Platelet-leukocyte aggregate formation and inflammation in patients with pulmonary arterial hypertension and CTEPH.

Pulmonary hypertension (PH) is defined by increased mean pulmonary artery pressure, and the clinical classification includes five etiologies, of which we investigated subgroup 1, pulmonary arterial hypertension (PAH) and subgroup 4, chronic thrombotic and/or embolic disease (CTEPH). Platelets participate in both innate and adaptive immune responses and could possibly contribute to the suggested systemic inflammation associated with PAH. In this study, we utilized flow cytometry to analyze platelet activation and platelet-monocyte (PMA) and granulocyte (PGA) aggregates in PAH and CTEPH patients and healthy control subjects. The plasma concentration of proinflammatory cytokines was measured by multiplex electrochemiluminescence. Our main finding is that circulating platelets are activated in the circulation and form aggregates with both monocytes and granulocytes in patients with idiopathic PAH (IPAH), associated PAH (APAH) and pulmonary hypertension due to CTEPH. There was a strong correlation between the platelet activation, assessed as P-selectin, and the number of aggregates formed. IL-6, IL-8, IL-10 and TNF-α were increased in all PH subgroups as compared to healthy controls, and PMAs were associated with circulating IL-6, IL-8 and IL-10, whereas PGAs were associated with IL-6. The increased concentrations of platelet-leukocyte aggregates found in PAH/CTEPH patients might thus contribute to the inflammatory state in PH.

Role of Extracellular Vesicles in Pulmonary Arterial Hypertension: Modulation of Pulmonary Endothelial Function and Angiogenesis.

OBJECTIVE: Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results: Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P+, CD144+, and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein (P=0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVs evaded lysosomes (P<0.01). As oppose to HC, PAH EVs stimulated hPAEC activation and induced transcription and translation of VEGF-A (vascular endothelial growth factor A; P<0.05) and FGF (fibroblast growth factor; P<0.005) which were released in the cell supernatant. These proangiogenic proteins were higher in patient with PAH plasma compered with HC. PAH EVs induced a complex network of angiotubes in vitro, which was abolished by inhibitory PSGL-1antibody. Anti-PSGL-1 also inhibited EV-induced endothelial cell activation and PAH EV dependent increase of VEGF-A. CONCLUSIONS: Patients with PAH have higher levels of EVs harboring increased amounts of angiogenic proteins, which induce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.

Secondary prevention medications after coronary artery bypass grafting and long-term survival: a population-based longitudinal study from the SWEDEHEART registry.

AIMS: To evaluate the long-term use of secondary prevention medications [statins, ß-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and platelet inhibitors] after coronary artery bypass grafting (CABG) and the association between medication use and mortality. METHODS AND RESULTS: All patients who underwent isolated CABG in Sweden from 2006 to 2015 and survived at least 6 months after discharge were included (n = 28 812). Individual patient data from SWEDEHEART and other mandatory nationwide registries were merged. Multivariable Cox regression models using time-updated data on dispensed prescriptions were used to assess associations between medication use and long-term mortality. Statins were dispensed to 93.9% of the patients 6 months after discharge and to 77.3% 8 years later. Corresponding figures for ß-blockers were 91.0% and 76.4%, for RAAS inhibitors 72.9% and 65.9%, and for platelet inhibitors 93.0% and 79.8%. All medications were dispensed less often to patients ≥75 years. Treatment with statins [hazard ratio (HR) 0.56, 95% confidence interval (95% CI) 0.52-0.60], RAAS inhibitors (HR 0.78, 95% CI 0.73-0.84), and platelet inhibitors (HR 0.74, 95% CI 0.69-0.81) were individually associated with lower mortality risk after adjustment for age, gender, comorbidities, and use of other secondary preventive drugs (all P < 0.001). There was no association between ß-blockers and mortality risk (HR 0.97, 95% CI 0.90-1.06; P = 0.54). CONCLUSION: The use of secondary prevention medications after CABG was high early after surgery but decreased significantly over time. The results of this observational study, with inherent risk of selection bias, suggest that treatment with statins, RAAS inhibitors, and platelet inhibitors is essential after CABG whereas the routine use of ß-blockers may be questioned.

Betablockers and clinical outcome after surgical aortic valve replacement: a report from the SWEDEHEART registry.

