74 research outputs found
Impact of diastolic pulmonary gradient and pulmonary artery pulse index on outcomes in heart transplant patientsâResults from the Eurotransplant database
BackgroundPredicting complications associated with pulmonary hypertension (PH) after cardiac transplantation is an important factor when considering cardiac transplantation. The transpulmonary gradient (TPG) is recommended to quantify PH in transplant candidates. Nonetheless, PH remains a common driver of mortality. The diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) can differentiate post- from combined pre- and post-capillary PH and may improve estimation of PH-associated risks. We used a large European cohort of transplant candidates to assess whether the pulmonary pulsatility index (PAPi), improves prediction of graft failure and mortality compared to DPG and PVR.MethodsOut of all patients undergoing heart transplantation between 2009 and 2019 in Eurotransplant member states (n = 10,465), we analyzed the impact of PH (mPAP > 25 mmHg) and right heart catheter hemodynamic data on graft failure and mortality within 1â5 years.ResultsIn 1,407 heart transplant patients with PH (79% male, median age 54 years, IQR 39â69 years), the median PVR was 2.5 WU (IQR 1.6 WU) with a median mPAP (pulmonary arterial pressure) of 32 mmHg (IQR 9 mmHg). Patients with low (< 3 mmHg) DPG had a better 5 year survival than those with higher DPG (log rank p = 0.023). TPG, mPAP, PAPi, and PVR did not improve prediction of survival. Low PAPi (OR = 2.24, p < 0.001) and high PVR (OR = 2.12, p = 0.005) were associated with graft failure.ConclusionPAPI and PVR are associated with graft failure in patients with PH undergoing cardiac transplantation. DPG is associated with survival in this cohort
Prediction of cardiac worsening through to cardiogenic shock in patients with acute heart failure
Aims: Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or newâonset CS in patients hospitalized for AHF. Methods and results: Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with followâup until death or discharge. WHF was defined by the RELAXâAHFâ2 criteria. CS was defined as SCAI stages BâE. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. Inâhospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21â36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32â231.81, P < 0.001). Chronic kidney disease (OR 2.20, 95% CI 1.25â3.93, P = 0.007), logarithmized serum creatinine (OR 2.90, 95% CI 1.51â5.82, P = 0.002), cystatin c (OR 1.86, 95% CI 1.27â2.77, P = 0.002), tricuspid valve regurgitation (OR 2.08, 95% CI 1.11â3.94, P = 0.023) and logarithmized proâadrenomedullin (OR 3.01, 95% CI 1.75â5.38, P < 0.001) were significant predictors of WHF. Chronic kidney disease (OR 3.17, 95% CI 1.16â9.58, P = 0.03), cystatin c (OR 1.88, 95% CI 1.00â3.53, P = 0.045), logarithmized proâadrenomedullin (OR 2.90, 95% CI 1.19â7.19, P = 0.019), and tricuspid valve regurgitation (OR 10.44, 95% CI 2.61â70.00, P = 0.003) were significantly with newâonset CS. Conclusions: Half of patients admitted with AHF experience WHF or newâonset CS. Chronic kidney disease, tricuspid valve regurgitation, and elevated proâadrenomedullin concentrations predict these events. They could potentially serve as early warning signs for further deterioration in AHF patients
Sex differences in clinical characteristics and outcomes in patients undergoing heart transplantation
Aims: Whether sex affects selection for and outcomes after heart transplantation (HTx) remains unclear. We aimed to show sex differences in preâtransplant characteristics and outcomes after HTx. Methods and results: From 1995 to 2019, 49 200 HTx recipients were prospectively enrolled in the Organ Procurement and Transplantation Network. Logistic regression models were used to evaluate clinical characteristics by sex. Multivariable Cox regression models were fitted to assess sex differences in allâcause mortality, cardiovascular mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. In 49 200 patients (median age 55 years, interquartile range 46â62; 24.6% women), 49 732 events occurred during a median followâup of 8.1 years. Men were older than women, had more often ischaemic cardiomyopathy (odds ratio [OR] 3.26, 95% confidence interval [CI] 3.11â3.42; P < 0.001), and a higher burden of cardiovascular risk factors, whereas women had less malignancies (OR 0.47, CI 0.44â0.51; P < 0.001). Men were more often treated in intensive care unit (OR 1.24, CI 1.12â1.37; P < 0.001) with a higher need for ventilatory (OR 1.24, CI 1.17â1.32; P < 0.001) or VAD (OR 1.53, CI 1.45â1.63; P < 0.001) support. After multivariable adjustment, men had a higher risk for CAV (hazard ratio [HR] 1.21, CI 1.13â1.29; P < 0.001) and malignancy (HR 1.80, CI 1.62â2.00; P < 0.001). There were no differences in allâcause mortality, cardiovascular mortality, and graft failure between sexes. Conclusions: In this US transplant registry, men and women differed in preâtransplant characteristics. Male sex was independently associated with incident CAV and malignancy even after multivariable adjustment. Our results underline the need for better personalized postâHTx management and care
Chromium-based bcc-superalloys strengthened by iron supplements
