Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation.

OBJECTIVES: Accelerated atherosclerotic disease typically complicates rheumatoid arthritis (RA), leading to premature cardiovascular death. Inflammatory macrophages are key effector cells in both rheumatoid synovitis and the plaques of coronary artery disease (CAD). Whether both diseases share macrophage-dependent pathogenic mechanisms is unknown. METHODS: Patients with RA or CAD (at least one myocardial infarction) and healthy age-matched controls were recruited into the study. Peripheral blood CD14+ monocytes were differentiated into macrophages. Metabolic profiles were assessed by Seahorse Analyzer, intracellular ATP concentrations were quantified and mitochondrial protein localisation was determined by confocal image analysis. RESULTS: In macrophages from patients with RA or CAD, mitochondria consumed more oxygen, generated more ATP and built tight interorganelle connections with the endoplasmic reticulum, forming mitochondria-associated membranes (MAM). Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch. In patient-derived macrophages, inactivated pGSK3b-Ser9 co-precipitated with the mitochondrial fraction. Immunostaining of atherosclerotic plaques and synovial lesions confirmed that most macrophages had inactivated GSK3b. MAM formation and GSK3b inactivation sustained production of the collagenase cathepsin K, a macrophage effector function closely correlated with clinical disease activity in RA and CAD. CONCLUSIONS: Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy.

Efficacy of optimal long-term management of multiple cardiovascular risk factors (CVD) on walking and quality of life in patients with peripheral artery disease (PAD): protocol for randomized controlled trial.

Peripheral artery disease (PAD) is an understudied chronic illness most prevalent in elderly individuals. PAD patients experience substantial walking impairment due to symptoms of limb ischemia that significantly diminishes quality of life (QOL). Cardiovascular disease (CVD) morbidity and mortality is increased in this population because of aggressive atherosclerosis resulting from untreated CVD risk factors. Despite current national guidelines recommending intensive CVD risk factor management for PAD patients, untreated CVD risk factors are common. Interventions that bridge this gap are imperative. The Vascular Insufficiency - Goals for Optimal Risk Reduction (VIGOR(2)) study is a randomized controlled trial (RCT) that examines the effectiveness of a long-term multifactor CVD risk reduction program on walking and quality of life in patients with PAD. The purpose of this article is to provide a detailed description of the design and methods of VIGOR(2). Clinical Trial Registration - URL: http://clinicaltrials.gov/ct2/show/NCT00537225.

Preoperative Computed Tomography Angiography Reveals Leaflet-Specific Calcification and Excursion Patterns in Aortic Stenosis.

BACKGROUND: Computed tomography-based evaluation of aortic stenosis (AS) by calcium scoring does not consider interleaflet differences in leaflet characteristics. Here, we sought to examine the functional implications of these differences. METHODS: We retrospectively reviewed the computed tomography angiograms of 200 male patients with degenerative calcific AS undergoing transcatheter aortic valve replacement and 20 male patients with normal aortic valves. We compared the computed tomography angiography (CTA)-derived aortic valve leaflet calcification load (AVLCCTA), appearance, and systolic leaflet excursion (LEsys) of individual leaflets. We performed computer simulations of normal valves to investigate how interleaflet differences in LEsys affect aortic valve area. We used linear regression to identify predictors of leaflet-specific calcification in patients with AS. RESULTS: In patients with AS, the noncoronary cusp (NCC) carried the greatest AVLCCTA (365.9 [237.3-595.4] Agatston unit), compared to the left coronary cusp (LCC, 278.5 [169.2-478.8] Agatston unit) and the right coronary cusp (RCC, 240.6 [137.3-439.0] Agatston unit; both P<0.001). However, LCC conferred the least LEsys (42.8° [38.8°-49.0°]) compared to NCC (44.8° [41.1°-49.78°], P=0.001) and RCC (47.7° [42.0°-52.3°], P<0.001) and was more often characterized as predominantly thickened (23.5%) compared to NCC (12.5%) and RCC (16.5%). Computer simulations of normal valves revealed greater reductions in aortic valve area following closures of NCC (-32.2 [-38.4 to -25.8]%) and RCC (-35.7 [-40.2 to -32.9]%) than LCC (-24.5 [-28.5 to -18.3]%; both P<0.001). By linear regression, the AVLCCTA of NCC and RCC, but not LCC, predicted LEsys (both P<0.001) in patients with AS. Both ostial occlusion and ostial height of the right coronary artery predicted AVLCCTA, RCC (P=0.005 and P=0.001). CONCLUSIONS: In male patients, the AVLCCTA of NCC and RCC contribute more to AS than that of LCC. LCC's propensity for noncalcific leaflet thickening and worse LEsys, however, should not be underestimated when using calcium scores to assess AS severity.

