Association of Plasma Myeloperoxidase with Inflammation and Diabetic status in HFpEF.

Background: Inflammation and oxidative stress are thought to play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) through the development of endothelial dysfunction. Myeloperoxidase (MPO) functions as a link between oxidative stress and inflammation and is an interesting therapeutic target. The objective of this observational cohort study was to compare MPO levels between HFpEF and old controls, to define clinical characteristics associated with high levels of MPO and to assess the relation between MPO levels and vascular function. Methods: Patients with HFpEF (N = 55) and controls > 60 years (N = 18) were prospectively included. All subjects underwent complete echocardiography and blood sampling. MPO levels were dosed by ELISA assay. Effective arterial elastance (Ea) and peripheral arterial tonometry (EndoPAT reactive hyperemia index RHI and augmentation index AIx) were used to assess vascular function. Characteristics between groups defined by the median of MPO were compared using independent samples t-test or chi square test. Results: Patients with HFpEF (80 ± 8.7 years, 65% female) had higher levels of MPO compared to controls (75 ± 5.0 years, 72% female) (34.7 ng/mL [22.7; 44.0] vs 22.6 [18.2; 32.0], p = 0.026). MPO levels were correlated with markers of inflammation; C-reactive protein (Pearson's R = 0.46, p = 0.001) and neutrophile to lymphocyte ratio (R = 0.36, p = 0.031) and with signs of left ventricular (LV) remodelling and elevated filling pressures, namely NT-proBNP levels (R = 0.32, p = 0.019), decreased LV ejection fraction (LVEF, R = -0.36, p = 0.008) and E/e' ratio (R = 0.35, p = 0.011). HFpEF patients with levels of MPO above the median were more often men (48% vs 21%, p = 0.037) and suffered more often from diabetes (48% vs 18%, p = 0.017). Intriguingly, they had lower indices of vascular stiffness (augmentation index 11.1 [0.1; 30.7] vs 19.9 [10.5; 33.4], p = 0.018 and arterial elastance Ea 2.06 ± 0.676 vs 2.43 ± 0.721, p = 0.065) and there was no difference in endothelial function (1.82 [1.34; 2.30] vs 1.66 [1.32; 1.95], p = 0.55). Conclusions: HFpEF patients have higher levels of MPO than controls, reflecting leukocyte activation and oxidative stress. Among patients, high levels of MPO are associated with male sex, diabetic status, subtle left ventricular dysfunction and pronounced diastolic dysfunction. The association between oxidative stress and vascular stiffness, on the other hand could not be demonstrated. Clinical Trial Registration: Clinical trial NCT03197350.

Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C). METHODS: We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves. RESULTS: Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m2, p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m2, p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients. Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1-2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1-4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels). CONCLUSION: Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.

Multivendor comparison of global and regional 2D cardiovascular magnetic resonance feature tracking strains vs tissue tagging at 3T.

BACKGROUND: Cardiovascular magnetic resonance (CMR) 2D feature tracking (FT) left ventricular (LV) myocardial strain has seen widespread use to characterize myocardial deformation. Yet, validation of CMR FT measurements remains scarce, particularly for regional strain. Therefore, we aimed to perform intervendor comparison of 3 different FT software against tagging. METHODS: In 61 subjects (18 healthy subjects, 18 patients with chronic myocardial infarction, 15 with dilated cardiomyopathy, and 10 with LV hypertrophy due to hypertrophic cardiomyopathy or aortic stenosis) were prospectively compared global (G) and regional transmural peak-systolic Lagrangian longitudinal (LS), circumferential (CS) and radial strains (RS) by 3 FT software (cvi42, Segment, and Tomtec) among each other and with tagging at 3T. We also evaluated the ability of regional LS, CS, and RS by different FT software vs tagging to identify late gadolinium enhancement (LGE) in the 18 infarct patients. RESULTS: GLS and GCS by all 3 software had an excellent agreement among each other (ICC = 0.94-0.98 for GLS and ICC = 0.96-0.98 for GCS respectively) and against tagging (ICC = 0.92-0.94 for GLS and ICC = 0.88-0.91 for GCS respectively), while GRS showed inconsistent agreement between vendors (ICC 0.10-0.81). For regional LS, the agreement was good (ICC = 0.68) between 2 vendors but less vs the 3rd (ICC 0.50-0.59) and moderate to poor (ICC 0.44-0.47) between all three FT software and tagging. Also, for regional CS agreement between 2 software was higher (ICC = 0.80) than against the 3rd (ICC = 0.58-0.60), and both better agreed with tagging (ICC = 0.70-0.72) than the 3rd (ICC = 0.57). Regional RS had more variation in the agreement between methods ranging from good (ICC = 0.75) to poor (ICC = 0.05). Finally, the accuracy of scar detection by regional strains differed among the 3 FT software. While the accuracy of regional LS was similar, CS by one software was less accurate (AUC 0.68) than tagging (AUC 0.80, p < 0.006) and RS less accurate (AUC 0.578) than the other two (AUC 0.76 and 0.73, p < 0.02) to discriminate segments with LGE. CONCLUSIONS: We confirm good agreement of CMR FT and little intervendor difference for GLS and GCS evaluation, with variable agreement for GRS. For regional strain evaluation, intervendor difference was larger, especially for RS, and the diagnostic performance varied more substantially among different vendors for regional strain analysis.

