Economic evaluation of first-line cryoballoon ablation versus antiarrhythmic drug therapy for the treatment of paroxysmal atrial fibrillation from an English National Health Service perspective.

INTRODUCTION: Three recent randomised controlled trials have demonstrated that pulmonary vein isolation as an initial rhythm control strategy with cryoablation reduces atrial arrhythmia recurrence in patients with symptomatic paroxysmal atrial fibrillation (PAF) compared with antiarrhythmic drug (AAD) therapy. The aim of this study was to evaluate the cost-effectiveness of first-line cryoablation compared with first-line AADs for treating symptomatic PAF in an English National Health Service (NHS) setting. METHODS: Individual patient-level data from 703 participants with PAF enrolled into Cryo-FIRST (Catheter Cryoablation Versus Antiarrhythmic Drug as First-Line Therapy of Paroxysmal Atrial Fibrillation), STOP AF First (Cryoballoon Catheter Ablation in an Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation) and EARLY-AF (Early Aggressive Invasive Intervention for Atrial Fibrillation) were used to derive the parameters applied in the cost-effectiveness model (CEM). The CEM comprised a hybrid decision tree and Markov structure. The decision tree had a 1-year time horizon and was used to inform the initial health state allocation in the first cycle of the Markov model (40-year time horizon; 3-month cycle length). Health benefits were expressed in quality-adjusted life years (QALYs). Costs and benefits were discounted at 3.5% per year. Model outcomes were generated using probabilistic sensitivity analysis. RESULTS: The results estimated that cryoablation would yield more QALYs (+0.17) and higher costs (+£641) per patient over a lifetime than AADs. This produced an incremental cost-effectiveness ratio of £3783 per QALY gained. Independent of initial treatment, individuals were expected to receive ~1.2 ablations over a lifetime. There was a 45% relative reduction in time spent in AF health states for those initially treated with cryoablation. DISCUSSION: AF rhythm control with first-line cryoablation is cost effective compared with first-line AADs in an English NHS setting.

The Cost-Effectiveness of First-Line Cryoablation vs First-Line Antiarrhythmic Drugs in Canadian Patients With Paroxysmal Atrial Fibrillation.

BACKGROUND: The EARLY-AF (NCT02825979), STOP AF First (NCT03118518), and Cryo-FIRST (NCT01803438) randomised controlled trials (RCTs) demonstrated that cryoballoon pulmonary vein isolation reduces atrial fibrillation (AF) recurrence compared with antiarrhythmic drugs (AADs) in patients with symptomatic paroxysmal atrial fibrillation (PAF). The present study developed a cost-effectiveness model (CEM) of first-line cryoablation compared with first-line AADs for PAF, from the Canadian health care payer's perspective. METHODS: Data from the 3 RCTs were analysed to estimate key CEM parameters. The model structure used a decision tree for the first 12 months and a Markov model with a 3-month cycle length for the remaining lifetime time horizon. Costs were set at 2023 Canadian dollars, health benefits were expressed as quality-adjusted life years (QALYs), and both were discounted 3% annually. Probabilistic sensitivity analysis (PSA) considered parameter uncertainty. RESULTS: The statistical analysis estimated that first-line cryoablation generates a 47% reduction (P < 0.001) in the rate of AF recurrence, a 73% reduction in the rate of subsequent ablation (P < 0.001), and a 4.3% (P = 0.025) increase in health-related quality of life, compared with first-line AADs. The PSA indicates that an individual treated with first-line cryoablation accrues less costs (-$3,862) and more QALYs (0.19) compared with first-line AADs. Cryoablation is cost-saving in 98.4% of PSA iterations and has a 99.9% probability of being cost-effective at a cost-effectiveness threshold of $50,000 per QALY gained. Cost-effectiveness results were robust to changes in key model parameters. CONCLUSIONS: First-line cryoballoon ablation is cost-effective when compared with AADs for patients with symptomatic PAF.

