roche Diagnostics; consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Dr Koglin: Employee of Merck. Dr Armstrong: Grants and personal fees from Merck and Bayer; grants from Sanofi-aventis Recherche & Developpement, Boehringer Ingelheim, and CSL Limited; and personal fees from AstraZeneca and Novartis. Dr Butler: Consulting fees from Bayer, Merck, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Janssen, Luitpold, Medtronic, Novartis, Vifor, and Novo Nordisk.

Rationale & Objective: Access patency outcomes for arteriovenous fistulas (AVFs) as compared with arteriovenous grafts (AVGs) in patients receiving hemodialysis (HD) who have achieved a functioning permanent access are not fully explored., Study Design: Observational cohort study., Setting & Population: Fee-for-service Medicare beneficiaries aged ≥18 years with kidney failure who were newly using a permanent access for maintenance HD from the United States Renal Data System (2010-2015). Patients using an oral anticoagulant were excluded., Exposure: AVG or AVF., Outcomes: Loss of primary unassisted, primary assisted, and secondary patency., Analytical Approach: Outcomes were characterized using cumulative incidence curves, and HRs adjusted for sociodemographic and clinical factors were estimated for the comparison of AVF versus AVG., Results: The cohort included 60,329 and 17,763 patients newly using an AVF and AVG, respectively, for HD. Over 3 years of follow-up, AVG users, compared to AVF users, had a higher cumulative incidence of loss of primary unassisted patency (87% vs 69%; HR, 1.56; 95% CI, 1.52-1.60), loss of primary assisted patency (69% vs 25%; HR, 3.79; 95% CI, 3.67-3.92), and loss of secondary patency (22% vs 10%; HR, 2.03; 95% CI, 1.92-2.16). Stratified analyses revealed differences by subgroups; in particular, incidence of patency loss was higher among patients who underwent prior interventions to maintain prefunctional access patency and Black patients., Limitations: This analysis focused on outcomes occurring after first successful use of a permanent access and thus does not inform about risk of patency loss during access maturation., Conclusions: Among patients with kidney failure who successfully used a permanent access for HD, patency loss was consistently substantially higher in those using AVGs compared with AVFs. New interventions, such as prophylactic drugs, are needed to improve access longevity and reduce the need for invasive interventions, particularly among patients unable to receive a fistula., (© 2022 National Kidney Foundation Inc.)

Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Soluble guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide-sGC-cyclic guanosine monophosphate cascade - a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower-risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher- and lower-risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, pre-clinical studies and post-hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects - these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow-up in a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally treated, low-risk HFrEF patients (i.e. those without recently worsening heart failure)., (© 2022 European Society of Cardiology.)

Prolonged exposure to chronic sleep restriction (CSR) and shiftwork are both associated with incident hypertension and cardiovascular disease. We hypothesized that the combination of CSR and shiftwork's rotating sleep schedule (causing recurrent circadian disruption, RCD) would increase blood pressure, renal sodium retention, potassium excretion, and aldosterone excretion. Seventeen healthy participants were studied during a 32-day inpatient protocol that included 20-h "days" with associated scheduled sleep/wake and eating behaviors. Participants were randomly assigned to restricted (1:3.3 sleep:wake, CSR group) or standard (1:2 sleep:wake, Control group) ratios of sleep:wake duration. Systolic blood pressure during circadian misalignment was ∼6% higher in CSR conditions. Renal sodium and potassium excretion showed robust circadian patterns; potassium excretion also displayed some influence of the scheduled behaviors (sleep/wake, fasting during sleep so made parallel fasting/feeding). In contrast, the timing of renal aldosterone excretion was affected predominately by scheduled behaviors. Per 20-h "day," total sodium excretion increased, and total potassium excretion decreased during RCD without a change in total aldosterone excretion. Lastly, a reduced total renal sodium excretion was found despite constant oral sodium consumption and total aldosterone excretion, suggesting a positive total body sodium balance independent of aldosterone excretion. These findings may provide mechanistic insight into the observed adverse cardiovascular and renal effects of shiftwork., Competing Interests: AM reports consultancy for Somni Coporation; EK has received travel reimbursement from the Sleep Research Society, the National Sleep Foundation, the Santa Fe Institute, the World Conference of Chronobiology, the Gordon Research Conference, and the German Sleep Society (DGSM); she was paid by the Puerto Rico Trust for a grant review, and has consulted for the American Academy of Sleep Medicine Foundation, Circadian Therapeutics, the National Sleep Foundation, Sanofi-Genzyme, and Yale University Press. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McMullan, McHill, Hull, Wang, Forman and Klerman.)