OBJECTIVES: Previous reports suggest that betablockers appear non-beneficial after surgical aortic valve replacement (SAVR). This study aims to clarify the associations between betablockers and long-term outcome after SAVR. METHODS: All patients with isolated SAVR due to aortic stenosis in Sweden between 2006 and 2020, alive at 6 months after surgery, were included. Patients were identified in the SWEDEHEART registry, and records were merged with data from 3 other mandatory national registries. Association between dispensed betablockers and major adverse cardiovascular events (MACE) (all-cause mortality, myocardial infarction and stroke) was analyzed using Cox proportional hazards models, with time-updated data on medication and adjusted for age, sex and comorbidities at baseline. RESULTS: In total, 11 849 patients were included [median follow-up 5.4 years (range 0-13.5)]. Betablockers were prescribed to 79.7% of patients at baseline, decreasing to 62.2% after 5 years. Continuing treatment was associated with higher risk of MACE [adjusted hazard ratio 1.14 (95% confidence interval, CI 1.05-1.23)]. The association was consistent over subgroups based on age, sex and comorbidities except atrial fibrillation [hazard ratio (HR) 1.05 (95% CI 0.93-1.19)]. A sensitivity analysis including time-updated data on comorbidites attenuated the difference between the groups [HR 1.04 (95% CI 0.95-1.14, P = 0.33)]. CONCLUSIONS: Treatment with betablockers did not appear to be associated with inferior long-term outcome after SAVR, when adjusting for new concomitant diseases. Thus, it is likely that it is the underlying cardiac diseases that are associated with MACE rather than betablocker treatment.

The four-item PRECISE-DAPT score identifies coronary artery bypass grafting patients with increased risk for post-discharge major bleeding.

AIMS: Early identification of patients with increased bleeding risk increases the possibility to individualize antithrombotic treatment. We validated the PRECISE-DAPT score, originally developed to estimate bleeding risk in patients on dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), in coronary artery bypass grafting (CABG) patients. METHODS AND RESULTS: All patients who underwent first time, isolated CABG in Sweden 2009-2020 and survived until discharge were included. The four-item PRECISE-DAPT score, based on age, estimated glomerular filtration rate, preoperative haemoglobin concentration, and previous spontaneous bleeding, was calculated in patients discharged on DAPT (n = 6 838), or antiplatelet monotherapy (n = 15 406). High bleeding risk was defined as a score ≥ 25 in accordance with previous studies and major bleeding as hospitalization due to bleeding. Associations were assessed by C-statistics and Cox regression models.Major bleeding occurred during the first postoperative year in 130 patients (1.9%) in the DAPT group, and in 197 patients (1.3%) in the monotherapy group. The score identified 32.9% of the patients in the DAPT group and 38.2% in monotherapy groups as having high bleeding risk. The area under the ROC-curve for the score was 0.67 (95%CI 0.62-0.72) for DAPT and 0.71 (0.67-0.74) for monotherapy. The hazard ratio for high bleeding risk vs. very low risk was 4.14 (2.07-8.26) for DAPT patients, and 4.95 (2.61-9.39) for monotherapy patients, both p < 0.001. CONCLUSIONS: The PRECISE-DAPT identifies patients with increased risk for major bleeding after discharge following CABG with moderate accuracy. The accuracy is comparable to what previously has been reported for patients after PCI.

Postdischarge major bleeding, myocardial infarction, and mortality risk after coronary artery bypass grafting.

OBJECTIVE: To investigate the incidence and mortality risk associated with postdischarge major bleeding after coronary artery bypass grafting (CABG), and relate this to the incidence of, and mortality risk from, postdischarge myocardial infarction. METHODS: All patients undergoing first-time isolated CABG in Sweden in 2006-2017 and surviving 14 days after hospital discharge were included in a cohort study. Individual patient data from the SWEDEHEART Registry and five other mandatory nationwide registries were merged. Piecewise Cox proportional hazards models were used to investigate associations between major bleeding, defined as hospitalisation for bleeding, with subsequent mortality risk. Similar Cox proportional hazards models were used to investigate the association between postdischarge myocardial infarction and mortality risk. RESULTS: Among 36 633 patients, 2429 (6.6%) had a major bleeding event and 2231 (6.1%) had a myocardial infarction. Median follow-up was 6.0 (range 0-11) years. Major bleeding was associated with higher mortality risk <30 days (adjusted HR (aHR)=20.2 (95% CI 17.3 to 23.5)), 30-365 days (aHR=3.8 (95% CI 3.4 to 4.3)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event. Myocardial infarction was associated with higher mortality risk <30 days (aHR=20.0 (95% CI 16.7 to 23.8)), 30-365 days (aHR=4.1 (95% CI 3.6 to 4.8)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event. CONCLUSIONS: The increase in mortality risk associated with a postdischarge major bleeding after CABG is substantial and is similar to the mortality risk associated with a postdischarge myocardial infarction.