An economic evaluation of first-line cryoballoon ablation vs antiarrhythmic drug therapy for the treatment of paroxysmal atrial fibrillation from a U.S. Medicare perspective.

Background: Three recent randomized controlled trials have demonstrated that, as an initial rhythm control strategy, first-line cryoballoon ablation (cryoablation) reduces atrial arrhythmia recurrence compared with antiarrhythmic drugs (AADs) in patients with symptomatic paroxysmal atrial fibrillation (PAF). Objective: The study sought to evaluate the cost-effectiveness of first-line cryoablation compared with first-line AADs for treating symptomatic PAF from a U.S. Medicare payer perspective. Methods: Individual patient-level data from 703 participants with PAF enrolled into the Cryo-FIRST (NCT01803438), STOP AF First (NCT03118518), and EARLY-AF (NCT02825979) trials were used to derive parameters for the cost-effectiveness model. The cost-effectiveness model used a hybrid decision tree and Markov structure. The decision tree had a 1-year time horizon and was used to inform the initial health state allocation in the first cycle of the Markov model. The Markov model used a 40-year time horizon (3-month cycle length). Health benefits were expressed in quality-adjusted life years (QALYs). Costs and benefits were discounted at 3% per year. Results: Cryoablation was estimated to yield higher QALYs (+0.17) and higher costs (+$4274) per patient over a 40-year time horizon than AADs. Ultimately, this produced an average incremental cost-effectiveness ratio of $24,637 per QALY gained. Independent of initial treatment, individuals were expected to receive ∼1.2 ablations over a lifetime. There was a 45% relative reduction in time spent in atrial fibrillation health states for those initially treated with cryoablation compared with AADs. Conclusion: Initial rhythm control with first-line cryoballoon ablation is highly cost-effective compared with first-line AADs from a U.S. Medicare payer perspective.

Quality of life after the initial treatment of atrial fibrillation with cryoablation versus drug therapy.

BACKGROUND: The STOP AF First trial recently demonstrated that initial treatment with cryoballoon ablation (CBA) is safe and superior to antiarrhythmic drug (AAD) therapy for preventing atrial arrhythmia recurrence in patients with symptomatic atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the change in quality of life (QoL) and symptoms after first-line CBA vs AAD therapy. METHODS: Patients with symptomatic AF not previously receiving rhythm control therapy were randomized to AAD (class I or III) or CBA (Arctic Front Advance, Medtronic, Mounds View, MN). QoL was evaluated at baseline and at 6 and 12 months by using the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and the European Quality of Life-5 Dimensions questionnaires. A review of AF-associated symptoms was conducted at baseline and at 1, 3, 6, and 12 months. RESULTS: In total, 203 subjects received either CBA (n = 104 [51.2%]) or AAD therapy (n = 99 [48.8%]). Improvements in the AFEQT summary and subscale scores were significantly larger with CBA than with AAD therapy at 6 and 12 months (P < .02 for all). Clinically meaningful improvement (>5 points) in the AFEQT summary score from baseline to 12 months was observed in 96.0% (100) of patients in the CBA arm vs 72.2% (71) of patients in the AAD arm (P < .001). No significant between-group differences were observed in the change in the European Quality of Life-5 Dimensions index or visual analog scale scores. Overall, 54.4% (57) of the CBA group vs 29.7% (29) of the AAD group reported no AF-specific symptom recurrence after a 90-day blanking period (P = .0005). CONCLUSION: First-line CBA vs AAD therapy is associated with larger improvements in AF-specific QoL and a higher rate of symptom resolution.

Initial rhythm control with cryoballoon ablation vs drug therapy: Impact on quality of life and symptoms.

BACKGROUND: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized. METHODS: Patients aged 18 to 75 with symptomatic paroxysmal AF naïve to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary. RESULTS: Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs AAD (all P <0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5 -14.2, P <0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P <0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs 15.2 days/year post-blanking; IRR: 0.30, P <0.001). CONCLUSIONS: In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01803438.

