Increased Dephospho-uncarboxylated Matrix Gla-Protein Is Associated With Lower Axial Skeletal Muscle Mass in Patients With Hypertension.

BACKGROUND: Matrix Gla-protein (MGP) is a well-established inhibitor of vascular calcification that is activated by vitamin K-dependent carboxylation. In the setting of vitamin K2 deficiency, dephospho-uncarboxylated MGP (dpucMGP) levels increase, and have been associated with large artery stiffening. Vitamin K2 is also a mitochondrial electron carrier in muscle, but the relationship of vitamin K2 deficiency and dpucMGP with muscle mass is not well understood. We therefore aimed to examine the association of vitamin K2 deficiency and dpucMGP with skeletal muscle mass in patients with hypertension. METHODS: We studied 155 hypertensive adults without heart failure. Axial skeletal muscle mass was measured using magnetic resonance imaging from axial steady-state free precession images. DpucMGP was measured with ELISA. Carotid-femoral pulse wave velocity (CF-PWV) was measured from high-fidelity arterial tonometry recordings. RESULTS: We found an inverse relationship between dpucMGP levels and axial muscle mass, with progressively rising dpucMGP levels correlating with decreasing axial muscle mass. In an unadjusted linear regression model, correlates of dpucMGP included axial skeletal muscle area factor (ß = -0.32; P < 0.0001) and CF-PWV (ß = 0.31; P = 0.0008). In adjusted analyses, independent correlates of dpucMGP included axial skeletal muscle area factor (ß = -0.30; P = 0.0003) and CF-PWV (ß = 0.20; P = 0.019). CONCLUSIONS: In hypertensive adults, dpucMGP is independently associated with lower axial muscle mass, in addition to increased large artery stiffness. Further studies are required to investigate the role of vitamin K supplementation in this population.

Body Composition, Natriuretic Peptides, and Adverse Outcomes in Heart Failure With Preserved and Reduced Ejection Fraction.

OBJECTIVES: The purpose of this study was to determine the relationship between body composition, N-terminal B-type natriuretic peptide (NT-proBNP) levels, and heart failure (HF) phenotypes and outcomes. BACKGROUND: Abnormalities in body composition can influence metabolic dysfunction and HF severity; however, data assessing fat distribution and skeletal muscle (SM) size in HF with reduced (HFrEF) and preserved EF (HFpEF) are limited. Further, whether NPs relate more closely to axial muscle mass than measures of adiposity is not well studied. METHODS: We studied 572 adults without HF (n = 367), with HFrEF (n = 113), or with HFpEF (n = 92). Cardiac magnetic resonance was used to assess subcutaneous and visceral abdominal fat, paracardial fat, and axial SM size. We measured NT-proBNP in 334 participants. We used Cox regression to analyze the relationship between body composition and mortality. RESULTS: Compared with controls, pericardial and subcutaneous fat thickness were significantly increased in HFpEF, whereas patients with HFrEF had reduced axial SM size after adjusting for age, sex, race, and body height (p < 0.05 for comparisons). Lower axial SM size, but not fat, was significantly predictive of death in unadjusted (standardized hazard ratio: 0.63; p < 0.0001) and multivariable-adjusted analyses (standardized hazard ratio = 0.72; p = 0.0007). NT-proBNP levels more closely related to lower axial SM rather than fat distribution or body mass index (BMI) in network analysis, and when simultaneously assessed, only SM (p = 0.0002) but not BMI (p = 0.18) was associated with NT-proBNP. However, both NT-proBNP and axial SM mass were independently predictive of death (p < 0.05). CONCLUSIONS: HFpEF and HFrEF have distinct abnormalities in body composition. Reduced axial SM, but not fat, independently predicts mortality. Greater axial SM more closely associates with lower NT-proBNP rather than adiposity. Lower NT-proBNP levels in HFpEF compared with HFrEF relate more closely to muscle mass rather than obesity.

Evaluation of a Patient-Specific, Low-Cost, 3-Dimensional-Printed Transesophageal Echocardiography Human Heart Phantom.