Statin treatment after surgical aortic valve replacement for aortic stenosis is associated with better long-term outcome.

OBJECTIVES: The aim of this study was to evaluate the association between statin use after surgical aortic valve replacement for aortic stenosis and long-term risk for major adverse cardiovascular events (MACEs) in a large population-based, nationwide cohort. METHODS: All patients who underwent isolated surgical aortic valve replacement due to aortic stenosis in Sweden 2006-2020 and survived 6 months after discharge were included. Individual patient data from 5 nationwide registries were merged. Primary outcome is MACE (defined as all-cause mortality, myocardial infarction or stroke). Multivariable Cox regression model adjusted for age, sex, comorbidities, valve type, operation year and secondary prevention medications is used to evaluate the association between time-updated dispense of statins and long-term outcome in the entire study population and in subgroups based on age, sex and comorbidities. RESULTS: A total of 11 894 patients were included. Statins were dispensed to 49.8% (5918/11894) of patients at baseline, and 51.0% (874/1713) after 10 years. At baseline, 3.6% of patients were dispensed low dose, 69.4% medium dose and 27.0% high-dose statins. After adjustments, ongoing statin treatment was associated with a reduced risk for MACE [adjusted hazard ratio 0.77 (95% confidence interval 0.71-0.83). P < 0.001], mainly driven by a reduction in all-cause mortality [adjusted hazard ratio, 0.70 (0.64-0.76)], P < 0.001. The results were consistent in all subgroups. CONCLUSIONS: The results suggest that statin therapy might be beneficial for patients undergoing surgical aortic valve replacement for aortic stenosis. Randomized controlled trials are warranted to establish causality between statin treatment and improved outcome.

Role of Salt Concentration in Stabilizing Charged Ni-Rich Cathode Interfaces in Li-Ion Batteries.

The cathode-electrolyte interphase (CEI) in Li-ion batteries plays a key role in suppressing undesired side reactions while facilitating Li-ion transport. Ni-rich layered cathode materials offer improved energy densities, but their high interfacial reactivities can negatively impact the cycle life and rate performance. Here we investigate the role of electrolyte salt concentration, specifically LiPF6 (0.5-5 m), in altering the interfacial reactivity of charged LiN0.8Mn0.1Co0.1O2 (NMC811) cathodes in standard carbonate-based electrolytes (EC/EMC vol %/vol % 3:7). Extended potential holds of NMC811/Li4Ti5O12 (LTO) cells reveal that the parasitic electrolyte oxidation currents observed are strongly dependent on the electrolyte salt concentration. X-ray photoelectron and absorption spectroscopy (XPS/XAS) reveal that a thicker LixPOyFz-/LiF-rich CEI is formed in the higher concentration electrolytes. This suppresses reactions with solvent molecules resulting in a thinner, or less-dense, reduced surface layer (RSL) with lower charge transfer resistance and lower oxidation currents at high potentials. The thicker CEI also limits access of acidic species to the RSL suppressing transition-metal dissolution into the electrolyte, as confirmed by nuclear magnetic resonance (NMR) spectroscopy and inductively coupled plasma optical emission spectroscopy (ICP-OES). This provides insight into the main degradation processes occurring at Ni-rich cathode interfaces in contact with carbonate-based electrolytes and how electrolyte formulation can help to mitigate these.

Distinguishing bulk redox from near-surface degradation in lithium nickel oxide cathodes.