Cost-effectiveness of an insertable cardiac monitor to detect atrial fibrillation in patients with cryptogenic stroke.

Background: We assessed cost-effectiveness of insertable cardiac monitors (ICMs) in a US cryptogenic stroke population. Materials & methods: We modelled lifetime costs and quality-adjusted life years for three monitoring strategies post cryptogenic stroke: ICM starting immediately, ICM starting after Holter monitoring (delayed ICM) and standard of care involving intermittent ECG and Holter monitoring. Patient characteristics and detection efficacy were based on the CRYSTAL-AF trial. AF detection altered the modelled anticoagulation therapy and subsequent stroke and bleed risks. Results & conclusion: Immediate ICM was found to be cost-effective versus standard of care and cost-saving versus delayed ICM. Results were robust to sensitivity analyses. ICMs are a cost-effective diagnostic tool for the prevention of recurrent stroke in a US cryptogenic stroke population.

Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation.

BACKGROUND: In patients with symptomatic paroxysmal atrial fibrillation that has not responded to medication, catheter ablation is more effective than antiarrhythmic drug therapy for maintaining sinus rhythm. However, the safety and efficacy of cryoballoon ablation as initial first-line therapy have not been established. METHODS: We performed a multicenter trial in which patients 18 to 80 years of age who had paroxysmal atrial fibrillation for which they had not previously received rhythm-control therapy were randomly assigned (1:1) to receive treatment with antiarrhythmic drugs (class I or III agents) or pulmonary vein isolation with a cryoballoon. Arrhythmia monitoring included 12-lead electrocardiography conducted at baseline and at 1, 3, 6, and 12 months; patient-activated telephone monitoring conducted weekly and when symptoms were present during months 3 through 12; and 24-hour ambulatory monitoring conducted at 6 and 12 months. The primary efficacy end point was treatment success (defined as freedom from initial failure of the procedure or atrial arrhythmia recurrence after a 90-day blanking period to allow recovery from the procedure or drug dose adjustment, evaluated in a Kaplan-Meier analysis). The primary safety end point was assessed in the ablation group only and was a composite of several procedure-related and cryoballoon system-related serious adverse events. RESULTS: Of the 203 participants who underwent randomization and received treatment, 104 underwent ablation, and 99 initially received drug therapy. In the ablation group, initial success of the procedure was achieved in 97% of patients. The Kaplan-Meier estimate of the percentage of patients with treatment success at 12 months was 74.6% (95% confidence interval [CI], 65.0 to 82.0) in the ablation group and 45.0% (95% CI, 34.6 to 54.7) in the drug-therapy group (P<0.001 by log-rank test). Two primary safety end-point events occurred in the ablation group (Kaplan-Meier estimate of the percentage of patients with an event within 12 months, 1.9%; 95% CI, 0.5 to 7.5). CONCLUSIONS: Cryoballoon ablation as initial therapy was superior to drug therapy for the prevention of atrial arrhythmia recurrence in patients with paroxysmal atrial fibrillation. Serious procedure-related adverse events were uncommon. (Supported by Medtronic; STOP AF First ClinicalTrials.gov number, NCT03118518.).

Rhythm monitoring strategies in patients at high risk for atrial fibrillation and stroke: A comparative analysis from the REVEAL AF study.