OBJECTIVE: Currently available 3-dimensional (3D) modeling and printing techniques allow for the creation of patient-specific models based on 3D medical imaging data. The authors hypothesized that a low-cost, patient-specific, cardiac computed tomography-based phantom, created using desktop 3D printing and casting, would have comparable image quality, accuracy, and usability to an existing commercially available echocardiographic phantom. DESIGN: Blinded comparative study. SETTING: Simulation laboratory at a single academic institution. PARTICIPANTS: Voluntary cardiac anesthesiologists at a single academic institution. INTERVENTIONS: Stage 1 of the study consisted of an online questionnaire in which a set of basic transesophageal echocardiography (TEE) views obtained from the 3D printed phantom and commercial phantom were presented to participants, who had to identify the views and evaluate their fidelity to clinical images on a Likert scale. In stage 2, participants performed an unblinded basic TEE examination on both phantoms. MEASUREMENTS AND MAIN RESULTS: The time needed to acquire each basic view was recorded. Overall usability of the phantoms was assessed through a questionnaire. The participants could recognize most of the views. Fidelity ratings for both phantoms were similar (p < 0.05), with the exception of a midesophageal 2-chamber view that was observed better on the 3D printed phantom. The time required to obtain the views was shorter for the 3D printed phantom, although not statistically significant for most views. The overall user experience was better for the 3D phantom for all categories examined (p < 0.05). CONCLUSIONS: The study suggested that a 3D-printed TEE phantom is comparable with the commercially available one with good usability.

Axial Muscle Size as a Strong Predictor of Death in Subjects With and Without Heart Failure.

Background The impact of skeletal muscle size, quantified using simple noninvasive images routinely obtained during cardiac magnetic resonance imaging studies on mortality in the heart failure ( HF ) population is currently unknown. Methods and Results We prospectively enrolled 567 subjects without HF (n=364), with HF with reduced ejection fraction (n=111), or with HF with preserved ejection fraction (n=92), who underwent a cardiac magnetic resonance imaging. Skeletal muscle cross-sectional area was assessed with manual tracing of major thoracic muscle groups on axial chest magnetic resonance images. Factor analysis was used to identify a latent factor underlying the shared variability in thoracic muscle cross-sectional area. Cox regression was used to assess the relationship between these measurements and all-cause mortality (median follow up, 36.4 months). A higher overall thoracic muscle area factor assessed with principal component analysis was independently associated with lower mortality (standardized hazard ratio, 0.51; P<0.0001). The thoracic muscle area factor was predictive of death in subjects with HF with preserved ejection fraction, HF with reduced ejection fraction, and those without HF . Among all muscle groups, the pectoralis major cross-sectional area was the most representative of overall muscle area and was also the most robust predictor of death. A higher pectoralis major cross-sectional area predicted a lower mortality (standardized hazard ratio, 0.49; P<0.0001), which persisted after adjustment for various confounders (standardized hazard ratio, 0.55; P=0.0017). Conclusions Axial muscle size, and in particular smaller size of the pectoralis major, is independently associated with higher risk of mortality in patients with and without HF . Further work should clarify the role of muscle wasting as a therapeutic target in patients with HF .

Usefulness of Left Ventricular Strain by Cardiac Magnetic Resonance Feature-Tracking to Predict Cardiovascular Events in Patients With and Without Heart Failure.