Outcomes of Veterans Undergoing TAVR Within Veterans Affairs Medical Centers: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

OBJECTIVES: This study sought to describe clinical and procedural characteristics of veterans undergoing transcatheter aortic valve replacement (TAVR) within U.S. Department of Veterans Affairs (VA) centers and to examine their association with short- and long-term mortality, length of stay (LOS), and rehospitalization within 30 days. BACKGROUND: Veterans with severe aortic stenosis frequently undergo TAVR at VA medical centers. METHODS: Consecutive veterans undergoing TAVR between 2012 and 2017 were included. Patient and procedural characteristics were obtained from the VA Clinical Assessment, Reporting, and Tracking system. The primary outcomes were 30-day and 1-year survival, LOS >6 days, and rehospitalization within 30 days. Logistic regression and Cox proportional hazards analyses were performed to evaluate the associations between pre-procedural characteristics and LOS and rehospitalization. RESULTS: Nine hundred fifty-nine veterans underwent TAVR at 8 VA centers during the study period, 860 (90%) by transfemoral access, 50 (5%) transapical, 36 (3.8%) transaxillary, and 3 (0.3%) transaortic. Men predominated (939 of 959 [98%]), with an average age of 78.1 years. There were 28 deaths within 30 days (2.9%) and 134 at 1 year (14.0%). Median LOS was 5 days, and 141 veterans were rehospitalized within 30 days (14.7%). Nonfemoral access (odds ratio: 1.74; 95% confidence interval [CI]: 1.10 to 2.74), heart failure (odds ratio: 2.51; 95% CI: 1.83 to 3.44), and atrial fibrillation (odds ratio: 1.40; 95% CI: 1.01 to 1.95) were associated with increased LOS. Atrial fibrillation was associated with 30-day rehospitalization (hazard ratio: 1.79; 95% CI: 1.22 to 2.63). CONCLUSIONS: Veterans undergoing TAVR at VA centers are predominantly elderly men with significant comorbidities. Clinical outcomes of mortality and rehospitalization at 30 days and 1-year mortality compare favorably with benchmark outcome data outside the VA.

Glucose metabolism controls disease-specific signatures of macrophage effector functions.

BACKGROUND: In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling. METHODS: To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA). RESULTS: Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1ß and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1ß and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokinehicytokinehiPD-L1hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function. CONCLUSIONS: We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment. FUNDING: Supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779 U19 AI057266, R01 AI129191), I01 BX001669, and the Cahill Discovery Fund.

Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity.

Patients with coronary artery disease (CAD) are at high risk for reactivation of the varicella zoster virus (VZV) and development of herpes zoster (HZ). Here, we found that macrophages from patients with CAD actively suppress T cell activation and expansion, leading to defective VZV-specific T cell immunity. Monocyte-derived and plaque-infiltrating macrophages from patients with CAD spontaneously expressed high surface density of the immunoinhibitory ligand programmed death ligand-1 (PD-L1), thereby providing negative signals to programmed death-1+ (PD-1+) T cells. We determined that aberrant PD-L1 expression in patient-derived macrophages was metabolically controlled. Oversupply of the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulatory factor 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, CAD macrophages respond to nutrient excess by activating the immunoinhibitory PD-1/PD-L1 checkpoint, leading to impaired T cell immunity. This finding indicates that metabolite-based immunotherapy may be a potential strategy for restoring adaptive immunity in CAD.

The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease.

Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1ß, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1ß production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.

Abnormal cardiovascular response to exercise in patients with peripheral arterial disease: Implications for management.