Pulmonary hypertension due to left heart disease: diagnostic value of pulmonary artery distensibility.

OBJECTIVES: To evaluate how pulmonary artery (PA) distensibility performs in detecting pulmonary hypertension due to left heart disease (PH-LHD) in comparison with parameters from ungated computed tomography (CT) and echocardiography. METHODS: One hundred patients (79 men, mean age = 63 ± 17 years) with either severe heart failure with reduced ejection fraction (HFrEF), aortic stenosis, or primary mitral regurgitation prospectively underwent right heart catheterization, ungated CT, ECG-gated CT, and echocardiography. During the ECG-gated CT, the right PA distensibility was calculated. In ungated CT, dPA, dPA/AA, the ratio of dPA to the diameter of the vertebra, segmental PA diameter, segmental PA-to-bronchus ratio, and the main PA volume were measured; the egg-and-banana sign was recorded. During echocardiography, the tricuspid regurgitation (TR) gradient was measured. The areas under the ROC curves (AUC) of these signs were computed and compared with DeLong test. Correlation between PA distensibility and PA pressure (PAP) was investigated through Pearson's coefficient. RESULTS: PA distensibility was lower in patients with PH than in those without PH (11.4 vs. 21.2%, p < 0.001) and correlated negatively with mean PAP (r = - 0.72, p < 0.001). Age, PA size, and mean PAP were independent predictors of PA distensibility. PA distensibility < 18% detected PH-LHD with 96% sensitivity and 73% specificity; its AUC was 0.92, larger than that of any other sign at ungated CT and TR gradient (AUC ranging from 0.54 to 0.83, DeLong: p ranging from 0.020 to < 0.001). CONCLUSION: PA distensibility on an ECG-gated CT can detect PH-LHD better than the parameters reflecting PA dilatation in ungated CT or TR gradient in the echocardiography of patients with severe HFrEF, aortic stenosis, or mitral regurgitation. KEY POINTS: • In left heart disease, pulmonary artery distensibility is lower in patients with PH than in those without pulmonary hypertension (11.4 vs. 21.2%, p < 0.001). • In left heart disease, pulmonary artery distensibility detects pulmonary hypertension with an area under the receiver operating curve of 0.92. • In left heart disease, the area under the receiver operating curve of pulmonary artery distensibility for detecting pulmonary hypertension is larger than that of all other signs at ungated CT (p from 0.019 to < 0.001) and tricuspid regurgitation gradient at echocardiography (p = 0.020).

Assessment of Left Ventricular Reverse Remodeling by Cardiac MRI in Patients Undergoing Repair Surgery for Severe Aortic or Mitral Regurgitation.