Rationale & Objective: The risks of major bleeding, thrombosis, and cardiovascular events are elevated in patients receiving maintenance hemodialysis (HD). Our objective was to compare the risk of these outcomes in HD according to the permanent vascular access type., Study Design: Observational cohort study., Setting & Participants: Using data from the United States Renal Data System (2010-2015), we included patients with kidney failure who were greater than 18 years, had Medicare as the primary payer, were not using an oral anticoagulant, and were newly using an arteriovenous (AV) access for HD., Exposure: AV graft (AVG) or AV fistula (AVF)., Outcomes: Major bleeding, venous thromboembolism, ischemic stroke, myocardial infarction, cardiovascular death, and critical limb ischemia., Analytical Approach: Comparing 17,763 AVG and 60,329 AVF users, we estimated the 3-year incidence rates and incidence rate ratios (IRRs) of each outcome using Poisson regression. IRRs were adjusted for sociodemographic and clinical covariates., Results: The use of an AVG, compared with that of an AVF, was associated with an increased risk of venous thromboembolism (10.8 vs 5.3 events per 100 person-years; adjusted IRR, 1.74; 95% CI, 1.63-1.85) but not with the risk of major bleeding (IRR, 1.04; 95% CI, 0.93-1.17). The use of an AVG was also potentially associated with a slightly increased risk of cardiovascular death (IRR, 1.09; 95% CI, 1.01-1.16)., Limitations: This analysis focused on patients with a functioning AV access; adverse events that may occur during access maturation should also be considered when selecting a vascular access., Conclusions: The use of an AVG, relative to an AVF, in HD is associated with an increased risk of venous thromboembolism. Given recent guidelines emphasizing selection of the "right access" for the "right patient," the results of this study should potentially be considered as one additional factor when selecting the optimal access for HD., (© 2022 Merck Sharp & Dohme Corp., a subsidiary Merck & Co., Inc., Kenilworth, NJ, USA and The Author(s).)

Septoria nodorum blotch (SNB) is a necrotrophic disease of wheat prominent in some parts of the world, including Western Australia (WA) causing significant losses in grain yield. The genetic mechanisms for resistance are complex involving multiple quantitative trait loci. In order to decipher comparable or independent regulation, this study identified the genetic control for glume compared to foliar resistance across four environments in WA against 37 different isolates. High proportion of the phenotypic variation across environments was contributed by genotype (84.0% for glume response and 82.7% for foliar response) with genotype-by-environment interactions accounting for a proportion of the variation for both glume and foliar response (14.7 and 16.2%, respectively). Despite high phenotypic correlation across environments, most of the eight and 14 QTL detected for glume and foliar resistance using genome wide association analysis (GWAS), respectively, were identified as environment-specific. QTL for glume and foliar resistance neither co-located nor were in LD in any particular environment indicating autonomous genetic mechanisms control SNB response in adult plants, regulated by independent biological mechanisms and influenced by significant genotype-by- environment interactions. Known Snn and Tsn loci and QTL were compared with 22 environment-specific QTL. None of the eight QTL for glume or the 14 for foliar response were co-located or in linkage disequilibrium with Snn and only one foliar QTL was in LD with Tsn loci on the physical map. Therefore, glume and foliar response to SNB in wheat is regulated by multiple environment-specific loci which function independently, with limited influence of known NE- Snn interactions for disease progression in Western Australian environments. Breeding for stable resistance would consequently rely on recurrent phenotypic selection to capture and retain favorable alleles for both glume and foliar resistance relevant to a particular environment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Francki, Walker, McMullan and Morris.)