There is controversy regarding the utility of left ventricular (LV) mechanics assessed by feature-tracking steady-state free-precession (FT-SSFP), a readily implementable technique in clinical practice. In particular, whether LV mechanics assessed by FT-SSFP predicts outcomes in subjects with heart failure (HF) with reduced ejection fraction (HFrEF), with preserved ejection fraction (HFpEF), or without HF is unknown. We aimed to assess whether LV mechanics measured with FT-SSFP cine magnetic resonance imaging (MRI) predicts adverse outcomes. We prospectively enrolled 612 adults without HF (n = 402), with HF with reduced ejection fraction (HFrEF; n = 113), or HFpEF (n = 97) and assessed LV strain using FT-SSFP cine MRI. Over a median follow-up of 39.5 months, 75 participants had an HF admission, and 85 died. In Cox proportional hazards models, lower global longitudinal (Standardized hazard ratio 1.56, 95% confidence interval [CI] 1.22 to 2.00, p = 0.0004), circumferential (Standardized HR 1.46, 95% CI 1.08 to 1.95, p = 0.0123), and radial strain (Standardized HR 0.59, 95% CI 0.43 to 0.83, p = 0.0019) were independently associated with the composite endpoint, after adjustment for HF status, LV ejection fraction (LVEF), age, sex, ethnicity, body mass index, systolic and diastolic blood pressure, hypertension, diabetes, coronary artery disease, and glomerular filtration rate. Furthermore, global longitudinal strain stratified the risk of adverse outcomes across tertiles better than LVEF. In analyses that included only participants with a preserved LVEF, systolic radial, circumferential and longitudinal strain were independently predictive of adverse outcomes. We conclude that LV longitudinal, circumferential and radial strain measured using FT-SSFP cine MRI (a readily implementable technique in clinical practice) predict the risk of adverse events, independently of LVEF.

Right Atrial Phasic Function in Heart Failure With Preserved and Reduced Ejection Fraction.

OBJECTIVES: This study researched right atrial (RA) deformation indexes and their association with all-cause mortality among subjects with or without heart failure (HF). BACKGROUND: Although left atrial dysfunction is well described in HF, patterns of RA dysfunction and their prognostic implications are unclear. Cardiac magnetic resonance (CMR) imaging can provide excellent visualization of the RA. We used CMR to characterize RA phasic function in HF and to assess its prognostic implications. METHODS: This study prospectively examined 608 adults without HF (n = 407), as well as adults with HF with a reduced ejection fraction (HFrEF) (n = 105) or with HF with a preserved ejection fraction (HFpEF) (n = 96). Phasic RA function was measured via volume measurements and feature-tracking methods to derive longitudinal strain. All-cause death was ascertained over a median follow-up of 38.9 months. Standardized hazard ratios (HRs) were computed via Cox regression. RESULTS: Measures of RA phasic function were more prominently impaired in subjects with HFrEF than those in subjects with HFpEF. In analyses that adjusted for demographic factors, HF status, left ventricular ejection fraction, right ventricular end-diastolic volume index, and right ventricular ejection fraction, RA reservoir strain (HR: 0.66; 95% confidence interval [CI]: 0.47 to 0.92; p = 0.0154), RA expansion index (HR: 0.53; 95% CI: 0.31 to 0.91; p = 0.0116), RA conduit strain (HR: 0.58; 95% CI: 0.40 to 0.84; p = 0.0039), and RA conduit strain rate (HR: 1.51; 95% CI: 1.02 to 2.220; p = 0.0373) independently predicted all-cause mortality. In contrast, RA booster pump function and RA volume index did not independently predict the risk of death. CONCLUSIONS: Phasic RA function is predictive of the risk of all-cause death in a diverse group of subjects with and without HF. RA conduit and reservoir function are independent predictors of mortality.

Vitamin K Status, Warfarin Use, and Arterial Stiffness in Heart Failure.

Large artery stiffening contributes to the pathophysiology of heart failure (HF) and associated comorbidities. MGP (matrix Gla-protein) is a potent inhibitor of vascular calcification. MGP activation is vitamin K-dependent. We aimed (1) to compare dp-ucMGP (dephospho-uncarboxylated MGP) levels between subjects with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) and subjects without HF; (2) to assess the relationship between dp-ucMGP levels and arterial stiffness; and (3) to assess the relationship between warfarin use, dp-ucMGP levels, and arterial stiffness in HF. We enrolled 348 subjects with HFpEF (n=96), HFrEF (n=53), or no HF (n=199). Carotid-femoral pulse wave velocity, a measure of large artery stiffness, was measured with arterial tonometry. Dp-ucMGP was measured with ELISA. Dp-ucMGP levels were greater in both HFrEF (582 pmol/L; 95% CI, 444-721 pmol/L) and HFpEF (549 pmol/L; 95% CI, 455-643 pmol/L) compared with controls (426 pmol/L; 95% CI, 377-475 pmol/L; ANCOVA P=0.0067). Levels of dp-ucMGP were positively associated with carotid-femoral pulse wave velocity (standardized ß, 0.31; 95% CI, 0.19-0.42; P<0.0001), which was also true in analyses restricted to patients with HF (standardized ß, 0.34; 95% CI, 0.16-0.52; P=0.0002). Warfarin use was significantly associated with carotid-femoral pulse wave velocity (standardized ß, 0.13; 95% CI, 0.004-0.26; P=0.043), but this relationship was eliminated after adjustment for dp-ucMGP. In conclusion, levels of dp-ucMGP are increased in HFpEF and HFrEF and are independently associated with arterial stiffness. Future studies should investigate whether vitamin K supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffness in HFpEF and HFrEF.