Ni-rich layered oxide cathodes can deliver higher energy density batteries, but uncertainties remain over their charge compensation mechanisms and the degradation processes that limit cycle life. Trapped molecular O2 has been identified within LiNiO2 at high states of charge, as seen for Li-rich cathodes where excess capacity is associated with reversible oxygen redox. Here we show that bulk redox in LiNiO2 occurs by Ni-O rehybridization, lowering the electron density on O sites, but importantly without the involvement of molecular O2. Instead, trapped O2 is related to degradation at surfaces in contact with the electrolyte, and is accompanied by Ni reduction. O2 is removed on discharge, but excess Ni2+ persists forming a reduced surface layer, associated with impeded Li transport. This implicates the instability of delithiated LiNiO2 in contact with the electrolyte in surface degradation through O2 formation and Ni reduction, highlighting the importance of surface stabilisation strategies in suppressing LiNiO2 degradation.

Use of echocardiographic pulmonary acceleration time and estimated vascular resistance for the evaluation of possible pulmonary hypertension.

BACKGROUND: During ultrasound examination, tricuspid regurgitation may be absent or gives a signal that is not reliable for the estimation of systolic pulmonary pressure. The aim of this study was to evaluate the usefulness of acceleration time (AT) from the right ventricular outflow tract (RVOT) as an estimation of the trans-tricuspid valve gradient (TTVG) and to investigate the correlation between estimated and invasive pulmonary vascular resistance (PVR). METHODS: The AT was correlated to the TTVG measured with routine standard echocardiography in 121 patients. In a subgroup of 29 patients, systolic pulmonary pressure (SPAP) and mean pulmonary arterial pressure (MPAP) were obtained from recent right heart catheterization (RHC). RESULTS: We found no significant correlation between the estimation of right atrial pressure (RAP) by echocardiography and the RAP obtained by RHC. Estimated SPAP (TTGV + RAP mean from RHC) showed a good linear relation to invasively measured SPAP. TTVG and AT showed a non-linear relation, similar to SPAP and MPAP measured by catheterization and AT. For detection of SPAP above 38 mmHg a cut-off for AT of 100 ms resulted in a sensitivity of 89% and a specificity of 84%. For detection of MPAP above 25 mmHg a cut-off for AT of 100 ms resulted in similar sensitivity and specificity. Invasive PVR and the ratio of TTVG and the time velocity integral of the RVOT (TVI (RVOT) ) had a strong linear relation. CONCLUSIONS: Our study confirms that AT appears to be useful for the evaluation of pulmonary hypertension. In high risk patients, an AT of less than 100 ms indicates a high probability of pulmonary hypertension. Furthermore, PVR estimation by ultrasound seems preferably be done by using the ratio of TTVG and TVI RVOT.

Beta blockers and long-term outcome after coronary artery bypass grafting: a nationwide observational study.

AIMS: Beta blockers are associated with improved outcomes for selected patients with cardiovascular disease. We assessed long-term utilization of beta blockers after coronary artery bypass grafting (CABG) and its association with outcome. METHODS AND RESULTS: All 35 184 patients in Sweden who underwent first-time isolated CABG between 1 January 2006 and 31 December 2017 and were followed for at least 6 months were included in a nationwide observational study. Multivariable Cox regression models using time-updated data on dispensed prescriptions were used to assess associations between different types of beta blockers and outcomes. The primary outcome was major adverse cardiovascular events (MACEs), a composite of all-cause mortality, stroke, and myocardial infarction (MI). Subgroup analyses were performed in patients with and without previous MI, heart failure, and reduced left ventricular ejection fraction (LVEF). Median follow-up was 5.2 years (range 0-11). At baseline, 33 159 (94.2%) patients were dispensed beta blockers, 30 563 (92.2%) of which were cardioselective beta blockers. After 10 years, the dispensing of cardioselective beta blockers had declined to 73.7% of all patients. Ongoing treatment with cardioselective beta blockers was associated with a slight reduction in MACEs [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.89-0.98, P = 0.0063]. The reduction was largely driven by a reduced risk of MI (HR 0.83, 95% CI 0.75-0.92, P = 0.0003), while there was no significant reduction in all-cause mortality (HR 0.99, 95% CI 0.93-1.05) and stroke (HR 0.96, 95% CI 0.87-1.05). The reduced risk for MI was consistent in all the investigated subgroups. CONCLUSION: Ongoing treatment with cardioselective beta blockers after CABG is associated with a reduction in MACEs, mainly because of reduced long-term risk for MI. The association between cardioselective beta blockers and MI was consistent in patients with and patients without previous MI, heart failure, atrial fibrillation, or reduced LVEF.