The slow rate of genetic gain for improving resistance to Septoria nodorum blotch (SNB) is due to the inherent complex interactions between host, isolates, and environments. Breeding for improved SNB resistance requires evaluation and selection of wheat genotypes consistently expressing low SNB response in different target production environments. The study focused on evaluating 232 genotypes from global origins for resistance to SNB in the flag leaf expressed in different Western Australian environments. The aim was to identify resistant donor germplasm against historical and contemporary pathogen isolates and enhance our knowledge of the genetic basis of genotype-by-environment interactions for SNB response. Australian wheat varieties, inbred lines from Centro Internacional de Mejoramiento de Maiz y Trigo (CIMMYT), and International Center for Agricultural Research in the Dry Areas (ICARDA), and landraces from discrete regions of the world showed low to moderate phenotypic correlation for disease response amongst genotypes when evaluated with historical and contemporary isolates at two locations across 3 years in Western Australia (WA). Significant ( P < 0.001) genotype-by-environment interactions were detected regardless of same or different isolates used as an inoculum source. Joint regression analysis identified 19 genotypes that consistently expressed low disease severity under infection with different isolates in multi-locations. The CIMMYT inbred lines, 30ZJN09 and ZJN12 Qno25, were particularly pertinent as they had low SNB response and highest trait stability at two locations across 3 years. Genome wide association studies detected 20 QTL associated with SNB resistance on chromosomes 1A, 1B, 4B, 5A, 5B, 6A, 7A, 7B, and 7D. QTL on chromosomes 1B and 5B were previously reported in similar genomic regions. Multiple QTL were identified on 1B, 5B, 6A, and 5A and detected in response to SNB infection against different isolates and specific environments. Known SnTox- Snn interactions were either not evident or variable across WA environments and SNB response may involve other multiple complex biological mechanisms., (Copyright © 2020 Francki, Walker, McMullan and Morris.)

Introduction: Poor sleep associates with adverse chronic kidney disease (CKD) outcomes yet the biological mechanisms underlying this relation remain unclear. One proposed mechanism is via allostatic load, a cumulative biologic measure of stress., Methods: Using data from 5177 Jackson Heart Study participants with sleep measures available, we examined the association of self-reported sleep duration: very short, short, recommended, and long (≤5, 6, 7-8, or ≥9 hours per 24 hours, respectively) and sleep quality (high, moderate, low) with prevalent baseline CKD, and estimated glomerular filtration rate (eGFR) decline and incident CKD at follow-up. CKD was defined as eGFR <60 ml/min per 1.73 m 2 or urine albumin-to-creatinine ratio ≥30 mg/g. Models were adjusted for demographics, comorbidities, and kidney function. We further evaluated allostatic load (quantified at baseline using 11 biomarkers from neuroendocrine, metabolic, autonomic, and immune domains) as a mediator of these relations using a process analysis approach., Results: Participants with very short sleep duration (vs. 7-8 hours) had greater odds of prevalent CKD (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.03-1.66). Very short, short, or long sleep duration (vs. 7-8 hours) was not associated with kidney outcomes over a median follow-up of 8 years. Low sleep quality (vs. high) associated with greater odds of prevalent CKD (OR 1.26, 95% CI 1.00-1.60) and 0.18 ml/min per 1.73 m 2 (95% CI 0.00-0.36) faster eGFR decline per year. Allostatic load did not mediate the associations of sleep duration or sleep quality with kidney outcomes., Conclusions: Very short sleep duration and low sleep quality were associated with adverse kidney outcomes in this all-black cohort, but allostatic load did not appear to mediate these associations.

Weight gain and obesity have reached epidemic proportions in modern society. Insufficient sleep-which is also prevalent in modern society-and eating at inappropriate circadian times have been identified as risk factors for weight gain, yet the impact of chronic insufficient sleep on the circadian timing of subjective hunger and physiologic metabolic outcomes are not well understood. We investigated how chronic insufficient sleep impacts the circadian timing of subjective hunger and fasting metabolic hormones in a 32-day in-laboratory randomized single-blind control study, with healthy younger participants (range, 20-34 years) randomized to either Control (1:2 sleep:wake ratio, 6.67 h sleep:13.33 h wake, n  = 7, equivalent to 8 h of sleep per 24 h) or chronic sleep restriction (CSR, 1:3.3 sleep:wake ratio, 4.67 h sleep:15.33 h wake, n  = 8, equivalent to 5.6 h of sleep per 24 h) conditions. Participants lived on a "20 h day" designed to distribute all behaviors and food intake equally across all phases of the circadian cycle over every six consecutive 20 h protocol days. During each 20 h day, participants were provided a nutritionist-designed, isocaloric diet consisting of 45-50% carbohydrate, 30-35% fat, and 15-20% protein adjusted for sex, weight, and age. Subjective non-numeric ratings of hunger were recorded before and after meals and fasting blood samples were taken within 5 min of awakening. Subjective levels of hunger and fasting concentrations of leptin, ghrelin, insulin, glucose, adiponectin, and cortisol all demonstrated circadian patterns; there were no differences, however, between CSR and Control conditions in subjective hunger ratings or any fasting hormone concentrations. These findings suggest that chronic insufficient sleep may have a limited role in altering the robust circadian profile of subjective hunger and fasted metabolic hormones., Clinical Trial Registration: The study was registered as clinical trial #NCT01581125.