Exercise is beneficial in improving claudication and functional capacity in patients with peripheral arterial disease (PAD). However, the physiologic response during and after exercise testing in this patient population has not been fully described. This study examined the cardiovascular response to exercise and explored the potential contribution of vascular noncompliance to exercise-induced hypertension in 124 patients with PAD and claudication and 31 comparison (C) patients with PAD with no walking limitations. Maximal walking distance was determined by an exercise treadmill test. Heart rate and blood pressure were monitored before, during, and immediately after an exercise test. Vascular compliance of the small and large vessels was measured using pulse waveform analysis. Individuals with low supine resting heart rate had longer pain-free walking distance (r = -0.195, P = .019) and maximal walking versus the C group (62 beats/min, standard deviation [SD] = 10, P = .02). Systolic blood pressure during supine rest was significantly lower for the PAD group (mean = 141 mm Hg, +/- SD = 22) versus the C group (mean = 153 mm Hg, +/- SD = 20, P = .003). Vascular compliance of large vessels was higher in the C group (mean = 4.13 +/- 4.13 mL/mm Hg x 100) compared with the PAD group (mean = 2.95 +/- 1.6 mL/mm Hg x 100). This study describes the exaggerated exercise cardiovascular response and impaired vascular compliance in patients with PAD. These results provide further evidence supporting the importance of a monitored treadmill exercise test before initiation of an exercise program to ensure safe and accurate exercise recommendations, and to identify individuals that require more intensive pharmacotherapy to prevent exercise-induced hypertension and tachycardia.

Predictors of physical function in patients with peripherial arterial disease and claudication.

Limitation of walking due to claudication is the hallmark of peripheral arterial disease. The purpose of this secondary analysis was to identify biobehavioral predictors of physical function in peripheral arterial disease patients that included walking ability, gender, age, disease severity, environmental factors (social support), and medical comorbidity (arthritis). All subjects performed an exercise treadmill test to determine initial and absolute claudication distance. The sample consisted of 97 peripheral arterial disease patients, 71 (73%) men and 26 (27%) women, with a mean age of 73+/-8 years (range 52-90 years). Initial claudication distance occurred at 171.88+/-136.35 m. Absolute claudication distance was 421.03+/-286.37 m. A simultaneous multiple regression analysis was performed to determine predictors of physical function. The model accounted for 35% of the variance (p<0.001) and included personal characteristics (age, gender, years of education), severity of disease by ankle-brachial index, environmental factors of social support (marital status), absolute claudication distance, and arthritis. Education (p=0.011), absolute claudication distance (p=0.014), social support (p=0.026), arthritis (p=0.028), and age (p=0.033) were the strongest predictors of physical function. This study identifies biobehavioral factors that place peripheral arterial disease patients at greater risk for reduced physical function and provides a rationale for interventions that improve walking ability.

Exercise patterns and cardiovascular fitness of patients with peripheral arterial disease.

Peripheral arterial disease (PAD) is characterized by walking impairment as the result of claudication, which is improved by exercise. Few studies have examined the impact of existing exercise patterns in community-dwelling patients with PAD on cardiovascular fitness and absolute claudication distance (ACD). This descriptive study examines exercise patterns, walking distance, and cardiovascular fitness in a sample of community-dwelling older adults with PAD. Approximately 50% of subjects reported walking 4 (+/-2) days per week for 38 +/- 24 minutes. ACD (exercisers = 459.9 +/- 272; non-exercisers = 351.2 +/- 266.3, P = .06) and initial claudication distance (exercisers = 198.5 +/- 139.7; non-exercisers = 138.7 +/- 95.8 P = .02) were similar between groups. The workload accomplished was approximately 4.1-4.7 metabolic equivalents. Resting heart rate (HR) was associated with initial claudication distance ( r = -.37, P = .001) and ACD ( r = -.46, P < .01) and was lower in the group of exercisers versus the non-exercisers ( P = .05). Mean resting SBP was elevated and continued to increase at peak exercise with no difference between groups ( P = .75). Quality of life was poor for both groups. Simultaneous multiple regression analysis was performed to determine predictors of peak exercise HR. The model included gender, age, current exercise, ankle-brachial index, coronary artery disease, beta blockers, ACD, and atrial fibrillation (R = 44%, P = .01). Higher peak exercise HR was associated with older age, female gender, no beta blockers, and greater ACD ( P < .01). The findings from this descriptive study demonstrate the need for larger long-term studies to address issues of exercise adherence and the psychologic and functional benefits of exercise.

Transcatheter CoreValve valve-in-valve implantation in a stentless porcine aortic valve for severe aortic regurgitation.

KEY CLINICAL MESSAGE: We describe the first valve-in-valve Corevalve transcatheter aortic valve replacement in the St. Jude Toronto stentless porcine aortic valve in the United States, which enabled this 59-year-old patient with a history of bacterial endocarditis and aortic regurgitation to avoid heart transplant with complete resolution of his severe left ventricular dysfunction.

Statin therapy in heart failure.