Statins for secondary prevention and major adverse events after coronary artery bypass grafting.

OBJECTIVE: The objective of this study was to evaluate the association of statin use after coronary artery bypass grafting (CABG) and long-term adverse events in a large population-based, nationwide cohort. METHODS: All 35,193 patients who underwent first-time isolated CABG in Sweden from 2006 to 2017 and survived at least 6 months after surgery were included. Individual patient data from the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) and 4 other nationwide registries were merged. Multivariable Cox regression models adjusted for age, sex, comorbidities, and time-updated treatment with other secondary preventive medications were used to evaluate the associations between statin treatment and outcomes. The primary end point was major adverse cardiovascular events (MACE). Median follow-up time to MACE was 5.3 (interquartile range, 2.5-8.2) years. RESULTS: Statins were dispensed to 95.7% of the patients six months after discharge and to 78.9% after 10 years. At baseline, 1.4% of patients were prescribed low-, 57.6% intermediate-, and 36.7% high-dose statins. Ongoing statin treatment was associated with markedly reduced risk of MACE (adjusted hazard ratio [aHR], 0.56 [95% CI, 0.53-0.59]), all-cause mortality (aHR, 0.53 [95% CI, 0.50-0.56]), cardiovascular death (aHR, 0.54 [95% CI, 0.50-0.59]), myocardial infarction (aHR, 0.61 [95% CI, 0.55-0.69]), stroke (aHR, 0.66 [95% CI, 0.59-0.73]), new revascularization (aHR, 0.79 [95% CI, 0.70-0.88]), new angiography (aHR, 0.81 [95% CI, 0.74-0.88]), and dementia (aHR, 0.74 [95% CI, 0.65-0.85]; all P < .01), irrespective of the statin dose. CONCLUSIONS: Ongoing statin use was associated with a markedly reduced incidence of adverse events and mortality after CABG. Initiating and maintaining statin medication is essential in CABG patients.

Associations between medical therapy after surgical aortic valve replacement for aortic stenosis and long-term mortality: a report from the SWEDEHEART registry.

AIMS: The association between the use of statins, renin-angiotensin system (RAS) inhibitors, and/or ß-blockers and long-term mortality in patients with aortic stenosis (AS) who underwent surgical aortic valve replacement (SAVR) is unknown. METHODS AND RESULTS: All patients with AS who underwent isolated first-time SAVR in Sweden from 2006 to 2017 and survived 6 months after discharge were included. Individual patient data from four mandatory nationwide registries were merged. Cox proportional hazards models, with time-updated data on medication status and adjusted for age, sex, comorbidities, type of prosthesis, and year of surgery, were used to investigate associations between dispensed statins, RAS inhibitors, and ß-blockers and all-cause mortality. In total, 9553 patients were included, and the median follow-up time was 4.9 years (range 0-11); 1738 patients (18.2%) died during follow-up. Statins were dispensed to 49.1% and 49.0% of the patients within 6 months of discharge from the hospital and after 10 years, respectively. Corresponding figures were 51.4% and 53.9% for RAS inhibitors and 79.3% and 60.7% for ß-blockers. Ongoing treatment was associated with lower mortality risk for statins {adjusted hazard ratio (aHR) 0.67 [95% confidence interval (95% CI) 0.60-0.74]; P < 0.001} and RAS inhibitors [aHR 0.84 (0.76-0.93); P < 0.001] but not for ß-blockers [aHR 1.17 (1.05-1.30); P = 0.004]. The associations were robust in subgroups based on age, sex, and comorbidities (P for interactions >0.05). CONCLUSIONS: The results of this large population-based real-world study support the use of statins and RAS inhibitors for patients who underwent SAVR due to AS.

Five year risk assessment and treatment patterns in patients with chronic thromboembolic pulmonary hypertension.