Background: Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown., Study Design: Prospective observational cohort study., Settings & Participants: 3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013., Predictor: Baseline uric acid concentrations., Outcomes: Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality., Results: During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ≥ 45mL/min/1.73m 2 (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m 2 . There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m 2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007)., Limitations: Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time., Conclusions: Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting., Design, Setting, Participants, & Measurements: In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping., Results: Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m 2 ) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group ( P =0.83), -4 (-16 to 9) in the allopurinol group ( P =0.32), and 1 (-21 to 17) in the placebo group ( P =0.96), with no significant treatment effect ( P =0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid ( P =0.43), -0.4±6.1 with allopurinol ( P =0.76), and 0.5±6.0 with placebo ( P =0.65); there was no significant treatment effect ( P =0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively., Conclusions: In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP., (Copyright © 2017 by the American Society of Nephrology.)

Objectives: Low nocturnal melatonin secretion is associated with cardiovascular risk factors, diabetes and hypertension, while individuals with prevalent cardiovascular disease have lower nocturnal melatonin levels. However, the prospective association of melatonin secretion with myocardial infarction (MI) has not been studied. We aimed to study the association between melatonin secretion and the risk of developing MI., Methods: We performed a prospective nested case-control study of participants from the Nurses' Health Study cohorts I and II. A total of 209 incident cases of fatal and non-fatal MI were identified among women who provided first morning voided urine specimens at baseline and were matched to 209 controls. Nocturnal melatonin secretion was assessed using 6-sulfatoxymelatonin concentrations in morning urines normalised to the urines' creatinine concentration. Multivariable conditional logistic regression was used to analyse associations independent of important risk factors., Results: Lower melatonin secretion was significantly associated with a higher risk of MI. After conditioning on matching variables, the OR for every one unit lower log-transformed sulfatoxymelatonin/creatinine ratio was 1.51 (95% CI 1.16 to 1.96). In multivariable models controlling for factors included in the American Heart Association Cardiovascular Risk Score plus circadian factors, every one unit lower in the ratio was associated with a significantly increased risk of MI (OR, 1.40; 95% CI 1.02 to 1.93). Women in the highest category had an estimated absolute risk of MI of 84 cases per 100 000 person-years compared with 197 cases per 100 000 person-years in the lowest category. The association was strongly modified by body mass index (BMI) (p value for interaction=0.02)., Conclusions: Lower melatonin secretion was significantly associated with a greater risk of incident MI in women with increased BMI. Melatonin may be a novel and modifiable risk factor for MI among such women., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: Disruption of vitamin D signaling in rodents causes activation of the rennin-angiotensin system (RAS) and development of hypertension. Observational studies in humans found lower circulating 25-hydroxyvitamin D [25(OH)D] is associated with increased RAS activity and blood pressure (BP). We performed the first randomized control trial to investigate the effects of vitamin D supplementation on the RAS in humans., Methods: Vitamin D deficient, [25(OH)D ≤20 ng/ml), overweight individuals without hypertension were randomized into a double-blind, placebo-controlled trial of 8-weeks treatment with ergocalciferol or placebo. Kidney-specific RAS activity, measured using renal plasma flow response to captopril in high sodium balance, was assessed at baseline and 8 weeks, as was systemic RAS activity and 24-h ambulatory BP., Results: In total, 84 participants completed the study. Mean 25[OH]D levels increased from 14.7 to 30.3 ng/ml in the ergocalciferol group, P value < 0.0001, and from 14.3 to 17.4 ng/ml in the placebo group, P value = 0.3. The renal plasma flow response to captopril was 33.9 ± 56.1 ml/min per 1.73 m at baseline and 35.7 ± 47.7 ml/min per 1.73 m at 8 weeks in the ergocalciferol group (P value = 0.83); and was 37.3 ± 46.9 ml/min per 1.73 m at baseline and 35.9 ± 26.2 ml/min per 1.73 m at 8 weeks in the placebo group (P value = 0.78). Ergocalciferol had no effect on PRA, AngII, or 24-h BP measurements., Conclusions: This trial found no benefit from correcting vitamin D deficiency on RAS activity or BP after 8 weeks. These findings are not consistent with the hypothesis that vitamin D is a modifiable target for lowering BP in vitamin D deficient individuals.

