Left Atrial Roof Enlargement Is a Distinct Feature of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: It remains unknown to what extent intrinsic atrial cardiomyopathy or left ventricular diastolic dysfunction drive atrial remodeling and functional failure in heart failure with preserved ejection fraction (HFpEF). Computational 3-dimensional (3D) models fitted to cardiovascular magnetic resonance allow state-of-the-art anatomic and functional assessment, and we hypothesized to identify a phenotype linked to HFpEF. METHODS: Patients with exertional dyspnea and diastolic dysfunction on echocardiography (E/e', >8) were prospectively recruited and classified as HFpEF or noncardiac dyspnea based on right heart catheterization. All patients underwent rest and exercise-stress right heart catheterization and cardiovascular magnetic resonance. Computational 3D anatomic left atrial (LA) models were generated based on short-axis cine sequences. A fully automated pipeline was developed to segment cardiovascular magnetic resonance images and build 3D statistical models of LA shape and find the 3D patterns discriminant between HFpEF and noncardiac dyspnea. In addition, atrial morphology and function were quantified by conventional volumetric analyses and deformation imaging. A clinical follow-up was conducted after 24 months for the evaluation of cardiovascular hospitalization. RESULTS: Beyond atrial size, the 3D LA models revealed roof dilation as the main feature found in masked HFpEF (diagnosed during exercise-stress only) preceding a pattern shift to overall atrial size in overt HFpEF (diagnosed at rest). Characteristics of the 3D model were integrated into the LA HFpEF shape score, a biomarker to characterize the gradual remodeling between noncardiac dyspnea and HFpEF. The LA HFpEF shape score was able to discriminate HFpEF (n=34) to noncardiac dyspnea (n=34; area under the curve, 0.81) and was associated with a risk for atrial fibrillation occurrence (hazard ratio, 1.02 [95% CI, 1.01-1.04]; P=0.003), as well as cardiovascular hospitalization (hazard ratio, 1.02 [95% CI, 1.00-1.04]; P=0.043). CONCLUSIONS: LA roof dilation is an early remodeling pattern in masked HFpEF advancing to overall LA enlargement in overt HFpEF. These distinct features predict the occurrence of atrial fibrillation and cardiovascular hospitalization. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621.

Incretin-based therapy and the risk of diabetic foot ulcers and related events.

AIM: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). METHODS: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. RESULTS: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. CONCLUSIONS: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Diagnostic criteria and long-term outcomes in AIH-PBC variant syndrome under combination therapy.

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043). Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

Obtaining Robust Density Functional Tight-Binding Parameters for Solids across the Periodic Table.

The density functional tight-binding (DFTB) approach allows electronic structure-based simulations at length and time scales far beyond what is possible with first-principles methods. This is achieved by using minimal basis sets and empirical approximations. Unfortunately, the sparse availability of parameters across the periodic table is a significant barrier to the use of DFTB in many cases. We therefore propose a workflow that allows the robust and consistent parametrization of DFTB across the periodic table. Importantly, our approach requires no element-pairwise parameters so that the parameters can be used for all element combinations and are readily extendable. This is achieved by parametrizing all elements on a consistent set of artificial homoelemental crystals, spanning a wide range of coordination environments. The transferability of the resulting periodic table baseline parameters to multielement systems and unknown structures is explored and the model is extensively benchmarked against previous specialized and general DFTB parametrizations.

Attosecond chronoscopy of the photoemission near a bandgap of a single-element layered dielectric.

We report on the energy dependence of the photoemission time delay from the single-element layered dielectric HOPG (highly oriented pyrolytic graphite). This system offers the unique opportunity to directly observe the Eisenbud-Wigner-Smith (EWS) time delays related to the bulk electronic band structure without being strongly perturbed by ubiquitous effects of transport, screening, and multiple scattering. We find the experimental streaking time shifts to be sensitive to the modulation of the density of states in the high-energy region (E ≈ 100 eV) of the band structure. The present attosecond chronoscopy experiments reveal an energy-dependent increase of the photoemission time delay when the final state energy of the excited electrons lies in the vicinity of the bandgap providing information difficult to access by conventional spectroscopy. Accompanying simulations further corroborate our interpretation.