AIMS: Repeated risk assessments and treatment patterns over long time are sparsely studied in chronic thromboembolic pulmonary hypertension (CTEPH); thus, we aimed to investigate changes in risk status and treatment patterns in incident patients with CTEPH over a 5 year period. METHODS AND RESULTS: Descriptive and explorative study including 311 patients diagnosed with CTEPH 2008-2019 from the Swedish pulmonary hypertension registry, stratified by pulmonary endarterectomy surgery (PEA). Risk and PH-specific treatment were assessed in surgically treated (PEA) and medically treated (non-PEA) patients at diagnosis and up to 5 years follow-up. Data are presented as median (Q1-Q3), count or per cent. Prior to surgery, 63% in the PEA-group [n = 98, age 64 (51-71) years, 37% female] used PH-specific treatment and 20, 69, and 10% were assessed as low, intermediate or high risk, respectively. After 1 year post-surgery, 34% had no PH-specific treatment or follow-up visit registered despite being alive at 5 years. Of patients with a 5 year visit (n = 23), 46% were at low and 54% at intermediate risk, while 91% used PH-specific treatment. In the non-PEA group [n = 213, age 72 (65-77) years, 56% female], 28% were assessed as low, 61% as intermediate and 11% as high risk. All patients at high risk versus 50% at low risk used PH-specific treatment. The 1 year mortality was 6%, while the risk was unchanged in 57% of the patients; 14% improved from intermediate to low risk, and 1% from high to low risk. At 5 years, 27% had a registered visit and 28% had died. Of patients with a 5 year visit (n = 58), 38% were at low, 59% at intermediate and 1% at high risk, and 86% used PH-specific treatment. CONCLUSIONS: Risk status assessed pre-surgery did not foresee long-term post-PEA risk and pre-surgery PH-specific treatment did not foresee long-term post-PEA treatment. Medically treated CTEPH patients tend to remain at the same risk over time, suggesting a need for improved treatment strategies in this group.

Cycle-Induced Interfacial Degradation and Transition-Metal Cross-Over in LiNi0.8Mn0.1Co0.1O2-Graphite Cells.

Ni-rich lithium nickel manganese cobalt (NMC) oxide cathode materials promise Li-ion batteries with increased energy density and lower cost. However, higher Ni content is accompanied by accelerated degradation and thus poor cycle lifetime, with the underlying mechanisms and their relative contributions still poorly understood. Here, we combine electrochemical analysis with surface-sensitive X-ray photoelectron and absorption spectroscopies to observe the interfacial degradation occurring in LiNi0.8Mn0.1Co0.1O2-graphite full cells over hundreds of cycles between fixed cell voltages (2.5-4.2 V). Capacity losses during the first ∼200 cycles are primarily attributable to a loss of active lithium through electrolyte reduction on the graphite anode, seen as thickening of the solid-electrolyte interphase (SEI). As a result, the cathode reaches ever-higher potentials at the end of charge, and with further cycling, a regime is entered where losses in accessible NMC capacity begin to limit cycle life. This is accompanied by accelerated transition-metal reduction at the NMC surface, thickening of the cathode electrolyte interphase, decomposition of residual lithium carbonate, and increased cell impedance. Transition-metal dissolution is also detected through increased incorporation into and thickening of the SEI, with Mn found to be initially most prevalent, while the proportion of Ni increases with cycling. The observed evolution of anode and cathode surface layers improves our understanding of the interconnected nature of the degradation occurring at each electrode and the impact on capacity retention, informing efforts to achieve a longer cycle lifetime in Ni-rich NMCs.

Electrolyte Reactivity at the Charged Ni-Rich Cathode Interface and Degradation in Li-Ion Batteries.

The chemical and electrochemical reactions at the positive electrode-electrolyte interface in Li-ion batteries are hugely influential on cycle life and safety. Ni-rich layered transition metal oxides exhibit higher interfacial reactivity than their lower Ni-content analogues, reacting via mechanisms that are poorly understood. Here, we study the pivotal role of the electrolyte solvent, specifically cyclic ethylene carbonate (EC) and linear ethyl methyl carbonate (EMC), in determining the interfacial reactivity at charged LiNi0.33Mn0.33Co0.33O2 (NMC111) and LiNi0.8Mn0.1Co0.1O2 (NMC811) cathodes by using both single-solvent model electrolytes and the mixed solvents used in commercial cells. While NMC111 exhibits similar parasitic currents with EC-containing and EC-free electrolytes during high voltage holds in NMC/Li4Ti5O12 (LTO) cells, this is not the case for NMC811. Online gas analysis reveals that the solvent-dependent reactivity for Ni-rich cathodes is related to the extent of lattice oxygen release and accompanying electrolyte decomposition, which is higher for EC-containing than EC-free electrolytes. Combined findings from electrochemical impedance spectroscopy (EIS), TEM, solution NMR, ICP, and XPS reveal that the electrolyte solvent has a profound impact on the degradation of the Ni-rich cathode and the electrolyte. Higher lattice oxygen release with EC-containing electrolytes is coupled with higher cathode interfacial impedance, a thicker oxygen-deficient rock-salt surface reconstruction layer, more electrolyte solvent and salt breakdown, and higher amounts of transition metal dissolution. These processes are suppressed in the EC-free electrolyte, highlighting the incompatibility between Ni-rich cathodes and conventional electrolyte solvents. Finally, new mechanistic insights into the chemical oxidation pathways of electrolyte solvents and, critically, the knock-on chemical and electrochemical reactions that further degrade the electrolyte and electrodes curtailing battery lifetime are provided.