The kidney is influenced by circadian rhythms and is entrained to the sleep-wake cycle allowing anticipation of the metabolic and physiological demands of the kidney throughout a 24-hour cycle. Although sleep disruption has been studied extensively in cardiovascular and metabolic disease, its association with chronic kidney disease has not been shown. We examined this in a prospective cohort study of 4238 participants from the Nurses' Health Study and analyzed the association of self-reported sleep duration with decline in renal function over an 11-year period (1989 to 2000). Individuals who reported shorter sleep duration were more likely to experience a rapid decline in estimated glomerular filtration rate (30% or more). Compared with sleeping 7 to 8 hours per night, the adjusted odds ratios for a rapid decline in renal function were a significant 1.79 (95% CI, 1.06-3.03) for 5 hours or less sleep per night, a significant 1.31 (95% CI, 1.01-1.71) for 6 hours sleep per night, but an insignificant 0.88 (95% CI, 0.50-1.57) for 9 or more hours sleep per night. Similarly, there was a significant trend in the adjusted annualized decline in estimated glomerular filtration rate of 1.2 ml/min/1.73 m(2)/year, 0.9 ml/min/1.73 m(2)/year, 0.8 ml/min/1.73 m(2)/year, and 0.8 ml/min/1.73 m(2)/year for individuals sleeping 5 hours or less per night, 6 hours per night, 7 to 8 hours per night, and 9 hours or more per night, respectively. Thus, shorter sleep duration is prospectively and independently associated with faster decline in renal function., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: Ambulatory blood pressure measurement allows quantification of diurnal changes in blood pressure. While decreased nocturnal blood pressure dipping and elevated morning blood pressure surge are associated with an increased risk of cardiovascular events, the utility of ambulatory blood pressure measurements to predict renal events is unclear. African Americans, in addition to having an increased risk of chronic kidney disease (CKD), also have an increased prevalence of hypertension. Thus, we selected an African American population to study the association of ambulatory blood pressure parameters with incidence of CKD., Methods: Prospective cohort study of 603 participants with normal renal function enrolled in the Jackson Heart Study who underwent baseline 24-h ambulatory blood pressure monitoring between 2000 and 2004, with median follow-up of 8.1 years. We analyzed the association of nocturnal dipping and morning surge with both incident CKD [estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m] and annual rate of eGFR decline. In additional analyses, we examined the relation of nocturnal, daytime, white-coat, and masked hypertension with CKD incidence., Results: We found that 10% higher nocturnal dipping was significantly associated with a decreased risk of incident CKD [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.32-0.96] and a 0.4 ml/min per 1.73 m slower annual decline in eGFR. Morning surge was not associated with the incidence of CKD. Additional analyses revealed that isolated nocturnal hypertension and mean asleep SBP were associated with a nonsignificantly higher risk of CKD (OR 2.34, 95% CI 0.90-6.08) and (OR 1.31, 95% CI 0.99-1.72), respectively, in fully adjusted models., Conclusions: Loss of nocturnal blood pressure dipping, but not morning blood pressure surge, may promote the decline in GFR and increase the risk for development of CKD in high-risk individuals.