Plasmodium LCCL domain-containing modular proteins have their origins in the ancestral alveolate.

Plasmodium species encode a unique set of six modular proteins named LCCL lectin domain adhesive-like proteins (LAPs) that operate as a complex and that are essential for malaria parasite transmission from mosquito to vertebrate. LAPs possess complex architectures obtained through unique assemblies of conserved domains associated with lipid, protein and carbohydrate interactions, including the name-defining LCCL domain. Here, we assessed the prevalence of Plasmodium LAP orthologues across eukaryotic life. Our findings show orthologous conservation in all apicomplexans, with lineage-specific repertoires acquired through differential lap gene loss and duplication. Besides Apicomplexa, LAPs are found in their closest relatives: the photosynthetic chromerids, which encode the broadest repertoire including a novel membrane-bound LCCL protein. LAPs are notably absent from other alveolate lineages (dinoflagellates, perkinsids and ciliates), but are encoded by predatory colponemids, a sister group to the alveolates. These results reveal that the LAPs are much older than previously thought and pre-date not only the Apicomplexa but the Alveolata altogether.

Gender-specific aspects of socialisation and risk of cardiovascular disease among community-dwelling older adults: a prospective cohort study using machine learning algorithms and a conventional method.

BACKGROUND: Gender influences cardiovascular disease (CVD) through norms, social relations, roles and behaviours. This study identified gender-specific aspects of socialisation associated with CVD. METHODS: A longitudinal study was conducted, involving 9936 (5,231 women and 4705 men) initially healthy, community-dwelling Australians aged 70 years or more from the ASPirin in Reducing Events in the Elderly (ASPREE) study and ASPREE Longitudinal Study of Older Persons, with a median follow-up time of 6.4 years. Variable categorisation, variable selection (using machine learning (ML) models; Elastic Net and extreme gradient boosting) and Cox-regression were employed separately by binary gender to identity socialisation factors (n=25 considered) associated with CVD. RESULTS: Different socialisation factors were identified using the ML models. In the Cox model, for both genders, being married/partnered was associated with a reduced risk of CVD (men: HR 0.76, 95% CI 0.60 to 0.96; women: HR 0.67, 95% CI 0.58 to 0.95). For men, having 3-8 relatives they felt close to and could call on for help (HR 0.76, 95% CI 0.58 to 0.99; reference <3 relatives), having 3-8 relatives they felt at ease talking with about private matters (HR 0.70, 95% CI 0.55 to 0.90; reference <3 relatives) or playing games such as chess or cards (HR 0.82, 95% CI 0.67 to 1.00) was associated with reduced risk of CVD. For women, living with others (HR 0.71, 95% CI 0.55 to 0.91) or having ≥3 friends they felt at ease talking with about private matters (HR 0.74, 95% CI 0.58 to 0.95; reference <3 friends) was associated with a lower risk of CVD. CONCLUSIONS: This study demonstrates the need to prioritise gender-specific social factors to improve cardiovascular health in older adults.

CMR-based cardiac phenotyping in different forms of heart failure.

Heart failure (HF) is a heterogenous disease requiring precise diagnostics and knowledge of pathophysiological processes. Since structural and functional imaging data are scarce we hypothesized that cardiac magnetic resonance (CMR)-based analyses would provide accurate characterization and mechanistic insights into different HF groups comprising preserved (HFpEF), mid-range (HFmrEF) and reduced ejection fraction (HFrEF). 22 HFpEF, 17 HFmrEF and 15 HFrEF patients as well as 19 healthy volunteers were included. CMR image assessment contained left atrial (LA) and left ventricular (LV) volumetric evaluation as well as left atrioventricular coupling index (LACI). Furthermore, CMR feature-tracking included LV and LA strain in terms of reservoir (Es), conduit (Ee) and active boosterpump (Ea) function. CMR-based tissue characterization comprised T1 mapping as well as late-gadolinium enhancement (LGE) analyses. HFpEF patients showed predominant atrial impairment (Es 20.8%vs.25.4%, p = 0.02 and Ee 8.3%vs.13.5%, p = 0.001) and increased LACI compared to healthy controls (14.5%vs.23.3%, p = 0.004). Patients with HFmrEF showed LV enlargement but mostly preserved LA function with a compensatory increase in LA boosterpump (LA Ea: 15.0%, p = 0.049). In HFrEF LA and LV functional impairment was documented (Es: 14.2%, Ee: 5.4% p < 0.001 respectively; Ea: 8.8%, p = 0.02). This was paralleled by non-invasively assessed progressive fibrosis (T1 mapping and LGE; HFrEF > HFmrEF > HFpEF). CMR-imaging reveals insights into HF phenotypes with mainly atrial affection in HFpEF, ventricular affection with atrial compensation in HFmrEF and global impairment in HFrEF paralleled by progressive LV fibrosis. These data suggest a necessity for a personalized HF management based on imaging findings for future optimized patient management.