OBJECTIVE: To evaluate left ventricular (LV) reverse remodeling after repair surgery for mitral regurgitation (MR) or aortic regurgitation (AR), aiming at determining optimal preoperative thresholds for normalization of LV volumes and function after surgery. DESIGN: Observational prospective cohort study. SETTING: Single-center, academic, tertiary care cardiovascular center. PARTICIPANTS: Patients and volunteers. INTERVENTIONS: Cardiac magnetic resonance with measurement of indexed LV end-diastolic volume (LVEDVi) and end-systolic volume (LVESVi), mass (LVmassi), and ejection fraction (LVEF) was performed preoperatively and postoperatively. MEASUREMENTS AND MAIN RESULTS: The authors included 29 patients with AR and 59 patients with MR (46 ± 12 and 56 ± 12 years, follow-up 222 ± 57 days). Both AR and MR repair resulted in a significant reduction of LV volumes and mass (respectively, delta change in LVEDVi -55 mL/m² and -43 mL/m²; in LVESVi -26 mL/m² and -10 mL/m²; and in LVmassi -24 g/m² and -12 g/m²; p < 0.001 for all). Yet despite the absence of perioperative necrosis, 7 (24%) patients with AR had persistent LV dilatation (LVEDVi >106 mL/m²) relative to controls and 16 (27%) patients with MR developed systolic LV dysfunction (LVEF <50%) postoperatively. Binary logistic regression analysis indicated preoperative LV volumes as the most accurate parameter for predicting both incomplete LV reverse remodeling in AR and LV dysfunction in MR. Receiver operating characteristic-determined thresholds were LVEDVi >155 mL/m² for AR and >129 mL/m² for MR. CONCLUSION: Although both AR and MR repair allow significant reverse postoperative LV remodeling, persistent LV dilatation after AR correction and systolic LV dysfunction after MR repair are common and best predicted by increased preoperative LV volumes. This highlights the importance of considering LV volumes in the decision-making process.

Pulmonary hypertension due to left heart disease: diagnostic and prognostic value of CT in chronic systolic heart failure.

OBJECTIVES: To evaluate the ability of chest computed tomography (CT) to predict pulmonary hypertension (PH) and outcome in chronic heart failure with reduced ejection fraction (HFrEF). METHODS: We reviewed 119 consecutive patients with HFrEF by CT, transthoracic echocardiography (TTE) and right heart catheterization (RHC). CT-derived pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio), left atrial, right atrial, right ventricular (RV) and left ventricular volumes were correlated with RHC mean pulmonary arterial pressure (mPAP) . Diagnostic accuracy to predict PH and ability to predict primary composite endpoint of all-cause mortality and HF events were evaluated. RESULTS: RV volume was significantly higher in 81 patients with PH compared to 38 patients without PH (133 ml/m2 vs. 79 ml/m2, p < 0.001) and was moderately correlated with mPAP (r=0.55, p < 0.001). Also, RV volume had higher ability to predict PH (area under the curve: 0.88) than PA diameter (0.79), PA:A ratio (0.76) by CT and tricuspid regurgitation gradient (0.83) and RV basal diameter by TTE (0.84, all p < 0.001). During the follow-up period (median: 3.4 years), 51 patients (43%) had HF events or died. After correction for important clinical, TTE and RHC parameters, RV volume (adjusted hazard ratio [HR]: 1.71, 95% CI 1.31-2.23, p < 0.001) and PA diameter (HR: 1.61, 95% CI 1.18-2.22, p = 0.003) were independent predictors of the primary endpoint. CONCLUSION: In patients with HFrEF, measurement of RV volume and PA diameter on ungated CT are non-invasive markers of PH and may help to predict the patient outcome. KEY POINTS: • Right ventricular (RV) volume measured by chest CT has good ability to identify pulmonary hypertension (PH) in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). • The accuracy of pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio) to predict PH was similar to previous studies, however, with lower cut-offs (28.1 mm and 0.92, respectively). • Chest CT-derived PA diameter and RV volume independently predict all-cause mortality and HF events and improve outcome prediction in patients with advanced HFrEF.

Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction.