Arterial Properties as Determinants of Left Ventricular Mass and Fibrosis in Severe Aortic Stenosis: Findings From ACRIN PA 4008.

Background The role of arterial load in severe aortic stenosis is increasingly recognized. However, patterns of pulsatile load and their implications in this population are unknown. We aimed to assess the relationship between the arterial properties and both (1) left ventricular remodeling and fibrosis and (2) the clinical course of patients with severe aortic stenosis undergoing aortic valve replacement ( AVR ). Methods and Results We enrolled 38 participants with symptomatic severe aortic stenosis scheduled to undergo surgical AVR . Aortic root characteristic impedance, wave reflections parameters (reflection magnitude, reflected wave transit time), and myocardial extracellular mass were measured with cardiac magnetic resonance imaging and arterial tonometry Cardiac magnetic resonance imaging was repeated at 6 months in 30 participants. A reduction in cellular mass (133.6 versus 113.9 g; P=0.002) but not extracellular mass (42.3 versus 40.6 g; P=0.67) was seen after AVR . Participants with higher extracellular mass exhibited greater reflection magnitude (0.68 versus 0.54; P=0.006) and lower aortic root characteristic impedance (56.3 versus 96.9 dynes/s per cm5; P=0.006). Reflection magnitude was a significant predictor of smaller improvement in the quality of life (Kansas City Cardiomyopathy Questionnaire score) after AVR ( R=-0.51; P=0.0026). The 6-minute walk distance at 6 months after AVR was positively correlated with the reflected wave transit time ( R=0.52; P=0.01). Conclusions Consistent with animal studies, arterial wave reflections are associated with interstitial volume expansion in severe aortic stenosis and predict a smaller improvement in quality of life following AVR . Future trials should assess whether wave reflections represent a potential therapeutic target to mitigate myocardial interstitial remodeling and to improve the clinical status of this patient population.

Left Atrial Phasic Function by Cardiac Magnetic Resonance Feature Tracking Is a Strong Predictor of Incident Cardiovascular Events.

BACKGROUND: The prognostic importance of left atrial (LA) dysfunction is increasingly recognized. Magnetic resonance imaging can provide excellent visualization of the LA wall. We aimed to study the association of LA dysfunction measured using feature-tracking magnetic resonance imaging with incident adverse cardiovascular events among subjects with or without heart failure (HF) at baseline. METHODS AND RESULTS: We prospectively studied 640 adults without HF (n=419), HF with preserved ejection fraction (n=101), or HF with reduced ejection fraction (n=120). We measured phasic LA function by volumetric and feature-tracking methods to derive longitudinal strain. The composite outcome of incident HF hospitalization or death was adjudicated during a median follow-up of 37.1 months. Measures of LA phasic function were more prominently impaired in subjects with HF with reduced ejection fraction than among subjects with HF with preserved ejection fraction. In unadjusted Cox proportional hazards models, all measures of phasic LA function and volumes (maximum, minimum, and diastatic) were associated with the composite outcome. However, in analyses that adjusted for clinical risk factors, HF status, maximum LA volume, left ventricular mass, and left ventricular ejection fraction, measures of conduit and reservoir LA function, but not booster-pump function, were associated with the composite outcome. The strongest associations were observed for conduit longitudinal strain (standardized hazard ratio, 0.66; 95% CI, 0.49-0.88; P=0.004), conduit strain rate (standardized hazard ratio, 1.59; 95% CI, 1.16-2.16; P=0.0035), and reservoir strain (standardized hazard ratio, 0.68; 95% CI, 0.52-0.89; P=0.0055). CONCLUSIONS: Phasic LA function measured using magnetic resonance imaging feature tracking is independently predictive of the risk of incident HF admission or death, even after adjusting for LA volume and left ventricular remodeling.