Testosterone and the risk of incident atrial fibrillation in older men: further analysis of the ASPREE study.

Background: A cardiovascular safety trial of testosterone in men with cardiovascular risk factors or disease found no difference in rates of major adverse cardiovascular events (MACE) or death but noted more atrial fibrillation (AF) events in testosterone-treated men. We investigated the relationship between endogenous testosterone concentrations with risk of developing AF in healthy older men. Methods: Post-hoc analysis of 4570 male participants in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Men were aged ≥ 70 years, had no history of cardiovascular disease (including AF), thyroid disease, prostate cancer, dementia, or life-threatening illnesses. Risk of AF was modelled using Cox proportional hazards regression. Findings: Median (IQR) age was 73.7 (71.6-77.1) years and median (IQR) follow-up 4.4 (3.3-5.5) years, during which 286 men developed AF (15.3 per 1000 participant-years). Baseline testosterone was higher in men who developed incident AF compared men who did not [17.0 (12.4-21.2) vs 15.7 (12.2-20.0) nmol/L]. There was a non-linear association of baseline testosterone with incident AF. The risk for AF was higher in men with testosterone in quintiles (Q) 4&5 (Q4:Q3, HR = 1.91; 95%CI = 1.29-2.83 and Q5:Q3HR = 1.98; 95%CI = 1.33-2.94). Results were similar after excluding men who experienced MACE or heart failure during follow-up. Interpretation: Circulating testosterone concentrations within the high-normal range are independently associated with an increased risk of incident AF amongst healthy older men. This suggests that AF may be an adverse consequence of high-normal total testosterone concentrations. Funding: National Institute on Aging and National Cancer Institute at the National Institutes of Health; Australian Government (NHMRC, CSIRO); Monash University; and AlfredHealth.

Pneumothorax risk reduction during CT-guided lung biopsy - Effect of fluid application to the pleura before lung puncture and the gravitational effect of pleural pressure.

PURPOSE: This study investigated strategies to reduce pneumothorax risk in CT-guided lung biopsy. The approach involved administering 10 ml of 1 % lidocaine fluid in the subpleural or pleural space before lung puncture and utilizing the gravitational effect of pleural pressure with specific patient positioning. METHOD: We retrospectively analyzed 72 percutaneous CT-guided lung biopsies performed at a single center between January 2020 and April 2023. These were grouped based on fluid administration during the biopsy and whether the biopsies were conducted in dependent or non-dependent lung regions. Confounding factors like patient demographics, lesion characteristics, and procedural details were assessed. Patient characteristics and the occurrence of pneumothoraces were compared using a Kurskal-Wallis test for continuous variables and a Fisher's exact test for categorical variables. Multivariable logistic regression was used to identify potential confounders. RESULTS: Subpleural or pleural fluid administration and performing biopsies in dependent lung areas were significantly linked to lower peri-interventional pneumothorax incidence (n = 15; 65 % without fluid in non-dependent areas, n = 5; 42 % without fluid in dependent areas, n = 5; 36 % with fluid in non-dependent areas,n = 0; 0 % with fluid in dependent areas; p = .001). Even after adjusting for various factors, biopsy in dependent areas and fluid administration remained independently associated with reduced pneumothorax risk (OR 0.071, p<=.01 for lesions with fluid administration; OR 0.077, p = .016 for lesions in dependent areas). CONCLUSIONS: Pre-puncture fluid administration to the pleura and consideration of gravitational effects during patient positioning can effectively decrease pneumothorax occurrences in CT-guided lung biopsy.

Velocity-compensated intravoxel incoherent motion of the human calf muscle.