BACKGROUND: Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The study aim was to evaluate the presence, associations, and prognostic significance of diffuse fibrosis in HFpEF patients compared to age- and sex-matched controls. METHODS: We prospectively included 118 consecutive HFpEF patients. Diffuse myocardial fibrosis was estimated by extracellular volume (ECV) quantified by cardiovascular magnetic resonance with the modified Look-Locker inversion recovery sequence. We determined an ECV age- and sex-adjusted cutoff value (33%) in 26 controls. RESULTS: Mean ECV was significantly higher in HFpEF patients versus healthy controls (32.9 ± 4.8% vs 28.2 ± 2.4%, P <  0.001). Multivariate logistic regression showed that body mass index (BMI) (odds ratio (OR) =0.92 [0.86-0.98], P = 0.011), diabetes (OR = 2.62 [1.11-6.18], P = 0.028), and transmitral peak E wave velocity (OR = 1.02 [1.00-1.03], P = 0.022) were significantly associated with abnormal ECV value. During a median follow-up of 11 ± 6 months, the primary outcome (all-cause mortality or first heart failure hospitalization) occurred in 38 patients. In multivariate Cox regression analysis, diabetes (hazard ratio (HR) =1.98 [1.04; 3.76], P = 0.038) and hemoglobin level (HR = 0.81 [0.67; 0.98], P = 0.028) were significant predictors of composite outcome. The ECV ability to improve this model added significant prognostic information. We then developed a risk score including diabetes, hemoglobin and ECV > 33% demonstrating significant prediction of risk and validated this score in a validation cohort of 53 patients. Kaplan-Meier curves showed a significant difference according to tertiles of the probability score (P <  0.001). CONCLUSION: Among HFpEF patients, high ECV, likely reflecting abnormal diffuse myocardial fibrosis, was associated with a higher rate of all-cause death and first HF hospitalization in short term follow up. TRIAL REGISTRATION: Characterization of Heart Failure With Preserved Ejection Fraction. TRIAL REGISTRATION NUMBER: NCT03197350 . Date of registration: 20/06/2017. This trial was retrospectively registered.

Age and sex corrected normal reference values of T1, T2 T2* and ECV in healthy subjects at 3T CMR.

BACKGROUND: Myocardial T1, T2 and T2* imaging techniques become increasingly used in clinical practice. While normal values for T1, T2 and T2* times are well established for 1.5 Tesla (T) cardiovascular magnetic resonance (CMR), data for 3T remain scarce. Therefore we sought to determine normal reference values relative to gender and age and day to day reproducibility for native T1, T2, T2* mapping and extracellular volume (ECV) at 3T in healthy subjects. METHODS: After careful exclusion of cardiovascular abnormality, 75 healthy subjects aged 20 to 90 years old (mean 56 ± 19 years, 47% women) underwent left-ventricular T1 (3-(3)-3-(3)-5 MOLLI)), T2 (8 echo- spin echo-imaging) and T2 * (8 echo gradient echo imaging) mapping at 3T CMR (Philips Ingenia 3T and computation of extracellular volume after administration of 0.2 mmol/kg Gadovist). Inter- and intra-observer reproducibility was estimated by intraclass correlation coefficient (ICC). Day to day reproducibility was assessed in 10 other volunteers. RESULTS: Mean myocardial T1 at 3T was 1122 ± 57 ms, T2 52 ± 6 ms, T2* 24 ± 5 ms and ECV 26.6 ± 3.2%. T1 (1139 ± 37 vs 1109 ± 73 ms, p < 0.05) and ECV (28 ± 3 vs 25 ± 2%, p < 0.001), but not T2 (53 ± 8 vs 51 ± 4, p = NS) were significantly greater in age matched women than in men. T1 (r = 0.40, p < 0.001) and ECV (r = 0.37, p = 0.001) increased, while T2 decreased significantly (r = -0.25, p < 0.05) with increasing age. T2* was not influenced by either gender or age. Intra and inter-observer reproducibility was high (ICC ranging between 0.81-0.99), and day to day coefficient of variation was low (6.2% for T1, 7% for T2, 11% for T2* and 11.5% for ECV). CONCLUSIONS: We provide normal myocardial T2, T2*,T1 and ECV reference values for 3T CMR which are significantly different from those reported at 1.5 Tesla CMR. Myocardial T1 and ECV values are gender and age dependent. Measurement had high inter and intra-observer reproducibility and good day-to-day reproducibility.

High field magnetic resonance imaging of rodents in cardiovascular research.

Transgenic and gene knockout rodent models are primordial to study pathophysiological processes in cardiovascular research. Over time, cardiac MRI has become a gold standard for in vivo evaluation of such models. Technical advances have led to the development of magnets with increasingly high field strength, allowing specific investigation of cardiac anatomy, global and regional function, viability, perfusion or vascular parameters. The aim of this report is to provide a review of the various sequences and techniques available to image mice on 7-11.7 T magnets and relevant to the clinical setting in humans. Specific technical aspects due to the rise of the magnetic field are also discussed.