BACKGROUND: Reducing atrial fibrillation (AF)-related stroke requires timely AF diagnosis, but the optimal monitoring strategy is unknown. OBJECTIVE: We used insertable cardiac monitor (ICM) data from the REVEAL AF study to compare AF detection rates by various short-term continuous monitoring (STM) strategies. METHODS AND RESULTS: Patients without known AF, but with CHADS2 scores ≥3 (or = 2 with ≥1 additional AF risk factor) received an ICM for AF detection. One-time STM strategies were assessed by computing AF incidence at 1, 2, 7, 14, and 30 days post-ICM insertion. Repeated STM strategies (quarterly 24-hour, 48-hour, 7-day, or monthly 24-hour monitoring) were modeled by randomly selecting day(s) within a 30-day window around each nominal evaluation date over a 1-year period (simulated 10,000 times). Endpoints included AF ≥6 minutes, AF ≥1 hour, and daily AF burden ≥1 and ≥ 5.5 hours. The impact of compliance on AF detection was evaluated using daily compliance rates of 85%, 75%, 65% and 55% during follow-up months 1-3, 4-6, 7-9, and 9-12, respectively. Based on data from 385 patients (71.5 ±â€¯9.9 years; CHADS2 score 3.0 ±â€¯1.0) the incidence of AF ≥6 minutes via ICM at 12 months was 27.1% (95% CI, 22.5-31.5%). This exceeded the range of estimated rates from all modeled one-time and repeated STM strategies (0.8% for 24-hour Holter monitoring to 10.6% for quarterly 7-day monitoring). Findings were similar for all AF endpoints. Modeled non-compliance reduced AF detection by 4.5% to 22.9%. CONCLUSIONS: Most AF episodes detected via ICMs would go undetected via conventional STM strategies, thus preventing optimal prophylaxis for adverse consequences.

Changes in Management Following Detection of Previously Unknown Atrial Fibrillation by an Insertable Cardiac Monitor (from the REVEAL AF Study).

The REVEAL AF study demonstrated a high incidence of previously undetected atrial fibrillation (AF) using insertable cardiac monitors (ICMs) in patients with risk factors for AF and stroke. This analysis evaluated whether ICM monitoring led to changes in clinical management after AF detection. Patients with CHADS2 scores ≥3 (or =2 with ≥1 additional AF risk factor) but no history of AF received an ICM and were followed 18 to 30 months. Physicians recorded changes in clinical management in response to AF detection at scheduled (every 6 months) and unscheduled follow-up visits. Changes in clinical management included oral anticoagulation, rhythm or rate control pharmacotherapy, cardioversion, ablation, and cardiac subspecialist referral. In 387 patients who met inclusion criteria and received an ICM, AF was found in 115. A change in clinical management was taken in 87 patients with AF (76%). In 80 of these 87, a change was taken at the first visit after AF detection. In total, 31 patients (27%) with AF had ≥2 visits at which changes in clinical management were taken. The most common change was initiation of oral anticoagulation (n = 73, 63% of patients with AF). Patients with a change in clinical management at the first visit after AF detection tended to have longer AF episodes and a higher maximal daily AF burden compared with AF patients for whom no change was taken (longest episode: 52 vs 28 minutes; maximal daily AF burden:112 vs 23 minutes). Changes in management more frequently occurred at visits where patients reported AF-compatible symptoms (65% vs 46% of visits, p = 0.01). In conclusion, ICM monitoring to identify AF guides both immediate and long-term patient management in a population at high risk for stroke.

Baseline Demographics, Safety, and Patient Acceptance of an Insertable Cardiac Monitor for Atrial Fibrillation Screening: The REVEAL-AF Study.

Given the high prevalence and risk of stroke associated with atrial fibrillation (AF), detection strategies have important public health implications. The ongoing prospective, single-arm, open-label, multicenter REVEAL AF trial is evaluating the incidence of previously undetected AF using an insertable cardiac monitor (ICM) in patients without prior AF or device implantation, but who could be at risk for AF due to their demographic characteristics, +/- non-specific but compatible symptoms. Enrollment required an elevated AF risk profile defined as CHADS2≥3 or CHADS2=2 plus one or more of the following: coronary artery disease, renal impairment, sleep apnea or chronic obstructive pulmonary disease. Exclusions included stroke or transient ischemic attack occurring in the previous year. Of 450 subjects screened, 399 underwent a device insertion attempt, and 395 were included in the final analysis (Reveal XT: n=122; Reveal LINQ: n=273; excluded: n=4). Participants were primarily identified by demographic characteristics and the presence of nonspecific symptoms, but without prior documentation of "overt" AF. The most common symptoms were palpitations (51%), dizziness/lightheadedness/pre-syncope (36%), and shortness of breath (36%). Over 100 subjects were enrolled in each pre-defined CHADS2 subgroup (2, 3 and ≥4). AF risk factors not included in the CHADS2 score were well represented (prevalence≥15%). Procedure and/or device related serious adverse events were low, with the miniaturized Reveal LINQ ICM having a more favorable safety profile than the predicate Reveal XT (all: n=13 [3.3%]; LINQ: n=6 [2.2%]; XT: n=7 [5.7%]). These data demonstrate that REVEAL AF was successful in enrolling its target population, high risk patients were willing to undergo ICM monitoring for AF screening, and ICM use in this group is becoming increasingly safe with advancements in technology. A clinically meaningful incidence of device detected AF in this study will inform clinical decisions regarding ICM use for AF screening in patients at risk.

Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

Cellular senescence is emerging as a key mechanism of age-related vascular endothelial dysfunction, but evidence in healthy humans is lacking. Moreover, the influence of lifestyle factors such as habitual exercise on endothelial cell (EC) senescence is unknown. We tested the hypothesis that EC senescence increases with sedentary, but not physically active, aging and is associated with vascular endothelial dysfunction. Protein expression (quantitative immunofluorescence) of p53, a transcription factor related to increased cellular senescence, and the cyclin-dependent kinase inhibitors p21 and p16 were 116%, 119%, and 128% greater (all P < 0.05), respectively, in ECs obtained from antecubital veins of older sedentary (60 ± 1 yr, n = 12) versus young sedentary (22 ± 1 yr, n = 9) adults. These age-related differences were not present (all P > 0.05) in venous ECs from older exercising adults (57 ± 1 yr, n = 13). Furthermore, venous EC protein levels of p53 (r = -0.49, P = 0.003), p21 (r = -0.38, P = 0.03), and p16 (r = -0.58, P = 0.002) were inversely associated with vascular endothelial function (brachial artery flow-mediated dilation). Similarly, protein expression of p53 and p21 was 26% and 23% higher (both P < 0.05), respectively, in ECs sampled from brachial arteries of healthy older sedentary (63 ± 1 yr, n = 18) versus young sedentary (25 ± 1 yr, n = 9) adults; age-related changes in arterial EC p53 and p21 expression were not observed (P > 0.05) in older habitually exercising adults (59 ± 1 yr, n = 14). These data indicate that EC senescence is associated with sedentary aging and is linked to endothelial dysfunction. Moreover, these data suggest that prevention of EC senescence may be one mechanism by which aerobic exercise protects against endothelial dysfunction with age.NEW & NOTEWORTHY Our study provides novel evidence in humans of increased endothelial cell senescence with sedentary aging, which is associated with impaired vascular endothelial function. Furthermore, our data suggest an absence of age-related increases in endothelial cell senescence in older exercising adults, which is linked with preserved vascular endothelial function.

In-office insertion of a miniaturized insertable cardiac monitor: Results from the Reveal LINQ In-Office 2 randomized study.

BACKGROUND: Recent miniaturization of an insertable cardiac monitor (ICM) may make it possible to move device insertion from a hospital to office setting. However, the safety of this strategy is unknown. OBJECTIVES: The primary objective was to compare the safety of inserting the Reveal LINQ ICM in an office vs a hospital environment. Ancillary objectives included summarizing device- and procedure-related adverse events and responses to a physician questionnaire. METHODS: Five hundred twenty-one patients indicated for an ICM were randomized (1:1 ratio) to undergo ICM insertion in a hospital or office environment at 26 centers in the United States in the Reveal LINQ In-Office 2 study (ClinicalTrials.gov identifier NCT02395536). Patients were followed for 90 days. RESULTS: ICM insertion was successful in all 482 attempted patients (office: 251; hospital: 231). The untoward event rate (composite of unsuccessful insertion and ICM- or insertion-related complications) was 0.8% (2 of 244) in the office and 0.9% (2 of 227) in the hospital (95% confidence interval, -3.0% to 2.9%; 5% noninferiority: P < .001). In addition, adverse events occurred during 2.5% (6 of 244) of office and 4.4% (10 of 227) of hospital insertions (95% confidence interval [office minus inhospital rates], -5.8% to 1.9%; 5% noninferiority: P < .001). Physicians indicated that for procedures performed in an office vs a hospital, there were fewer delays >15 minutes (16% vs 35%; P < .001) and patient response was more often "very positive." Physicians considered the office location "very convenient" more frequently than the hospital location (85% vs 27%; P < .001). CONCLUSION: The safety profile for the insertion of the Reveal LINQ ICM is excellent irrespective of insertion environment. These results may expand site of service options for LINQ insertion.