Ambulatory blood pressure parameters, nocturnal dipping and morning surge, are associated with cardiovascular outcomes in several populations. While significant variation exists between racial groups in ambulatory blood pressure measurements and the incidence of cardiovascular disease, the effect of race on the associations of dipping and morning surge with cardiovascular outcomes is unknown. In a prospective analysis of 197 African American and 197 Japanese individuals with non-diabetic chronic kidney disease matched by age and renal function, we analyzed the associations of dipping and morning surge with cardiovascular events for both races and assessed whether these relations differed by race. Higher sleep-trough morning surge was independently associated with cardiovascular events in Japanese (hazard ratio, 1.93 per 10 mm Hg; 95% confidence interval, 1.20-3.10) but not in African American participants, with race an effect modifier (P-value <.01). Dipping was not associated with cardiovascular events in either racial group. In individuals with chronic kidney disease, the association between morning surge and cardiovascular events appears to be dependent upon race, with higher morning surge a risk factors in Japanese but not in African Americans., (Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Increased systolic blood pressure variability between outpatient visits is associated with increased incidence of cardiovascular end points. However, few studies have examined the association of visit-to-visit variability in systolic blood pressure with clinically relevant kidney disease outcomes. We analyzed the association of systolic blood pressure visit-to-visit variability with renal and cardiovascular morbidity and mortality among individuals with diabetes and nephropathy., Study Design: Observational analysis of IDNT (Irbesartan Diabetic Nephropathy Trial) and the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study., Setting & Participants: 2,739 participants with type 2 diabetes and nephropathy with at least 1 year of blood pressure measurements available., Predictors: Systolic blood pressure visit-to-visit variability was calculated from the SD of the systolic blood pressure from 4 visits occurring 3-12 months postrandomization., Outcomes: The kidney disease outcome was defined as time to confirmed doubling of serum creatinine level, end-stage renal disease, or death; the cardiovascular outcome was defined as time to cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, or revascularization., Results: Mean visit-to-visit variability in systolic blood pressure from 3 to 12 months postrandomization was 12.0±6.8(SD)mmHg. Following this ascertainment period, there were 954 kidney disease and 542 cardiovascular events. Greater systolic blood pressure visit-to-visit variability was associated independently with increased risk of the composite kidney disease end point (HR per 1-SD increment, 1.08 [95%CI, 1.01-1.16]; P=0.02) and end-stage renal disease, but not with the cardiovascular outcome., Limitations: Observational study with the potential for confounding., Conclusions: In diabetic individuals with nephropathy, systolic blood pressure visit-to-visit variability is associated independently with hard kidney disease outcomes., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The association of preawake (difference between pre- and postwaking blood pressure (BP)) and sleep-through surge (difference between sleeping nadir and postwaking BP) with cardiovascular events is unclear. Examination of factors associated with surge may provide novel insights. We examined the association of race, which associates with nocturnal dipping, and plasma renin activity (PRA) with preawake and sleep-through surge among individuals on a controlled diet., Methods: We performed a post hoc analysis of 323 subjects from the Dietary Approaches to Stop Hypertension trial who had available 24-hour BP data and who ingested a control diet during a 3-week run-in period. Linear regression models were fit to estimate the association of race and PRA with preawake and sleep-through surge., Results: Of the 323 individuals, 55% were black, 53% were men, and the average age was 45 years. After controlling for other factors, black race was associated with a 3.2mm Hg lower preawake and a 3.7mm Hg lower sleep-through surge compared with nonblacks. In nonblacks, higher PRA was associated with greater preawake surge only. There was no association of PRA with either preawake or sleep-through surge in blacks. Additional adjustment for dipping status resulted in attenuation of the race-surge associations., Conclusions: Black race is associated with lower preawake and sleep-through surge compared with nonblacks, but the effect is partially attenuated by dipping status. Higher PRA appears to be associated with a higher preawake surge in nonblacks only. Further research should address if morning surge is definitively associated with clinical outcomes in racial subgroups, independent of dipping.