Emergence of Multidrug-Resistant Influenza A(H1N1)pdm09 Virus Variants in an Immunocompromised Child Treated With Oseltamivir and Zanamivir.

Prolonged treatment of an immunocompromised child with oseltamivir and zanamivir for A(H1N1)pdm09 virus infection led to the emergence of viruses carrying H275Y and/or E119G in the neuraminidase (NA). When phenotypically evaluated by NA inhibition, the dual H275Y-E119G substitution caused highly reduced inhibition by 4 NA inhibitors: oseltamivir, zanamivir, peramivir, and laninamivir.

Histological Validation of measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T.

BACKGROUND: Gadolinium (Gd) Extracellular volume fraction (ECV) by Cardiovascular Magnetic Resonance (CMR) has been proposed as a non-invasive method for assessment of diffuse myocardial fibrosis. Yet only few studies used 3 T CMR to measure ECV, and the accuracy of ECV measurements at 3 T has not been established. Therefore the aims of the present study were to validate measurement of ECV by MOLLI T1 mapping by 3 T CMR against fibrosis measured by histopathology. We also evaluated the recently proposed hypothesis that native-T1 mapping without contrast injection would be sufficient to detect fibrosis. METHODS: 31 patients (age = 58 ± 17 years, 77% men) with either severe aortic stenosis (n = 12) severe aortic regurgitation (n = 9) or severe mitral regurgitation (n = 10), all free of coronary artery disease, underwent 3 T-CMR with late gadolinium enhancement (LGE) and pre- and post-contrast MOLLI T1 mapping and ECV computation, prior to valve surgery. LV biopsies were performed at the time of surgery, a median 13 [1-30] days later, and stained with picrosirius red. Pre-, and post-contrast T1 values, ECV, and amount of LGE were compared against magnitude of fibrosis by histopathology by Pearson correlation coefficients. RESULTS: The average amount of interstitial fibrosis by picrosirius red staining in biopsy samples was 6.1 ± 4.3%. ECV computed from pre-post contrast MOLLI T1 time changes was 28.9 ± 5.5%, and correlated (r = 0.78, p < 0.001) strongly with the magnitude of histological fibrosis. By opposition, neither amount of LGE (r = 0.17, p = 0.36) nor native pre-contrast myocardial T1 time (r = -0.18, p = 0.32) correlated with fibrosis by histopathology. CONCLUSIONS: ECV determined by 3 T CMR T1 MOLLI images closely correlates with histologically determined diffuse interstitial fibrosis, providing a non-invasive estimation for quantification of interstitial fibrosis in patients with valve diseases. By opposition, neither non-contrast T1 times nor the amount of LGE were indicative of the magnitude of diffuse interstitial fibrosis measured by histopathology.

Human placental transcriptome shows sexually dimorphic gene expression and responsiveness to maternal dietary n-3 long-chain polyunsaturated fatty acid intervention during pregnancy.

BACKGROUND: Previously we have examined the effect of maternal dietary n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on offspring fat mass. Considering the involvement of the placenta in fetal programming, we aimed to analyze the sex-specific gene expression in human term placenta and its response to the n-3 LCPUFA intervention, as well as their correlations to offspring adiposity. RESULTS: Placental gene expression was assessed in a control and n-3 LCPUFA intervention group by DNA microarrays, biological pathway analyses and RT-qPCR validation. Expression data were correlated with sex steroid hormone levels in placenta and cord plasma, and offspring anthropometric data. Transcriptome data revealed sexually dimorphic gene expression in control placentas per se, whereas in intervention placentas sex-specific expression changed, and more n-3 LCPUFA-regulated genes were found in female than male placentas. Sexually dimorphic gene expression and n-3 LCPUFA-responsive genes were enriched in the pathway for cell cycle and its associated modulator pathways. Significant mRNA expression changes for CDK6, PCNA, and TGFB1 were confirmed by RT-qPCR. CDK6 and PCNA mRNA levels correlated with offspring birth weight and birth weight percentiles. Significantly reduced placental estradiol-17ß/testosterone ratio upon intervention found in female offspring correlated with mRNA levels for the 'Wnt signaling' genes DVL1 and LRP6. CONCLUSIONS: Overall, human placentas show sexually dimorphic gene expression and responsiveness to maternal n-3 LCPUFA intervention during pregnancy with more pronounced effects in female placentas. The absence of correlations of analyzed placental gene expression with offspring adipose tissue growth in the first year is not mutually exclusive with programming effects, which may manifest later in life, or in other physiological processes.