Oral trehalose supplementation improves resistance artery endothelial function in healthy middle-aged and older adults.

We hypothesized that supplementation with trehalose, a disaccharide that reverses arterial aging in mice, would improve vascular function in middle-aged and older (MA/O) men and women. Thirty-two healthy adults aged 50-77 years consumed 100 g/day of trehalose (n=15) or maltose (n=17, isocaloric control) for 12 weeks (randomized, double-blind). In subjects with Δbody mass less than 2.3kg (5 lb.), resistance artery endothelial function, assessed by forearm blood flow to brachial artery infusion of acetylcholine (FBFACh), increased ~30% with trehalose (13.3±1.0 vs. 10.5±1.1 AUC, P=0.02), but not maltose (P=0.40). This improvement in FBFACh was abolished when endothelial nitric oxide (NO) production was inhibited. Endothelium-independent dilation, assessed by FBF to sodium nitroprusside (FBFSNP), also increased ~30% with trehalose (155±13 vs. 116±12 AUC, P=0.03) but not maltose (P=0.92). Changes in FBFACh and FBFSNP with trehalose were not significant when subjects with Δbody mass ≥ 2.3kg were included. Trehalose supplementation had no effect on conduit artery endothelial function, large elastic artery stiffness or circulating markers of oxidative stress or inflammation (all P>0.1) independent of changes in body weight. Our findings demonstrate that oral trehalose improves resistance artery (microvascular) function, a major risk factor for cardiovascular diseases, in MA/O adults, possibly through increasing NO bioavailability and smooth muscle sensitivity to NO.

Reduced large elastic artery stiffness with regular aerobic exercise in middle-aged and older adults: potential role of suppressed nuclear factor κ B signalling.

OBJECTIVE: Aortic pulse-wave velocity (aPWV) increases with age and is a strong independent predictor of incident cardiovascular diseases (CVDs) in healthy middle-aged and older adults. aPWV is lower in middle-aged and older adults who perform regular aerobic exercise than in their sedentary peers. As exercise is associated with reduced systemic inflammation, we hypothesized that suppression of the pro-inflammatory transcription factor nuclear factor κ B (NFκB) may mediate this process. METHODS: aPWV was measured in young sedentary [n = 10, blood pressure (BP) 108 ±â€Š3/59 ±â€Š2 mmHg; mean ± SEM], middle-aged and older sedentary (n = 9, 124 ±â€Š7/73 ±â€Š5 mmHg) and middle-aged and older aerobic exercise-trained (n = 12, 110 ±â€Š4/67 ±â€Š2 mmHg) healthy, nonhypertensive men and women. RESULTS: Baseline aPWV increased with age [626 ±â€Š14 (young sedentary) vs. 859 ±â€Š49 (middle-aged and older sedentary) cm/s, P < 0.001] but was 20% lower in middle-aged and older trained (686 ±â€Š30 cm/s) than in middle-aged and older sedentary (P < 0.005). Short-term (4 days  x  2500-4500 mg) treatment with the NFκB inhibitor salsalate (randomized, placebo-controlled cross-over design) reduced aPWV (to 783 ±â€Š44 cm/s, P < 0.05) without changing BP (P = 0.40) or heart rate (P = 0.90) in middle-aged and older sedentary, but had no effect in young sedentary (623 ±â€Š19) or middle-aged and older trained (699 ±â€Š30). Following salsalate treatment, aPWV no longer was significantly different in middle-aged and older sedentary vs. middle-aged and older trained (P = 0.29). The reduction in aPWV with salsalate administration was inversely related to baseline (placebo) aPWV (r = -0.60, P < 0.001). CONCLUSION: These results support the hypothesis that suppressed NFκB signalling may partially mediate the lower aortic stiffness in middle-aged and older adults who regularly perform aerobic exercise. Because aPWV predicts incident cardiovascular events in this population, this suggests that tonic suppression of NFκB signalling in middle-aged and older exercising adults may potentially lower cardiovascular risk.