Poor Glycemic Control Is Associated With Increased Extracellular Volume Fraction in Diabetes.

OBJECTIVE: We assessed whether poor glycemic control is associated with an increase in myocardial fibrosis among adults with diabetes. RESEARCH DESIGN AND METHODS: We studied 47 adults with type 2 diabetes and stratified them into three groups according to their hemoglobin A1c (HbA1c) level: <6.5% (group 1; n = 12), 6.5-7.5% (group 2; n = 20), and >7.5% (group 3; n = 15). Left ventricular (LV) mass was assessed using cardiac MRI. The extracellular volume fraction (ECVF), an index of myocardial fibrosis, was measured by using myocardial T1 mapping before and after the administration of a gadolinium-based contrast agent. RESULTS: Mean HbA1c was 5.84 ± 0.16%, 6.89 ± 0.14%, and 8.57 ± 0.2% in groups 1, 2, and 3, respectively. LV mass was not significantly different between the groups. The myocardial ECVF was significantly greater in groups 2 (mean 27.6% [95% CI 24.8-30.3]) and 3 (27.6% [24.4-30.8]) than in group 1 (21.1% [17.5-24.7]; P = 0.015). After adjusting for age, sex, BMI, blood pressure, and estimated glomerular filtration rate, the myocardial ECVF was significantly greater in groups 2 (27.4% [24.4-30.4]) and 3 (28% [24.5-31.5]) than in group 1 (20.9% [17.1-24.6]; P = 0.0156, ANCOVA). CONCLUSIONS: An increased myocardial ECVF, suggesting myocardial fibrosis, is independently associated with poor glycemic control among adults with diabetes. Further research should assess whether tight glycemic control can revert fibrosis to healthy myocardium or ameliorate it and its adverse clinical consequences.

Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure.

AIMS: The arginine vasopressin (AVP) pathway has been extensively studied in heart failure (HF) with reduced ejection fraction (HFrEF), but less is known about AVP in HF with preserved EF (HFpEF). Furthermore, the association between AVP and atrial natriuretic peptide (ANP, a well-known inhibitor of AVP secretion) in HF is unknown. METHODS AND RESULTS: We studied subjects with HFpEF (n = 28) and HFrEF (n = 25) and without HF (n = 71). Left ventricular (LV) mass and left atrial (LA) volumes were measured with cardiac magnetic resonance imaging. Arginine vasopressin and ANP were measured with enzyme-linked immunosorbent assay. Arginine vasopressin levels were significantly greater in HFpEF [0.96 pg/mL; 95% confidence interval (CI) = 0.83-1.1 pg/mL] compared with subjects without HF (0.69 pg/mL; 95% CI = 0.6-0.77 pg/mL; P = 0.0002). Heart failure with preserved ejection fraction (but not HFrEF) was a significant predictor of higher AVP after adjustment for potential confounders. Arginine vasopressin levels were independently associated with a greater LA volume and also paradoxically, with lower ANP levels. Key independent correlates of higher AVP were the presence of HFpEF (standardized ß = 0.32; 95% CI = 0.09-0.56; P = 0.0073) and the ANP/LA volume ratio (standardized ß = -0.23; 95% CI = -0.42 to -0.04; P = 0.0196). Arginine vasopressin levels were independently associated with LV mass (ß = 0.26; 95% CI = 0.09-0.43; P = 0.003) and with an increased risk of death or HF admissions during follow-up (hazard ratio = 1.61; 95% CI = 1.13-2.29; P = 0.008). CONCLUSIONS: Arginine vasopressin is increased in HFpEF and is associated with LV hypertrophy and poor outcomes. Higher AVP is associated with the combination of LA enlargement and paradoxically low ANP levels. These findings may indicate that a relative deficiency of ANP (an inhibitor of AVP secretion) in the setting of chronically increased LA pressure may contribute to AVP excess.