Revealing solid electrolyte interphase formation through interface-sensitive Operando X-ray absorption spectroscopy.

The solid electrolyte interphase (SEI) that forms on Li-ion battery anodes is critical to their long-term performance, however observing SEI formation processes at the buried electrode-electrolyte interface is a significant challenge. Here we show that operando soft X-ray absorption spectroscopy in total electron yield mode can resolve the chemical evolution of the SEI during electrochemical formation in a Li-ion cell, with nm-scale interface sensitivity. O, F, and Si K-edge spectra, acquired as a function of potential, reveal when key reactions occur on high-capacity amorphous Si anodes cycled with and without fluoroethylene carbonate (FEC). The sequential formation of inorganic (LiF) and organic (-(C=O)O-) components is thereby revealed, and results in layering of the SEI. The addition of FEC leads to SEI formation at higher potentials which is implicated in the rapid healing of SEI defects and the improved cycling performance observed. Operando TEY-XAS offers new insights into the formation mechanisms of electrode-electrolyte interphases and their stability for a wide variety of electrode materials and electrolyte formulations.

Renin-angiotensin system inhibition and outcome after coronary artery bypass grafting: A population-based study from the SWEDEHEART registry.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors are recommended postoperatively to coronary artery bypass grafting (CABG) patients with reduced left ventricular function, diabetes, hypertension or previous myocardial infarction, but not to remaining patients. The aim of the study was to assess the long-term utilization of RAS inhibitors after CABG in patients with and without indication for treatment, and its association with outcome. METHODS: All patients (n = 28,782) not meeting exclusion criterion in Sweden who underwent isolated first time CABG from 2006 to 2015 were included using nationwide registries. The association between treatment and outcome was assessed using adjusted Cox regression models with time-updated data on medications. The primary outcome was major adverse cardiovascular events (MACE), defined as all-cause mortality, stroke and/or myocardial infarction. RESULTS: At baseline 26,284 (91.3%) of the patients had at least one indication for RAS inhibition while 2498 (8.7%) had not. RAS inhibitors were dispensed to 77.0% and 29.7% of patients with and without indication respectively. Dispense declined over time. RAS inhibition was associated with a reduction in MACE in the whole study population (adjusted hazard ratio (aHR) 0.88, 95% confidence interval (95% CI) 0.83-0.93, p < 0.0001), and in patients with (aHR 0.87 95% CI: 0.82-0.93, p < 0.0001) and without indication (aHR 0.75, 95% CI: 0.58-0.98, p = 0.034). CONCLUSIONS: RAS inhibition is underutilized after CABG. The use of RAS inhibitors was associated with a reduction in MACE, both in patients with and without indication for treatment. The results suggest that RAS inhibition is beneficial for all CABG patients. Randomized controlled trials are necessary to confirm this hypothesis.

Comparison of Midterm Outcomes Associated With Aspirin and Ticagrelor vs Aspirin Monotherapy After Coronary Artery Bypass Grafting for Acute Coronary Syndrome.