Objectives: This study tested whether myocardial extracellular volume (ECV) is increased in patients with hypertension and atrial fibrillation (AF) undergoing pulmonary vein isolation and whether there is an association between ECV and post-procedural recurrence of AF., Background: Hypertension is associated with myocardial fibrosis, an increase in ECV, and AF. Data linking these findings are limited. T1 measurements pre-contrast and post-contrast in a cardiac magnetic resonance (CMR) study provide a method for quantification of ECV., Methods: Consecutive patients with hypertension and recurrent AF referred for pulmonary vein isolation underwent a contrast CMR study with measurement of ECV and were followed up prospectively for a median of 18 months. The endpoint of interest was late recurrence of AF., Results: Patients had elevated left ventricular (LV) volumes, LV mass, left atrial volumes, and increased ECV (patients with AF, 0.34 ± 0.03; healthy control patients, 0.29 ± 0.03; p < 0.001). There were positive associations between ECV and left atrial volume (r = 0.46, p < 0.01) and LV mass and a negative association between ECV and diastolic function (early mitral annular relaxation [E'], r = -0.55, p < 0.001). In the best overall multivariable model, ECV was the strongest predictor of the primary outcome of recurrent AF (hazard ratio: 1.29; 95% confidence interval: 1.15 to 1.44; p < 0.0001) and the secondary composite outcome of recurrent AF, heart failure admission, and death (hazard ratio: 1.35; 95% confidence interval: 1.21 to 1.51; p < 0.0001). Each 10% increase in ECV was associated with a 29% increased risk of recurrent AF., Conclusions: In patients with AF and hypertension, expansion of ECV is associated with diastolic function and left atrial remodeling and is a strong independent predictor of recurrent AF post-pulmonary vein isolation., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to identify the frequency, pattern, and prognostic significance of left ventricular (LV) late gadolinium enhancement (LGE) in patients with atrial fibrillation (AF)., Background: There are limited data on the presence, pattern, and prognostic significance of LV myocardial fibrosis in patients with AF. LGE during cardiac magnetic resonance imaging is a marker for myocardial fibrosis., Methods: A group of 664 consecutive patients without known prior myocardial infarction who were referred for radiofrequency ablation of AF were studied. Cardiac magnetic resonance imaging was requested to assess pulmonary venous anatomy., Results: Overall, 73% were men, with a mean age of 56 years and a mean LV ejection fraction of 56 ± 10%. LV LGE was found in 88 patients (13%). The endpoint was all-cause mortality, and in this cohort, 68 deaths were observed over a median follow-up period of 42 months. On univariate analysis, age (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1.03 to 1.08; chi-square likelihood ratio [LRχ(2)]: 15.2; p = 0.0001), diabetes (HR: 2.39; 95% CI: 1.41 to 4.09; LRχ(2): 10.3; p = 0.001), a history of heart failure (HR: 1.78; 95% CI: 1.09 to 2.91; LRχ(2): 5.37; p = 0.02), left atrial dimension (HR: 1.04; 95% CI: 1.01 to 1.08; LRχ(2): 6.47; p = 0.01), presence of LGE (HR: 5.08; 95% CI: 3.08 to 8.36; LRχ(2): 28.8; p < 0.0001), and LGE extent (HR: 1.15; 95% CI: 1.10 to 1.21; LRχ(2): 35.6; p < 0.0001) provided the strongest associations with mortality. The mortality rate was 8.1% per patient-year in patients with LGE compared with 2.3% patients without LGE. In the best overall multivariate model for mortality, age and the extent of LGE were independent predictors of mortality. Indeed, each 1% increase in the extent of LGE was associated with a 15% increased risk for death., Conclusions: In patients with AF, LV LGE is a frequent finding and is a powerful predictor of mortality., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Exogenous melatonin ameliorates insulin resistance in animals, while among humans, polymorphisms in the melatonin receptor gene are associated with insulin resistance. We aimed to investigate the association of endogenous nocturnal melatonin secretion with insulin resistance in humans. We analyzed the association between endogenous nocturnal melatonin secretion, estimated by measuring the main melatonin metabolite, 6-sulfatoxymelatonin, from the first morning urinary void, and the prevalence of insulin resistance based on fasting blood samples collected in a cross-sectional study of 1,075 US women (1997-1999) without diabetes, hypertension, or malignancy. Urinary 6-sulfatoxymelatonin level was standardized to urinary creatinine level; insulin resistance was defined as an insulin sensitivity index value (using the McAuley formula) less than 7.85. Logistic regression models included adjustment for age, body mass index, smoking, physical activity, alcohol intake, dietary glycemic index, family history of diabetes mellitus, blood pressure, plasma total cholesterol, uric acid, and estimated glomerular filtration rate. Higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance. In fully adjusted models, the odds ratio for insulin resistance was 0.45 (95% confidence interval: 0.28, 0.74) among women in the highest quartile of urinary 6-sulfatoxymelatonin:creatinine ratio compared with women in the lowest quartile. Nocturnal melatonin secretion is independently and inversely associated with insulin resistance.

Background and Objectives: Increased systolic BP visit-to-visit variability (SBV) may be associated with higher overall mortality and cardiovascular events. However, few studies have examined these associations in patients with CKD, and the relation of SBV with CKD progression and ESRD has not been shown. This study analyzed the association of SBV with overall mortality, cardiovascular mortality, cardiovascular events, and renal events among individuals enrolled in the African American Study of Kidney Disease (AASK) trial., Design, Setting, Participants, & Measurements: This was a prospective observational study of 908 participants during the trial phase of the AASK study, with at least 1 year of BP measurements available and followed for 3-6.4 years. SBV was calculated as the SD of the systolic pressure from five visits occurring 3-12 months after randomization. The association of SBV with risk of overall mortality, cardiovascular mortality, a composite of fatal and nonfatal cardiovascular events, and a composite of renal events was assessed using proportional hazards regression and adjusting for multiple potential confounders., Results: Greater SBV was associated with higher overall mortality. The adjusted hazard ratio (95% confidence interval) was 2.82 (1.14-6.95) comparing the highest with lowest tertile of SBV. A similar comparison revealed that greater SBV was also associated with cardiovascular mortality (adjusted hazard ratio, 4.91; 1.12-21.50). SBV was associated with both the cardiovascular renal composite endpoints in unadjusted but not adjusted analyses., Conclusions: In African Americans with CKD, SBV is strongly and independently associated with overall and cardiovascular mortality.