Chromium alloys are being considered for next-generation concentrated solar power applications operating > 800 °C. Cr offers advantages in melting point, cost, and oxidation resistance. However, improvements in mechanical performance are needed. Here, Cr-based body-centred-cubic (bcc) alloys of the type Cr(Fe)-NiAl are investigated, leading to âbcc-superalloysâ comprising a bcc-Cr(Fe) matrix (ÎČ) strengthened by ordered-bcc NiAl intermetallic precipitates (ÎČâ), with iron additions to tailor the precipitate volume fraction and mechanical properties at high temperatures. Computational design using CALculation of PHAse Diagram (CALPHAD) predicts that Fe increases the solubility of Ni and Al, increasing precipitate volume fraction, which is validated experimentally. Nano-scale, highly-coherent B2-NiAl precipitates with lattice misfit ⌠0.1% are formed in the Cr(Fe) matrix. The Cr(Fe)-NiAl A2-B2 alloys show remarkably low coarsening rate (âŒ102 nm3/h at 1000 °C), outperforming ferritic-superalloys, cobalt- and nickel-based superalloys. Low interfacial energies of ⌠40/20 mJ/m2 at 1000/1200 °C are determined based on the coarsening kinetics. The low coarsening rates are principally attributed to the low solubility of Ni and Al in the Cr matrix. The alloys show high compressive yield strength of âŒ320 MPa at 1000 °C. The Fe-modified alloy exhibits resistance to age softening, related to the low coarsening rate as well as the relatively stable Orowan strengthening as a function of precipitate radius. Microstructure tailoring with Fe additions offers a new design route to improve the balance of properties in âCr-superalloysâ, accelerating their development as a new class of high-temperature materials
Chromium-based bcc-superalloys strengthened by iron supplements
Chromium alloys are being considered for next-generation concentrated solar power applications operating > 800 °C. Cr offers advantages in melting point, cost, and oxidation resistance. However, improvements in mechanical performance are needed. Here, Cr-based body-centred-cubic (bcc) alloys of the type Cr(Fe)-NiAl are investigated, leading to âbcc-superalloysâ comprising a bcc-Cr(Fe) matrix (ÎČ) strengthened by ordered-bcc NiAl intermetallic precipitates (ÎČâ), with iron additions to tailor the precipitate volume fraction and mechanical properties at high temperatures. Computational design using CALculation of PHAse Diagram (CALPHAD) predicts that Fe increases the solubility of Ni and Al, increasing precipitate volume fraction, which is validated experimentally. Nano-scale, highly-coherent B2-NiAl precipitates with lattice misfit ⌠0.1% are formed in the Cr(Fe) matrix. The Cr(Fe)-NiAl A2-B2 alloys show remarkably low coarsening rate (âŒ102 nm3/h at 1000 °C), outperforming ferritic-superalloys, cobalt- and nickel-based superalloys. Low interfacial energies of ⌠40/20 mJ/m2 at 1000/1200 °C are determined based on the coarsening kinetics. The low coarsening rates are principally attributed to the low solubility of Ni and Al in the Cr matrix. The alloys show high compressive yield strength of âŒ320 MPa at 1000 °C. The Fe-modified alloy exhibits resistance to age softening, related to the low coarsening rate as well as the relatively stable Orowan strengthening as a function of precipitate radius. Microstructure tailoring with Fe additions offers a new design route to improve the balance of properties in âCr-superalloysâ, accelerating their development as a new class of high-temperature materials
Comparison of Cardiovascular Risk Factors in European Population Cohorts for Predicting Atrial Fibrillation and Heart Failure, Their Subsequent Onset, and Death
Background: Differences in risk factors for atrial fibrillation (AF) and heart failure (HF) are incompletely understood. Aim of this study was to understand whether risk factors and biomarkers show different associations with incident AF and HF and to investigate predictors of subsequent onset and mortality. Methods and Results: In N=58 693 individuals free of AF/HF from 5 population-based European cohorts, Cox regressions were used to find predictors for AF, HF, subsequent onset, and mortality. Differences between associations were estimated using bootstrapping. Median follow-up time was 13.8 years, with a mortality of 15.7%. AF and HF occurred in 5.0% and 5.4% of the participants, respectively, with 1.8% showing subsequent onset. Age, male sex, myocardial infarction, body mass index, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) showed similar associations with both diseases. Antihypertensive medication and smoking were stronger predictors of HF than AF. Cholesterol, diabetes mellitus, and hsCRP (high-sensitivity C-reactive protein) were associated with HF, but not with AF. No variable was exclusively associated with AF. Population-attributable risks were higher for HF (75.6%) than for AF (30.9%). Age, male sex, body mass index, diabetes mellitus, and NT-proBNP were associated with subsequent onset, which was associated with the highest all-cause mortality risk. Conclusions: Common risk factors and biomarkers showed different associations with AF and HF, and explained a higher proportion of HF than AF risk. As the subsequent onset of both diseases was strongly associated with mortality, prevention needs to be rigorously addressed and remains challenging, as conventional risk factors explained o:nly 31% of AF risk
VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro
Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3-kinase activation. Recombinant human VEGF-A165b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons
CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology
Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/â mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/â mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/â mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/â brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.CAG was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number P50 HD103525. This work was funded by PID2020-112831GB-I00 AEI /10.13039/501100011033 (MN). SS was supported by a grant from the NIH/NINDS (K23NS119666). SWS is supported by the Hospital for Sick Children Foundation, Autism Speaks, and the University of Toronto McLaughlin Center. EM-G was supported by a grant from MICIU FPU18/06240. EVS. was supported by a grant from the NIH (EY025718). CRF was supported by the fund to support clinical research careers in the Region of Southern Denmark (Region Syddanmarks pulje for kliniske forskerkarriereforlĂžb).Peer reviewe
Electrochemically controlled self-assembled monolayers characterized with molecular and sub-molecular resolution
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