You're only as old as your arteries: translational strategies for preserving vascular endothelial function with aging.

Endothelial dysfunction develops with age and increases the risk of age-associated vascular disorders. Nitric oxide insufficiency, oxidative stress, and chronic low-grade inflammation, induced by upregulation of adverse cellular signaling processes and imbalances in stress resistance pathways, mediate endothelial dysfunction with aging. Healthy lifestyle behaviors preserve endothelial function with aging by inhibiting these mechanisms, and novel nutraceutical compounds that favorably modulate these pathways hold promise as a complementary approach for preserving endothelial health.

Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor κB.

Habitual aerobic exercise prevents age-related impairments in endothelium-dependent dilation (EDD). We have hypothesized that the pro-inflammatory transcription factor nuclear factor κB (NF-κB) impairs EDD with sedentary aging, and habitual aerobic exercise prevents this age-related suppression of EDD by NF-κB. To test this hypothesis, we have inhibited NF-κB signalling via oral salsalate administration in healthy older aerobic exercise-trained adults (OT, n=14, 58 ± 2 years), older non-exercising adults (ON, n=16, 61 ± 1 years) and young non-exercising controls (YN, n=8, 23 ± 1 years). Salsalate reduced endothelial cell expression of NF-κB p65 by ~25% in ON (P<0.05) but did not significantly change expression in OT or YN (P>0.05). EDD, assessed by brachial artery flow-mediated dilation (FMD), was improved by salsalate in ON (4.0 ± 0.7% compared with 6.8 ± 0.7%, placebo compared with salsalate, P<0.001) but did not change with salsalate in OT or YN (OT: 7.2 ± 0.7% compared with 7.7 ± 0.6%; YN: 7.6 ± 0.9% compared with 8.1 ± 0.8%; placebo compared with salsalate, P>0.05). Endothelium-independent dilation was not affected by salsalate in any group (P>0.05). In ON, vitamin C infusion improved FMD by ~30% during placebo (P<0.001) but had no affect during salsalate (P>0.05). In OT and YN, vitamin C infusion did not affect FMD during either placebo or salsalate (P>0.05). Salsalate reduced endothelial cell nitrotyrosine content by ~25% and NADPH oxidase p47phox expression by ~30% in ON (P<0.05) but had no effect in OT or YN (P>0.05). Our results suggest that endothelial NF-κB signalling is associated with oxidative stress-related impairment of EDD in healthy non-exercising but not aerobically exercising older adults. This may be a key mechanism by which regular aerobic exercise preserves endothelial function and reduces cardiovascular risk with aging.

Vascular endothelial function and oxidative stress are related to dietary niacin intake among healthy middle-aged and older adults.