Shoot branching and leaf dissection in tomato are regulated by homologous gene modules.

Aerial plant architecture is predominantly determined by shoot branching and leaf morphology, which are governed by apparently unrelated developmental processes, axillary meristem formation, and leaf dissection. Here, we show that in tomato (Solanum lycopersicum), these processes share essential functions in boundary establishment. Potato leaf (C), a key regulator of leaf dissection, was identified to be the closest paralog of the shoot branching regulator Blind (Bl). Comparative genomics revealed that these two R2R3 MYB genes are orthologs of the Arabidopsis thaliana branching regulator REGULATOR OF AXILLARY MERISTEMS1 (RAX1). Expression studies and complementation analyses indicate that these genes have undergone sub- or neofunctionalization due to promoter differentiation. C acts in a pathway independent of other identified leaf dissection regulators. Furthermore, the known leaf complexity regulator Goblet (Gob) is crucial for axillary meristem initiation and acts in parallel to C and Bl. Finally, RNA in situ hybridization revealed that the branching regulator Lateral suppressor (Ls) is also expressed in leaves. All four boundary genes, C, Bl, Gob, and Ls, may act by suppressing growth, as indicated by gain-of-function plants. Thus, leaf architecture and shoot architecture rely on a conserved mechanism of boundary formation preceding the initiation of leaflets and axillary meristems.

Rapid leukocyte migration by integrin-independent flowing and squeezing.

All metazoan cells carry transmembrane receptors of the integrin family, which couple the contractile force of the actomyosin cytoskeleton to the extracellular environment. In agreement with this principle, rapidly migrating leukocytes use integrin-mediated adhesion when moving over two-dimensional surfaces. As migration on two-dimensional substrates naturally overemphasizes the role of adhesion, the contribution of integrins during three-dimensional movement of leukocytes within tissues has remained controversial. We studied the interplay between adhesive, contractile and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro. We ablated all integrin heterodimers from murine leukocytes, and show here that functional integrins do not contribute to migration in three-dimensional environments. Instead, these cells migrate by the sole force of actin-network expansion, which promotes protrusive flowing of the leading edge. Myosin II-dependent contraction is only required on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus.

Effect of maternal obesity with and without gestational diabetes on offspring subcutaneous and preperitoneal adipose tissue development from birth up to year-1.

BACKGROUND: Maternal obesity and gestational diabetes mellitus (GDM) may independently influence offspring fat mass and metabolic disease susceptibility. In this pilot study, body composition and fat distribution in offspring from obese women with and without GDM and lean women were assessed within the 1st year of life, and maternal and newborn plasma factors were related to offspring adipose tissue distribution. METHODS: Serum and plasma samples from pregnant obese women with (n = 16) or without (n = 13) GDM and normoglycemic lean women (n = 15) at 3rd trimester and offspring cord plasma were used for analyzing lipid profiles, insulin and adipokine levels. At week-1 and 6, month-4 and year-1, offspring anthropometrics and skinfold thickness (SFT) were measured and abdominal subcutaneous (SCA) and preperitoneal adipose tissue (PPA) were determined by ultrasonography. RESULTS: Cord insulin was significantly increased in the GDM group, whereas levels of cord leptin, total and high molecular weight (HMW) adiponectin were similar between the groups. Neonates of the GDM group showed significantly higher SFT and fat mass until week-6 and significantly increased SCA at week-1 compared to the lean group that persisted as strong trend at week-6. Interestingly, PPA in neonates of the GDM group was significantly elevated at week-1 compared to both the lean and obese group. At month-4 and year-1, significant differences in adipose tissue growth between the groups were not observed. Multiple linear regression analyses revealed that cord insulin levels are independently related to neonatal PPA that showed significant relation to PPA development at year-1. Maternal fasted C-peptide and HMW adiponectin levels at 3rd trimester emerged to be determinants for PPA at week-1. CONCLUSION: Maternal pregravid obesity combined with GDM leads to newborn hyperinsulinemia and increased offspring fat mass until week-6, whereas pregravid obesity without GDM does not. This strongly suggests the pivotal role of GDM in the adverse offspring outcome. Maternal C-peptide and HMW adiponectin levels in pregnancy emerge to be predictive for elevated PPA in newborns and might be indicative for the obesity risk at later life. Altogether, the findings from our pilot study warrant evaluation in long-term studies. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004370.