PURPOSE: To determine whether intravoxel incoherent motion (IVIM) describes the blood perfusion in muscles better, assuming pseudo diffusion (Bihan Model 1) or ballistic motion (Bihan Model 2). METHODS: IVIM parameters were measured in 18 healthy subjects with three different diffusion gradient time profiles (bipolar with two diffusion times and one with velocity compensation) and 17 b-values (0-600 s/mm2) at rest and after muscle activation. The diffusion coefficient, perfusion fraction, and pseudo-diffusion coefficient were estimated with a segmented fit in the gastrocnemius medialis (GM) and tibialis anterior (TA) muscles. RESULTS: Velocity-compensated gradients resulted in a decreased perfusion fraction (6.9% ± 1.4% vs. 4.4% ± 1.3% in the GM after activation) and pseudo-diffusion coefficient (0.069 ± 0.046 mm2/s vs. 0.014 ± 0.006 in the GM after activation) compared to the bipolar gradients with the longer diffusion encoding time. Increased diffusion coefficients, perfusion fractions, and pseudo-diffusion coefficients were observed in the GM after activation for all gradient profiles. However, the increase was significantly smaller for the velocity-compensated gradients. A diffusion time dependence was found for the pseudo-diffusion coefficient in the activated muscle. CONCLUSION: Velocity-compensated diffusion gradients significantly suppress the IVIM effect in the calf muscle, indicating that the ballistic limit is mostly reached, which is supported by the time dependence of the pseudo-diffusion coefficient.

Operando Characterization and Molecular Simulations Reveal the Growth Kinetics of Graphene on Liquid Copper During Chemical Vapor Deposition.

In recent years, liquid metal catalysts have emerged as a compelling choice for the controllable, large-scale, and high-quality synthesis of two-dimensional materials. At present, there is little mechanistic understanding of the intricate catalytic process, though, of its governing factors or what renders it superior to growth at the corresponding solid catalysts. Here, we report on a combined experimental and computational study of the kinetics of graphene growth during chemical vapor deposition on a liquid copper catalyst. By monitoring the growing graphene flakes in real time using in situ radiation-mode optical microscopy, we explore the growth morphology and kinetics over a wide range of CH4-to-H2 pressure ratios and deposition temperatures. Constant growth rates of the flakes' radius indicate a growth mode limited by precursor attachment, whereas methane-flux-dependent flake shapes point to limited precursor availability. Large-scale free energy simulations enabled by an efficient machine-learning moment tensor potential trained to density functional theory data provide quantitative barriers for key atomic-scale growth processes. The wealth of experimental and theoretical data can be consistently combined into a microkinetic model that reveals mixed growth kinetics that, in contrast to the situation at solid Cu, is partly controlled by precursor attachment alongside precursor availability. Key mechanistic aspects that directly point toward the improved graphene quality are a largely suppressed carbon dimer attachment due to the facile incorporation of this precursor species into the liquid surface and a low-barrier ring-opening process that self-heals 5-membered rings resulting from remaining dimer attachments.

Impact of Quantitative ST-T Analysis in Patients with Suspected Myocardial Infarction Presenting with Right Bundle Branch Block.

BACKGROUND: While left bundle branch block (LBBB) is a well-known risk feature in patients with acute myocardial infarction, and a rapid invasive management is recommended, data supporting this strategy for patients with right bundle branch block (RBBB) is less robust. METHODS: In total, 2139 patients with suspected ST-elevation myocardial infarction (STEMI) were triaged to acute coronary angiography based on a prehospital 12-lead electrocardiogram (ECG). Sensitivity and specificity for STEMI-ECG criteria were compared in RBBB and non-BBB patients. Adjusted hazard ratios for 1-year overall mortality were computed. RESULTS: STEMI was adjudicated in 1832/2139 (85.6%) of all patients and in 102/117 (87.2%) of RBBB patients. ST-segment deviation followed typical ST-T patterns in most RBBB patients. Of 17 RBBB patients without significant ST changes, STEMI was adjudicated in 14 (82%). Diagnostic accuracy of STEMI criteria was comparable in RBBB and non-RBBB patients for inferior (sensitivity: 51.1% vs 59.1%, P = .14; specificity: 66.7% vs 52.1%, P = .33) and anterior STEMI (sensitivity: 35.2% vs 36.6%, P = .80; specificity: 58.3% vs 49.5%, P = .55). Diagnostic performance was lower for lateral STEMI in RBBB patients (sensitivity: 14.8% vs 4.4%, P = .001; specificity: 75.0% vs 98.4%, P < .001). Patients with RBBB had higher 1-year mortality compared with non-BBB patients (hazard ratio 2.3%; 95% confidence interval, 1.25-4.21. CONCLUSION: ECG criteria used for detection of STEMI showed comparable diagnostic accuracy in RBBB and non-BBB patients. However, STEMI was frequently present in RBBB patients not fulfilling diagnostic ECG criteria. RBBB patients showed poorer outcome after 1 year. Consequently, the presence of RBBB in suspected STEMI cases signifies a high-risk feature, aligning with established guidelines.

