Effects of 1-year tofacitinib therapy on angiogenic biomarkers in rheumatoid arthritis.

OBJECTIVES: Cardiovascular (CV) morbidity and mortality, and perpetuated synovial angiogenesis have been associated with RA. In our study we evaluated angiogenic factors in relation to vascular inflammation and function, and clinical markers in RA patients undergoing 1-year tofacitinib therapy. METHODS: Thirty RA patients treated with either 5 mg or 10 mg twice daily tofacitinib were included in a 12-month follow-up study. Eventually, 26 patients completed the study and were included in data analysis. Levels of various angiogenic cytokines (TNF-α, IL-6), growth factors [VEGF, basic fibroblast (bFGF), epidermal (EGF), placental (PlGF)], cathepsin K (CathK), CXC chemokine ligand 8 (CXCL8), galectin-3 (Gal-3) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) were determined at baseline, and at 6 and 12 months after initiating tofacitinib treatment. In order to assess flow-mediated vasodilation, common carotid intima-media thickness (ccIMT) and carotid-femoral pulse-wave velocity, ultrasonography was performed. Synovial and aortic inflammation was also assessed by 18F-fluorodeoxyglucose-PET/CT. RESULTS: One-year tofacitinib therapy significantly decreased IL-6, VEGF, bFGF, EGF, PlGF and CathK, while it increased Gal-3 production (P < 0.05). bFGF, PlGF and NT-proBNP levels were higher, while platelet-endothelial cell adhesion molecule 1 (PECAM-1) levels were lower in RF-seropositive patients (P < 0.05). TNF-α, bFGF and PlGF correlated with post-treatment synovial inflammation, while aortic inflammation was rather dependent on IL-6 and PECAM-1 as determined by PET/CT (P < 0.05). In the correlation analyses, NT-proBNP, CXCL8 and Cath variables correlated with ccIMT (P < 0.05). CONCLUSIONS: Decreasing production of bFGF, PlGF or IL-6 by 1-year tofacitinib therapy potentially inhibits synovial and aortic inflammation. Although NT-proBNP, CXCL8 and CathK were associated with ccIMT, their role in RA-associated atherosclerosis needs to be further evaluated.

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach.

Introduction: Rheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA. Materials and methods: Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points. Results: Twenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other. Conclusion: One-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.

Effects of One-Year Tofacitinib Therapy on Lipids and Adipokines in Association with Vascular Pathophysiology in Rheumatoid Arthritis.

Background: Cardiovascular (CV) morbidity, mortality and metabolic syndrome are associated with rheumatoid arthritis (RA). A recent trial has suggested increased risk of major CV events (MACE) upon the Janus kinase (JAK) inhibitor tofacitinib compared with anti-tumor necrosis factor α (TNF-α) therapy. In our study, we evaluated lipids and other metabolic markers in relation to vascular function and clinical markers in RA patients undergoing one-year tofacitinib therapy. Patients and methods: Thirty RA patients treated with either 5 mg or 10 mg bid tofacitinib were included in a 12-month follow-up study. Various lipids, paraoxonase (PON1), myeloperoxidase (MPO), thrombospondin-1 (TSP-1) and adipokine levels, such as adiponectin, leptin, resistin, adipsin and chemerin were determined. In order to assess flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and arterial pulse-wave velocity (PWV) ultrasonography were performed. Assessments were carried out at baseline, and 6 and 12 months after initiating treatment. Results: One-year tofacitinib therapy significantly increased TC, HDL, LDL, APOA, APOB, leptin, adipsin and TSP-1, while significantly decreasing Lp(a), chemerin, PON1 and MPO levels. TG, lipid indices (TC/HDL and LDL/HDL), adiponectin and resistin showed no significant changes. Numerous associations were found between lipids, adipokines, clinical markers and IMT, FMD and PWV (p < 0.05). Regression analysis suggested, among others, association of BMI with CRP and PWV (p < 0.05). Adipokines variably correlated with age, BMI, CRP, CCP, FMD, IMT and PWV, while MPO, PON1 and TSP-1 variably correlated with age, disease duration, BMI, RF and PWV (p < 0.05). Conclusions: JAK inhibition by tofacitinib exerts balanced effects on lipids and other metabolic markers in RA. Various correlations may exist between metabolic, clinical parameters and vascular pathophysiology during tofacitinib treatment. Complex assessment of lipids, metabolic factors together with clinical parameters and vascular pathophysiology may be utilized in clinical practice to determine and monitor the CV status of patients in relation with clinical response to JAK inhibition.