PURPOSE OF REVIEW: The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. Mounting experimental and clinical evidence also suggest a potential benefit as well as theoretical harm of statin therapy in patients with heart failure. RECENT FINDINGS: This article briefly summarizes the therapeutic properties of statins that may be of benefit to patients with heart failure and the theoretical adverse effects of cholesterol reduction in this group of patients. A number of nonrandomized clinical studies over the past several years have shown an association between statin use and reduced overall mortality. Several large-scale randomized studies designed to confirm these findings are currently under way. SUMMARY: Statin therapy appears to improve clinical outcomes in patients with both ischemic and nonischemic cardiomyopathy independently of their cholesterol-lowering properties. The theoretical adverse properties of statins in heart failure patients have not been substantiated in small to medium-sized clinical trials. Although the encouraging results of these preliminary studies suggest a role for statin therapy in heart failure, larger studies are needed to validate these findings. Several ongoing randomized trials are currently under way to evaluate the effect of statin therapy on cardiovascular outcomes in heart failure patients. The results of these studies, expected in the next several years, should provide scientific evidence for the role of statins in the treatment of failure.

Suboptimal intensity of risk factor modification in PAD.

This study extends earlier trials indicating that atherosclerosis risk factors are underdetected and undertreated in peripheral arterial disease (PAD) patients. Recognition and treatment of hyperlipidemia and hypertension in PAD patients is suboptimal. Diabetes appears to be detected more frequently although glycemic control is still suboptimal. The use of antiplatelet therapy is particularly underutilized. Additionally, despite the demonstrated efficacy of regular exercise in PAD patients, almost half of the study sample was sedentary. Approximately one third of the current study sample was overweight and nearly one third was obese by ATP-III guidelines. Only 31% of subjects were taking dietary measures to improve their cardiovascular health, and even fewer were physically active. To rectify suboptimal management of risk factors, there is a need for increased public awareness of PAD, reimbursement and implementation of screening programs and more aggressive treatment. Future studies are needed to examine innovative interventions for identification and management of cardiovascular risk factors in patients with PAD.

A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease.

Peripheral arterial disease (PAD) impairs walking capacity and is often associated with a profound endothelial vasodilator dysfunction, characterized by reduced bioactivity and/or synthesis of endothelium-derived nitric oxide (NO). Previous studies have suggested that dietary supplementation of L-arginine, the precursor of NO, improves endothelium-dependent vasodilation, limb blood flow and walking distance. However, these studies have been small, and have used large intravenous doses of L-arginine. The optimal dose of L-arginine has not been determined. Accordingly, this pilot study was conducted to establish the lowest effective oral dose of L-arginine to improve walking distance in preparation for the definitive study. Patients with PAD and intermittent claudication (n = 80) participated in this study. Eligibility criteria included: (1) ankle-brachial index (ABI) at rest < or = 0.90; (2) post-exercise reduction in ABI > or = 25%; and (3) difference in absolute claudication distance of < or = 25% between two consecutive treadmill tests. Treadmill testing was performed using the Skinner-Gardner protocol and community-based walking was assessed using the walking impairment questionnaire. Patients were randomly assigned to oral doses of 0, 3, 6 or 9 g of L-arginine daily in three divided doses for 12 weeks. Treadmill testing was performed prior to administration of the study drug and again after 12 weeks of treatment. The study drug was well tolerated, with no significant adverse effects of L-arginine therapy. The safety laboratory studies were unremarkable, except for a statistically significant reduction in hematocrit in the L-arginine-treated groups. There was no significant difference observed in absolute claudication distance between the groups. However, a trend was observed for a greater increase in walking distance in the group treated with 3 g L-arginine daily, and there was a trend for an improvement in walking speed in patients treated with L-arginine. This pilot study provided data for safety, for power calculation and for dosing for the larger definitive trial that is now underway.

Gender differences in perception of PAD: a pilot study.

Patients with peripheral arterial disease (PAD) report profound limitations in all domains of quality of life that are worse than those for patients with chronic pulmonary disease and moderate to severe heart failure. While claudication has detrimental effects on quality of life, little is understood about the factors that influence quality of life and whether these determinants are similar for men and women with PAD and claudication. The purpose of the present investigation was to evaluate the effect of claudication on quality of life in 71 men and 26 women (mean age 72 and 73 years respectively) with PAD. Disease severity as assessed by ankle brachial index (ABI) and community-based walking was similar for men and women, although men reported greater comorbid conditions than women. Despite the similarity in disease severity, women reported decreased physical functioning (p = 0.01), more bodily pain (p = 0.04) and greater mood disturbance (p = 0.012) than men. Claudication and PAD had a greater impact on women than on men and may result from the higher prevalence of mood disturbance and bodily pain reported by women.