Importance: Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance., Objective: To study the association between melatonin secretion and the risk of developing type 2 diabetes., Design, Setting, and Participants: Case-control study nested within the Nurses' Health Study cohort. Among participants without diabetes who provided urine and blood samples at baseline in 2000, we identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls using risk-set sampling., Main Outcome Measures: Associations between melatonin secretion at baseline and incidence of type 2 diabetes were evaluated with multivariable conditional logistic regression controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction., Results: The median urinary ratios of 6-sulfatoxymelatonin to creatinine were 28.2 ng/mg (5%-95% range, 5.5-84.2 ng/mg) among cases and 36.3 ng/mg (5%-95% range, 6.9-110.8 ng/mg) among controls. Women with lower ratios of 6-sulfatoxymelatonin to creatinine had increased risk of diabetes (multivariable odds ratio, 1.48 [95% CI, 1.11-1.98] per unit decrease in the estimated log ratio of 6-sulfatoxymelatonin to creatinine). Compared with women in the highest ratio category of 6-sulfatoxymelatonin to creatinine, those in the lowest category had a multivariable odds ratio of 2.17 (95% CI, 1.18-3.98) of developing type 2 diabetes. Women in the highest category of melatonin secretion had an estimated diabetes incidence rate of 4.27 cases/1000 person-years compared with 9.27 cases/1000 person-years in the lowest category., Conclusions and Relevance: Lower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes. Further research is warranted to assess if melatonin secretion is a modifiable risk factor for diabetes within the general population.

Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH(2)-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results.

We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-kappaB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1alpha activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.

Insulin-like growth factors and their receptor (IGF-1R) have been implicated in cancer pathophysiology. We demonstrate that IGF-1R is universally expressed in various hematologic (multiple myeloma, lymphoma, leukemia) and solid tumor (breast, prostate, lung, colon, thyroid, renal, adrenal cancer, retinoblastoma, and sarcoma) cells. Specific IGF-1R inhibition with neutralizing antibody, antagonistic peptide, or the selective kinase inhibitor NVP-ADW742 has in vitro activity against diverse tumor cell types (particularly multiple myeloma), even those resistant to conventional therapies, and triggers pleiotropic antiproliferative/proapoptotic molecular sequelae, delineated by global transcriptional and proteomic profiling. NVP-ADW742 monotherapy or its combination with cytotoxic chemotherapy had significant antitumor activity in an orthotopic xenograft MM model, providing in vivo proof of principle for therapeutic use of selective IGF-1R inhibitors in cancer.

Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones. HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We recently showed that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), potently induce apoptosis of human multiple myeloma (MM) cells. In this study, we focused on MM as a model to study the transcriptional profile of HDAC inhibitor treatment on tumor cells and to address their pathophysiological implications with confirmatory mechanistic and functional assays. We found that MM cells are irreversibly committed to cell death within few hours of incubation with SAHA. The hallmark molecular profile of MM cells before their commitment to SAHA-induced cell death is a constellation of antiproliferative and/or proapoptotic molecular events, including down-regulation of transcripts for members of the insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) and IL-6 receptor (IL-6R) signaling cascades, antiapoptotic molecules (e.g., caspase inhibitors), oncogenic kinases, DNA synthesis/repair enzymes, and transcription factors (e.g., XBP-1, E2F-1) implicated in MM pathophysiology. Importantly, SAHA treatment suppresses the activity of the proteasome and expression of its subunits, and enhances MM cell sensitivity to proteasome inhibition by bortezomib (PS-341). SAHA also enhances the anti-MM activity of other proapoptotic agents, including dexamethasone, cytotoxic chemotherapy, and thalidomide analogs. These findings highlight the pleiotropic antitumor effects of HDAC inhibition, and provide the framework for future clinical applications of SAHA to improve patient outcome in MM.