A Rare Case of Stenosis at the Inferior Vena Cava to Right Atrium Anastomosis After Bicaval Orthotopic Heart Transplantation.

Stenosis at either the superior or inferior caval anastomosis is a rare complication of orthotopic heart transplantation (OHT) and is unique to the bicaval surgical technique. The severity of stenosis dictates the degree of clinical significance, varying from asymptomatic to congestive end-organ injury and hemodynamic instability from impaired preload. Due to differences in the anatomic location of organ congestion, the clinical presentation also depends on which of the 2 anastomoses is involved. In this article, the authors describe a case of stenosis at the inferior vena cava to right atrium anastomosis, which was diagnosed intraoperatively during OHT after weaning from cardiopulmonary bypass. Transesophageal echocardiography provided an accurate and timely diagnosis of this complication, which allowed for immediate surgical correction. Surprisingly, a large, native Eustachian valve was found to be obstructing the anastomosis. Resection of the valve relieved the previously significant narrowing across the anastomosis. This case highlights the importance of thorough intraoperative transesophageal echocardiographic evaluation of graft anastomoses during OHT, as well as an understanding on the part of the echocardiographer of the specific surgical techniques employed during OHT.

Ablation of Cyclophilin D Results in an Activation of FAK, Akt, and ERK Pathways in the Mouse Heart.

Cyclophilin D (CypD) is a mitochondrial chaperone that regulates the mitochondrial permeability transition pore. Metabolically, deletion of Ppif (the gene encoding CypD) in mice is associated with elevated levels of mitochondrial matrix Ca2+ that leads to increased glucose as relative to fatty acid oxidation. Here, we characterized the adaptive mechanisms involved in the regulation of glucose metabolism including the regulation of Akt and ERK kinases that we evaluated by Western blot analysis of Ppif-/- in comparison to wild type (WT) mouse hearts. CypD loss led to adaptive mechanisms in the heart resulting in an upregulation of focal adhesion kinase (phosphorylated at Tyr925) and increased phosphorylation of Akt at S473. The increased activity of this pathway (pAktS473 increased to 170% and 145% in Ppif-/- versus WT males and females, respectively) could be responsible for the observed metabolic switch towards glycolysis. Furthermore, the phosphorylation of ERK1/2 proteins was elevated following CypD ablation. In addition, we observed differences in protein expression and activity in male versus female hearts that were independent of CypD expression. This included an upregulation of pAktS473 (to 273% and 269% in Ppif-/- and WT females as compared to their corresponding males, respectively). Furthermore, decreased levels of endothelial nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine were accompanied by an upregulation of eNOS in female mice. The higher extent of kinases phosphorylation may be responsible for the reported lowered tolerance of CypD animals to stress. Moreover, the higher nitric oxide production could be responsible for the cardioprotective properties observed only in female hearts. J. Cell. Biochem. 118: 2933-2940, 2017. © 2017 Wiley Periodicals, Inc.

Risk factors associated with acute heart failure during liver transplant surgery: a case control study.

BACKGROUND: Acute intraoperative heart failure (HF) is a rare but often fatal complication of liver transplant surgery. Little is known about the clinical course or predictive variables. Our aims were to provide a detailed clinical description and conduct a systematic search for characteristics associated with intraoperative HF. METHODS: A matched case-control study of adults undergoing primary liver transplant from 2009 to 2011 was conducted. Cases showed new onset HF with an ejection fraction less than 50% during liver transplant surgery. Controls were recipients without signs or symptoms of HF. Matching was based on: age, sex, model for end-stage liver disease at the time of transplant, type 2 diabetes, and ß-blocker use. Conditional logistic regression analyses were conducted. RESULTS: From 2009 to 2011, seven (3%) of 256 recipients developed intraoperative HF with one resulting death. All survivors regained normal systolic function within 6 months of surgery. Decreasing preoperative serum sodium (odds ratio, 1.41; 95% confidence interval, 1.02-1.94; P = 0.039) and increasing number of units of packed red blood cells transfused intraoperatively (odds ratio=1.2, 95% confidence interval, 1.001-1.467, P = 0.048) were associated with HF. CONCLUSION: No preoperative echocardiographic parameter predicted HF in affected patients. Two possible explanations are: our patients suffered from stress cardiomyopathy and therefore had no evidence of impaired contraction before the event or echocardiographic predictors of HF were masked by circulatory changes in patients with cirrhosis. Lower serum sodium and more red blood cell transfusions were associated with intraoperative HF. Lower mortality of our intraoperative cases compared to others may be influenced by earlier diagnosis and intervention.