Review and critical appraisal of the indications for cardiac magnetic resonance imaging in the ESC guidelines.

Cardiac MRI has made significant advances in the past decade, becoming an important technique for the evaluation of various cardiac pathologies. The aim of this document is to review the current indications for performing cardiac MRI based on the current ESC guidelines for STEMI, NSTEMI, chronic coronary artery disease, heart failure, arrhythmias, sudden cardiac death, valvular heart disease, pericardial disease and congenital heart disease. The review discusses the diagnostic and prognostic value of cMR for numerous cardiac diseases, and its important value in assessing structural heart disease and predicting arrhythmia risk. Additionally, it reflects upon the appropriateness of the guidelines and points out areas where the indications should be revised in future editions, based on the author's personal opinion. It is suggested that guideline criteria for the use of cMR should be more explicit to promote its use and lead to more specific reimbursements. However, further studies are needed to even better document the value of cMR in the future.

Cardiac structure, function, and coronary anatomy 10 years after isolated contemporary adjuvant radiotherapy in breast cancer patients with low cardiovascular baseline risk.

AIMS: The effects of isolated contemporary low-dose breast cancer (BC) radiotherapy (RT) on the heart remain poorly understood. This study aims to assess the long-term impacts of BC-RT on cardiac structure and function. METHODS AND RESULTS: Seventy-six women (62 ± 7 years) without history of prior heart disease, who had undergone RT for either first left (n = 36) or right (n = 40) BC, without additional medical oncology therapy apart from hormonal treatment 11 ± 1 years earlier, underwent transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), computed tomography coronary angiography (CTCA), NT-proBNP, and a 6-min walk test (6MWT). They were compared with 54 age-matched healthy female controls. By CTCA, 68% of BC patients exhibited no or very mild coronary disease, while only 11% had moderate stenosis (50-69%) and 3% had significant stenosis (>70%). Despite slightly reduced regional echocardiographic midventricular strains, BC patients exhibited similar global left and right ventricular volumes, ejection fractions, and global strains by echocardiography and CMR as controls. Mitral E/e' ratios were slightly higher, and mitral deceleration times were slightly lower, but NT-proBNP was similar to controls. Also, 6MWT was normal. None had late gadolinium enhancement, and extracellular volume fraction was similar in BC (28 ± 3 vs. 29 ± 3, P = 0.15) and controls. No differences were observed relative to dose or side of RT. CONCLUSION: Aside from minor alterations of regional strains and diastolic parameters, women who received isolated RT for BC had low prevalence of coronary disease, normal global systolic function, NT-proBNP, and exercise capacity and showed no structural changes by CMR, refuting significant long-term cardiotoxicity in such low-risk patients.

Left Atrial Glucose Metabolism Evaluation by 18F-FDG-PET in Persistent Atrial Fibrillation and in Sinus Rhythm.

The role of atrial metabolism alterations for initiation and atrial fibrillation (AF) persistence remains poorly understood. Therefore, we evaluated left atrial glucose metabolism by nicotinic acid derivative stimulated 18-fluorodeoxyglucose positron emission tomography in 36 patients with persistent AF undergoing catheter ablation before and 3 months after return to sinus rhythm and compared values against healthy controls. Under identical hemodynamics and metabolic conditions, and although left ventricular FDG uptake remained unchanged, patients in persistent AF presented significantly higher total left atrial and left atrial appendage uptake, which decreased significantly after return to sinus rhythm, despite improvement of passive and active atrial contractile function. These findings support a role of altered glucose metabolism and metabolic wasting underlying the pathophysiology of persistent AF.