Importance: Guidelines recommend dual antiplatelet therapy after coronary artery bypass grafting (CABG) for patients with acute coronary syndrome (ACS). However, the evidence for these recommendations is weak. Objective: To compare midterm outcomes after CABG in patients with ACS treated postoperatively with acetylsalicylic acid (ASA) and ticagrelor or with ASA monotherapy. Design, Setting, and Participants: This cohort study used merged data from several national registries of Swedish patients who were diagnosed with ACS and subsequently underwent CABG. All included patients underwent isolated CABG in Sweden between 2012 and 2017 with an ACS diagnosis less than 6 weeks before the procedure, survived 14 days after discharge from hospital, and were treated postoperatively with ASA plus ticagrelor or ASA monotherapy. A multivariable Cox regression model was used for the main analysis, and propensity score-matched models were performed as sensitivity analysis. Data were analyzed between May and September 2020. Exposures: Postoperative antiplatelet treatment, defined as filled prescriptions, with either ASA and ticagrelor or ASA only. Main Outcomes and Measures: Major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, and stroke, and major bleeding, at 12 months and at the end of follow-up. Results: A total of 6558 patients (5281 [80.5%] men; mean [SD] age at surgery, 67.6 [9.3] years) were included; 1813 (27.6%) were treated with ASA plus ticagrelor and 4745 (72.4%) were treated with ASA monotherapy. Crude MACE rate was 3.0 per 100 person years (95% CI, 2.5-3.6 per 100 person years) in the ASA plus ticagrelor group and 3.8 per 100 person years (95% CI, 3.5-4.1 per 100 person years) in the ASA group. After adjustment, there was no significant difference in MACE risk between ASA plus ticagrelor vs ASA only, neither during the first 12 months (adjusted hazard ratio [aHR], 0.84; 95% CI, 0.58-1.21; P = .34) or during total follow-up (aHR, 0.89; 95% CI, 0.71-1.11; P = .29). The use of ASA plus ticagrelor was associated with a significantly increased risk for major bleeding during the first 12 months (aHR, 1.90; 95% CI, 1.16-3.13; P = .011). Sensitivity analyses confirmed the results. Conclusions and Relevance: In patients with ACS who survived 2 weeks after CABG, no significant difference in the risk of death or ischemic events could be demonstrated between ASA plus ticagrelor and patients treated with ASA only, while the risk for major bleeding was higher in patients treated with ASA plus ticagrelor. Sufficiently powered prospective randomized trials comparing different antiplatelet therapy strategies after CABG are warranted.

Ipsilesional Mu Rhythm Desynchronization Correlates With Improvements in Affected Hand Grip Strength and Functional Connectivity in Sensorimotor Cortices Following BCI-FES Intervention for Upper Extremity in Stroke Survivors.

Stroke is a leading cause of acquired long-term upper extremity motor disability. Current standard of care trajectories fail to deliver sufficient motor rehabilitation to stroke survivors. Recent research suggests that use of brain-computer interface (BCI) devices improves motor function in stroke survivors, regardless of stroke severity and chronicity, and may induce and/or facilitate neuroplastic changes associated with motor rehabilitation. The present sub analyses of ongoing crossover-controlled trial NCT02098265 examine first whether, during movements of the affected hand compared to rest, ipsilesional Mu rhythm desynchronization of cerebral cortical sensorimotor areas [Brodmann's areas (BA) 1-7] is localized and tracks with changes in grip force strength. Secondly, we test the hypothesis that BCI intervention results in changes in frequency-specific directional flow of information transmission (direct path functional connectivity) in BA 1-7 by measuring changes in isolated effective coherence (iCoh) between cerebral cortical sensorimotor areas thought to relate to electrophysiological signatures of motor actions and motor learning. A sample of 16 stroke survivors with right hemisphere lesions (left hand motor impairment), received a maximum of 18-30 h of BCI intervention. Electroencephalograms were recorded during intervention sessions while outcome measures of motor function and capacity were assessed at baseline and completion of intervention. Greater desynchronization of Mu rhythm, during movements of the impaired hand compared to rest, were primarily localized to ipsilesional sensorimotor cortices (BA 1-7). In addition, increased Mu desynchronization in the ipsilesional primary motor cortex, Post vs. Pre BCI intervention, correlated significantly with improvements in hand function as assessed by grip force measurements. Moreover, the results show a significant change in the direction of causal information flow, as measured by iCoh, toward the ipsilesional motor (BA 4) and ipsilesional premotor cortices (BA 6) during BCI intervention. Significant iCoh increases from ipsilesional BA 4 to ipsilesional BA 6 were observed in both Mu [8-12 Hz] and Beta [18-26 Hz] frequency ranges. In summary, the present results are indicative of improvements in motor capacity and behavior, and they are consistent with the view that BCI-FES intervention improves functional motor capacity of the ipsilesional hemisphere and the impaired hand.