Use of Transesophageal Echocardiography to Improve the Safety of Transvenous Lead Extraction.

OBJECTIVES: The aim of this study was to evaluate the utility of transesophageal echocardiography (TEE) during transvenous lead extraction (TLE) involving both conventional and laser lead removal. BACKGROUND: TLE carries a small but measurable risk of serious adverse events. Few studies have examined the potential benefit of continuous monitoring with TEE during this procedure. METHODS: Continuous TEE monitoring was performed in 100 consecutive patients (67% male; average age, 57 ± 17 years) who underwent TLE in the past 5 years. Lead extraction was attempted for 193 leads. The average time since lead implant was 78 ± 55 months (range, 1.4 to 274.4 months). Indications for extraction were device endocarditis (n = 28), lead fracture (n = 28), recalled lead (n = 21), pocket infection (n = 17), and other (n = 6). RESULTS: Complete success occurred in 181 leads (94%), partial success in 4 leads (2%), and failure in 8 leads (4%). Eighty patients required laser lead extraction (80%). Major complications included 1 right ventricular and 2 right atrial/superior vena cava lacerations, which were detected and localized within 1 to 2 min with the use of TEE and resulted in prompt surgical repair. There was 1 upper gastrointestinal bleed caused by the TEE probe. TEE prevented premature termination and unnecessary surgery in 4 patients with hypotension but no intracardiac abnormalities seen on TEE. In-hospital mortality rate was 0%. In total, TEE provided immediately useful clinical information in 7 patients (7%). CONCLUSIONS: Continuous monitoring with TEE facilitates prompt diagnosis and treatment of intracardiac damage and prevents premature termination of cases with hypotension but no abnormalities on TEE.

A review of intraoperative goal-directed therapy using arterial waveform analysis for assessment of cardiac output.

Increasing evidence shows that goal-directed hemodynamic management can improve outcomes in surgical and intensive care settings. Arterial waveform analysis is one of the different techniques used for guiding goal-directed therapy. Multiple proprietary systems have developed algorithms for obtaining cardiac output from an arterial waveform, including the FloTrac, LiDCO, and PiCCO systems. These systems vary in terms of how they analyze the arterial pressure waveform as well as their requirements for invasive line placement and calibration. Although small-scale clinical trials using these monitors show promising data, large-scale multicenter trials are still needed to better determine how intraoperative goal-directed therapy with arterial waveform analysis can improve patient outcomes. This review provides a comparative analysis of the different arterial waveform monitors for intraoperative goal-directed therapy.

Early effect of tidal volume on lung injury biomarkers in surgical patients with healthy lungs.

BACKGROUND: The early biological impact of short-term mechanical ventilation on healthy lungs is unknown. The authors aimed to characterize the immediate tidal volume (VT)-related changes on lung injury biomarkers in patients with healthy lungs and low risk of pulmonary complications. METHODS: Twenty-eight healthy patients for knee replacement surgery were prospectively randomized to volume-controlled ventilation with VT 6 (VT6) or 10 (VT10) ml/kg predicted body weight. General anesthesia and other ventilatory parameters (positive end-expiratory pressure, 5 cm H2O, FIO2, 0.5, respiratory rate titrated for normocapnia) were managed similarly in the two groups. Exhaled breath condensate and blood samples were collected for nitrite, nitrate, tumor necrosis factor-α, interleukins-1ß, -6, -8, -10, -11, neutrophil elastase, and Clara Cell protein 16 measurements, at the onset of ventilation and 60 min later. RESULTS: No significant differences in biomarkers were detected between the VT groups at any time. The coefficient of variation of exhaled breath condensate nitrite and nitrate decreased in the VT6 but increased in the VT10 group after 60-min ventilation. Sixty-minute ventilation significantly increased plasma neutrophil elastase levels in the VT6 (35.2 ± 30.4 vs. 56.4 ± 51.7 ng/ml, P = 0.008) and Clara Cell protein 16 levels in the VT10 group (16.4 ± 8.8 vs. 18.7 ± 9.5 ng/ml, P = 0.015). Exhaled breath condensate nitrite correlated with plateau pressure (r = 0.27, P = 0.042) and plasma neutrophil elastase (r = 0.44, P = 0.001). Plasma Clara Cell protein 16 correlated with compliance (r = 0.34, P = 0.014). CONCLUSIONS: No tidal volume-related changes were observed in the selected lung injury biomarkers of patients with healthy lungs after 60-min ventilation. Plasma neutrophil elastase and plasma Clara Cell protein 16 might indicate atelectrauma and lung distention, respectively.