Circulating Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Kidney Dysfunction and Arterial Stiffness.

BACKGROUND: Large artery stiffening is increased in advanced chronic kidney disease (CKD) but likely develops progressively in earlier stages of CKD. Active matrix Gla-protein (MGP) is a potent vitamin K-dependent inhibitor of vascular calcification. A recent animal model demonstrated intrinsic abnormalities in vitamin K metabolism even in early CKD, but whether early human CKD is associated with vascular vitamin K deficiency is unknown. METHODS: We enrolled 137 adults without HF with varying degrees of renal function: normal estimated glomerular filtration rate (eGFR; >90 ml/min; n = 59), mildly reduced eGFR (stage 2 CKD: eGFR = 60-89 ml/min; n = 53) or at least moderately reduced eGFR (stage 3-5 CKD; eGFR < 60 ml/min; n = 25). Carotid-femoral pulse wave velocity (CF-PWV) was measured with carotid and femoral tonometry. Dephospho-uncarboxylated matrix gla-protein (dp-ucMGP) was measured with enzyme-linked immunosorbent assay (ELISA) (VitaK; Maastricht University; The Netherlands). RESULT: Dp-ucMGP levels were progressively increased with decreasing renal function (eGFR ≥ 90: 247 pmol/l; eGFR 60-89: 488 pmol/l; eGFR < 60: 953 pmol/l; P < 0.0001). These differences persisted after adjustment for multiple potential confounders (eGFR ≥ 90: 314 pmol/l; eGFR 60-89: 414 pmol/l; eGFR < 60: 770 pmol/l; P < 0.0001). In a multivariable model adjusted for various confounders, dp-ucMGP was a significant independent predictor of CF-PWV (ß = 0.21; P = 0.019). In formal mediation analyses, dp-ucMGP mediated a significant relationship between eGFR and higher CF-PWV (ß = -0.16; P = 0.005), whereas no significant dp-ucMGP-independent relationship was present (ß = -0.02; P = 0.80). CONCLUSIONS: CKD is associated with increased (inactive) dp-ucMGP, a vitamin K-dependent inhibitor of vascular calcification, which correlates with large artery stiffness. Further studies are needed to assess whether vitamin K2 supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffening in CKD.

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.

BACKGROUND: The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). PATIENTS AND METHODS: Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. RESULTS: A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. CONCLUSION: The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.

Hypercapnic acidosis attenuates pulmonary epithelial stretch-induced injury via inhibition of the canonical NF-κB pathway.

BACKGROUND: Hypercapnia, with its associated acidosis (HCA), is a consequence of respiratory failure and is also seen in critically ill patients managed with conventional "protective" ventilation strategies. Nuclear factor kappa-B (NF-κB), a pivotal transcription factor, is activated in the setting of injury and repair and is central to innate immunity. We have previously established that HCA protects against ventilation-induced lung injury in vivo, potentially via a mechanism involving inhibition of NF-κB signaling. We wished to further elucidate the role and mechanism of HCA-mediated inhibition of the NF-κB pathway in attenuating stretch-induced injury in vitro. METHODS: Initial experiments examined the effect of HCA on cyclic stretch-induced inflammation and injury in human bronchial and alveolar epithelial cells. Subsequent experiments examined the role of the canonical NF-κB pathway in mediating stretch-induced injury and the mechanism of action of HCA. The contribution of pH versus CO2 in mediating this effect of HCA was also examined. RESULTS: Pulmonary epithelial high cyclic stretch (22 % equibiaxial strain) activated NF-κB, enhanced interleukin-8 (IL-8) production, caused cell injury, and reduced cell survival. In contrast, physiologic stretch (10 % strain) did not activate inflammation or cause cell injury. HCA reduced cyclic mechanical stretch-induced NF-κB activation, attenuated IL-8 production, reduced injury, and enhanced survival, in bronchial and alveolar epithelial cells, following shorter (24 h) and longer (120 h) cyclic mechanical stretch. Pre-conditioning with HCA was less effective than when HCA was applied after commencement of cell stretch. HCA prevented the stretch-induced breakdown of the NF-κB cytosolic inhibitor IκBα, while IκBα overexpression "occluded" the effect of HCA. These effects were mediated by a pH-dependent mechanism rather than via CO2 per se. CONCLUSIONS: HCA attenuates adverse mechanical stretch-induced epithelial injury and death, via a pH-dependent mechanism that inhibits the canonical NF-κB activation by preventing IκBα breakdown.