We tested the hypothesis that vascular endothelial function and oxidative stress are related to dietary niacin intake among healthy middle-aged and older adults. In 127 men and women aged 48-77 yr, brachial artery flow-mediated dilation (FMD) was positively related to dietary niacin intake [%change (Δ): r = 0.20, P < 0.05; mmΔ: r = 0.25, P < 0.01]. In subjects with above-average dietary niacin intake (≥ 22 mg/day, NHANES III), FMD was 25% greater than in subjects with below-average intake (P < 0.05). Stepwise linear regression revealed that dietary niacin intake (above vs. below average) was an independent predictor of FMD (%Δ: ß = 1.8; mmΔ: ß = 0.05, both P < 0.05). Plasma oxidized low-density lipoprotein, a marker of systemic oxidative stress, was inversely related to niacin intake (r = -0.23, P < 0.05) and was lower in subjects with above- vs. below-average niacin intake (48 ± 2 vs. 57 ± 2 mg/dl, P < 0.01). Intravenous infusion of the antioxidant vitamin C improved brachial FMD in subjects with below-average niacin intake (P < 0.001, n = 33), but not above-average (P > 0.05, n = 20). In endothelial cells sampled from the brachial artery of a subgroup, dietary niacin intake was inversely related to nitrotyrosine, a marker of peroxynitrite-mediated oxidative damage (r = -0.30, P < 0.05, n = 55), and expression of the prooxidant enzyme, NADPH oxidase (r = -0.44, P < 0.01, n = 37), and these markers were lower in subjects with above- vs. below-average niacin intake [nitrotyrosine: 0.39 ± 0.05 vs. 0.56 ± 0.07; NADPH oxidase: 0.38 ± 0.05 vs. 0.53 ± 0.05 (ratio to human umbilical vein endothelial cell control), both P < 0.05]. Our findings support the hypothesis that higher dietary niacin intake is associated with greater vascular endothelial function related to lower systemic and vascular oxidative stress among healthy middle-aged and older adults.

Activation of the unfolded protein response in vascular endothelial cells of nondiabetic obese adults.

CONTEXT: Activation of the unfolded protein response (UPR) is emerging as an important molecular signature of cardiometabolic diseases associated with obesity. However, despite the well-established role of the vascular endothelium in obesity-related cardiometabolic dysfunction, it is unclear whether the UPR is activated in endothelial cells of obese adults. OBJECTIVE: The objective of the study was to determine whether markers of UPR activation are increased in endothelial cells (ECs) of nondiabetic obese adults with impaired endothelial function. DESIGN, SETTING, AND PARTICIPANTS: Endothelial cells were obtained from antecubital veins of the nondiabetic obese adults [body mass index (BMI) ≥ 30 kg/m(2), n = 12] with impaired endothelial function and from their nonobese peers (BMI < 30 kg/m(2), n = 14). MAIN OUTCOME VARIABLES: UPR activation via expression (quantitative immunofluorescence) of the proximal UPR sensors, inositol-requiring endoplasmic reticulum (ER)-to-nucleus signaling protein 1 (IRE1), RNA-dependent protein kinase-like ER eukaryotic initiation factor-2α kinase (PERK), and activating transcription factor 6 (ATF6), were the main outcome variables. RESULTS: IRE1 expression was greater in obese vs nonobese individuals (0.84 ± 0.09 vs 0.47 ± 0.02 IRE1 intensity/human umbilical vein EC (HUVEC) intensity (n = 10/8, P < .01). Obese individuals also had greater EC activation of UPR stress sensors PERK and ATF6, indicated by increased expression of phosphorylated PERK [p-PERK; 0.49 ± 0.05 vs 0.36 ± 0.03, p-PERK (threonine 981) intensity/HUVEC intensity, n = 10 men, 13 women, P < .05] and nuclear localization of ATF6 (0.38 ± 0.05 vs 0.23 ± 0.02, nuclear ATF6 intensity/HUVEC intensity, n = 5 men, 9 women, P < .01), respectively. Stepwise linear regression analysis revealed that indices of body fat (BMI and waist circumference) were the strongest independent predictors of all 3 UPR mediators, explaining between 18% and 59% of the variance in endothelial cell expression of IRE1, p-PERK, and nuclear ATF6 localization. CONCLUSION: These results provide novel evidence for UPR activation in the endothelial cells of nondiabetic obese adults with vascular endothelial dysfunction.