Association of DJ-1/PTEN/AKT- and ASK1/p38-mediated cell signalling with ischaemic cardiomyopathy.

AIMS: Dilated cardiomyopathies from chronic ischaemia (ISCM) or idiopathic (IDCM) pathological mechanisms are accompanied by similar clinical symptoms but may differ in protein expression, cell metabolism, and signalling processes at the cellular level. Using a combination of proteomic and metabolomic profiling, we sought to decipher the relationships between the metabolism and cellular signalling pathways in human heart tissues collected from patients with ISCM, IDCM, and those without heart disease and dilation. METHODS AND RESULTS: The comparative analysis suggested a decrease in glycolysis, Krebs cycle, and malate-aspartate shuttle activities in both types of cardiomyopathies and an increase in ketone body oxidation only in ISCM. Chronic ischaemic injury was associated with increased DJ-1 and decreased phosphatase and tensin homolog (PTEN) protein expression. The reduced PTEN expression was accompanied by increased phosphorylation of cell-protective AKT. Phosphorylation at T845 of apoptosis signal-regulating kinase 1 and p38 mitogen-activated protein kinase proteins, with no change in the phosphorylation of extracellular signal-regulated kinases, was also observed. The downregulation of peptidyl-prolyl cis/trans isomerase and NF-κB essential modulator potentially inhibits NF-κB-initiated processes. CONCLUSION: The present study characterized differences in the molecular mechanisms, metabolism, and pathological cell signalling associated with ISCM and IDCM, which may provide novel targets for intervention at the cellular level.

Constrictive pericarditis with a calcific mass invading into the right ventricular myocardium.

We present a rare and unique case of calcific constrictive pericarditis with a calcified pericardial mass invading the right ventricular myocardium. Perioperative two-dimensional and three-dimensional transesophageal echocardiography revealed the extent and structure of the pericardial mass and led to the repair of the right ventricular free wall as a surgical intervention.

Total ischemia time alters the longitudinal and circumferential shortening of the right ventricle in transplanted hearts.

OBJECTIVES: Ischemia time is a risk factor for mortality and right ventricular (RV) failure after heart transplantation. The purpose of this study was to determine the effect of ischemia time on known transesophageal echocardiography (TEE) parameters of RV function and on a novel quantitative measurement of RV circumferential shortening. METHODS: Right and left ventricular (LV) function was evaluated retrospectively in 20 consecutive patients after heart transplant using known TEE parameters as well as a quantitative measurement of circumferential contraction. The control group consisted of 20 patients undergoing coronary artery bypass grafting (CABG) with no documented RV dysfunction. RESULTS: Posttransplant TEE parameters of RV function were depressed compared with post-cardiopulmonary bypass CABG patients. Significant correlation was observed between tricuspid annular planar systolic excursion, basal, mid, and global circumferential shortening and total ischemia time. CONCLUSION: Total ischemia time of the transplanted heart may play a role in deterioration of longitudinal and circumferential shortening of the RV.

Detection of left ventricular apical thrombus with three-dimensional transesophageal echocardiography.

OBJECTIVE. Left ventricular (LV) thrombosis persists as a clinical challenge in echocardiographic diagnosis and is an important risk factor for perioperative embolic events in cardiac surgery. Appropriate detection and monitoring when thrombus is suspected is critical in surgical planning and in avoiding catastrophic patient outcomes. CASE PRESENTATION. The authors present a case of a laminated LV apical thrombus, which was discovered intraoperatively by real-time 3-dimensional (3D) transesophageal echocardiography. CLINICAL CHALLENGES. The clinical challenges were (a) LV thrombosis impact on surgical management, (b) key echocardiographic challenges in diagnosing LV thrombosis, and (c) role of 3D echocardiography in the diagnostic algorithm. CONCLUSION. Because of the lack of a gold standard, 2D transthoracic echocardiography remains the imaging modality of choice in assessment; however, there is increasing evidence that 3D technology can be more accurate in intracardiac mass detection and should be considered in the diagnostic algorithm.