A Randomized Controlled Trial of High-Flow Nasal Oxygen (Optiflow) as Part of an Enhanced Recovery Program After Lung Resection Surgery.

BACKGROUND: Patients undergoing thoracic surgery are at risk of postoperative pulmonary complications, which are associated with increased morbidity and mortality. High-flow nasal oxygen therapy delivers humidified, warmed positive airway pressure but has not been tested routinely after thoracic surgery. METHODS: We performed a randomized, controlled, blinded study. Patients undergoing elective lung resection were randomly assigned to either high-flow nasal oxygen or standard oxygen therapy. Patients were otherwise treated within an established enhanced recovery program. The primary outcome was the difference between the preoperative and postoperative 6-minute walk test. Secondary outcomes included hospital length of stay, spirometry, and patient-reported outcomes measured using the Postoperative Quality of Recovery Scale. RESULTS: Fifty-nine patients were randomly assigned to either high-flow nasal oxygen (n = 28) or standard oxygen (n = 31) therapy. We found no difference in the 6-minute walk test outcome or spirometry; however, length of hospital stay was significantly lower in the high-flow nasal oxygen group, median 2.5 days (range, 1 to 22), compared with the standard oxygen group, median 4.0 days (range, 2 to 18); geometric mean ratio was 0.68 (95% confidence interval: 0.48 to 0.86, p = 0.03). No significant differences in recovery domains were found, but patients in the high-flow nasal oxygen group reported significantly higher satisfaction (p = 0.046). CONCLUSIONS: Prophylactic high-flow nasal oxygen therapy, when incorporated into an enhanced recovery program, did not improve 6-minute walk test results but was associated with reduced length of hospital stay and improved satisfaction after lung resection, compared with standard oxygen. This finding has implications for reduced costs and better service provision, and a multicenter trial powered for length of stay is required.

Comparison of younger and older breast cancer survivors and age-matched controls on specific and overall quality of life domains.

BACKGROUND: Younger survivors (YS) of breast cancer often report more survivorship symptoms such as fatigue, depression, sexual difficulty, and cognitive problems than older survivors (OS). This study sought to determine the effect of breast cancer and age at diagnosis on quality of life (QoL) by comparing 3 groups: 1) YS diagnosed at age 45 years or before, 2) OS diagnosed between 55 and 70, and 3) for the YSs, age-matched controls (AC) of women not diagnosed with breast cancer. METHODS: Using a large Eastern Cooperative Oncology Group (ECOG) database, 505 YS were recruited who were aged 45 years or younger when diagnosed and 622 OS diagnosed at 55 to 70 years of age. YS, OS, and AC were compared on physical, psychological, social, spiritual, and overall QoL variables. RESULTS: Compared to both AC and to OS, YS reported more depressive symptoms (P = .005) and fatigue (P < .001), poorer self-reported attention function (P < .001), and poorer sexual function (P < .001) than either comparison group. However, YS also reported a greater sense of personal growth (P < .001) and perceived less social constraint (P < .001) from their partner than AC. CONCLUSIONS: YS reported worse functioning than AC relative to depression, fatigue, attention, sexual function, and spirituality. Perhaps even more important, YS fared worse than both AC and OS on body image, anxiety, sleep, marital satisfaction, and fear of recurrence, indicating that YS are at greater risk for long-term QoL problems than survivors diagnosed at a later age.