Neural graph distance embedding for molecular geometry generation.

This article introduces neural graph distance embedding (nGDE), a method for generating 3D molecular geometries. Leveraging a graph neural network trained on the OE62 dataset of molecular geometries, nGDE predicts interatomic distances based on molecular graphs. These distances are then used in multidimensional scaling to produce 3D geometries, subsequently refined with standard bioorganic forcefields. The machine learning-based graph distance introduced herein is found to be an improvement over the conventional shortest path distances used in graph drawing. Comparative analysis with a state-of-the-art distance geometry method demonstrates nGDE's competitive performance, particularly showcasing robustness in handling polycyclic molecules-a challenge for existing methods.

Impact of epicardial adipose tissue on cardiac function and morphology in patients with diastolic dysfunction.

AIMS: This study aimed to identify the impact of increased epicardial adipose tissue (EAT) and its regional distribution on cardiac function in patients with diastolic dysfunction. METHODS AND RESULTS: Sixty-eight patients with exertional dyspnoea (New York Heart Association ≥II), preserved ejection fraction (≥50%), and diastolic dysfunction (E/e' ≥ 8) underwent rest and stress right heart catheterization, transthoracic echocardiography, and cardiovascular magnetic resonance (CMR). EAT volumes were depicted from CMR short-axis stacks. First, the impact of increased EAT above the median was investigated. Second, the association of ventricular and atrial EAT with myocardial deformation at rest and during exercise stress was analysed in a multivariable regression analysis. Patients with high EAT had higher HFA-PEFF and H2FPEFF scores as well as N-terminal prohormone of brain natriuretic peptide levels (all P < 0.048). They were diagnosed with manifest heart failure with preserved ejection fraction (HFpEF) more frequently (low EAT: 37% vs. high EAT: 64%; P = 0.029) and had signs of adverse remodelling indicated by higher T1 times (P < 0.001). No differences in biventricular volumetry and left ventricular mass (all P > 0.074) were observed. Patients with high EAT had impaired atrial strain at rest and during exercise stress, and impaired ventricular strain during exercise stress. Regionally increased EAT was independently associated with functional impairment of the adjacent chambers. CONCLUSIONS: Patients with diastolic dysfunction and increased EAT show more pronounced signs of diastolic functional failure and adverse structural remodelling. Despite similar morphological characteristics, patients with high EAT show significant cardiac functional impairment, in particular in the atria. Our results indicate that regionally increased EAT directly induces atrial functional failure, which represents a distinct pathophysiological feature in HFpEF.

Discovering High Entropy Alloy Electrocatalysts in Vast Composition Spaces with Multiobjective Optimization.

High entropy alloys (HEAs) are a highly promising class of materials for electrocatalysis as their unique active site distributions break the scaling relations that limit the activity of conventional transition metal catalysts. Existing Bayesian optimization (BO)-based virtual screening approaches focus on catalytic activity as the sole objective and correspondingly tend to identify promising materials that are unlikely to be entropically stabilized. Here, we overcome this limitation with a multiobjective BO framework for HEAs that simultaneously targets activity, cost-effectiveness, and entropic stabilization. With diversity-guided batch selection further boosting its data efficiency, the framework readily identifies numerous promising candidates for the oxygen reduction reaction that strike the balance between all three objectives in hitherto unchartered HEA design spaces comprising up to 10 elements.

Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults.

Background: Recent studies have reported associations between high plasma high-density lipoprotein cholesterol (HDL-C) levels and risk of all-cause mortality, age-related macular degeneration, sepsis and fractures, but associations with dementia risk remain unclear. To determine whether high plasma HDL-C levels are associated with increased incident dementia risk in initially-healthy older people. Methods: We conducted a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial; a double-blind, randomized, placebo-controlled trial of daily low-dose aspirin in healthy older people. ASPREE recruited 16,703 participants aged ≥70 years (from Australia) and 2411 participants aged ≥65 years (from the US) between 2010 and 2014. Participants had no diagnosed cardiovascular disease, dementia, physical disability, or life-threatening illness at enrolment and were cognitively healthy (3MS score ≥78). All-cause dementia was a primary trial endpoint, and determined by DSM-IV criteria. Cox regression was used to examine hazard ratios between HDL-C categories <40 mg/dL, 40-60 mg/dL (reference category), 60-80 mg/dL, and >80 mg/dL and dementia. Restricted cubic spline curves were used to determine nonlinear associations. Data analysis was performed from October 2022 to January 2023. Findings: Of the 18,668 participants, 850 (4.6%) cases of incident dementia were recorded over 6.3 (SD 1.8) years. Participants with high HDL-C (>80 mg/dL) had a 27% higher risk of dementia (HR 1.27, 95% CI 1.03, 1.58). Age stratified analyses demonstrated that the risk of incident dementia was higher in participants ≥75 years compared to participants <75 years (HR 1.42, 95% CI 1.10, 1.83 vs HR 1.02, 95% CI 0.68, 1.51). Associations remained significant after adjusting for covariates including age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-PRS, and APOE genotype. Interpretation: In a population of initially-healthy older adults aged ≥75 years, high HDL-C levels were associated with increased risk of all-cause dementia. Funding: National Institutes of Health, USA; National Health and Medical Research Council Australia; Monash University (Melbourne, VIC, Australia); and the Victorian Cancer Agency (Australia).

Prognostic and diagnostic implications of impaired rest and exercise-stress left atrial compliance in heart failure with preserved ejection fraction: Insights from the HFpEF stress trial.

BACKGROUND: With emerging therapies, early diagnosis of heart failure with preserved ejection fraction (HFpEF) comes to the fore. Whilst the reference standard of exercise-stress right heart catheterisation is well established, the clinical routine struggles between feasibility of exercise-stress and diagnostic accuracy of available tests. METHODS: The HFpEF Stress Trial (DZHK-17) prospectively enrolled 75 patients with exertional dyspnoea and echocardiographic signs of diastolic dysfunction (E/e' > 8) who underwent simultaneous rest and exercise-stress echocardiography and right heart catheterisation (RHC). HFpEF was defined according to pulmonary capillary wedge pressure (HFpEF: PCWP rest: ≥15 mmHg stress: ≥25 mmHg). Patients were classified as non-cardiac dyspnoea (NCD) in the absence of HFpEF and cardiovascular disease. LA compliance was defined as reservoir strain (Es)/(E/e'). Follow-up was conducted after 4 years to evaluate cardiovascular hospitalisation (CVH). RESULTS: The final study population included 68 patients (HFpEF n = 34 and NCD n = 34) of which 23 reached the clinical endpoint, 1 patient was lost to follow-up. Patients with HFpEF according to the HFA-PEFF score (≥5 points) had significantly lower LA compliance at rest (p < 0.001) compared to patients with a score ≤ 4. LA compliance at rest outperformed E/e' (AUC 0.78 vs 0.87, p = 0.024) and showed a statistical trend to outperform Es (AUC 0.79 vs 0.87, p = 0.090) for the diagnosis of HFpEF. LA compliance at rest predicted CVH (HR 2.83, 95% CI 1.70-4.74, p < 0.001) irrespective of concomitant atrial fibrillation. CONCLUSIONS: LA compliance at rest can be obtained from clinical routine imaging and bears strong diagnostic and prognostic accuracy. Addition of LA compliance can improve the role of echocardiography as the primary test and gatekeeper.

Rest and exercise-stress estimated pulmonary capillary wedge pressure using real-time free-breathing cardiovascular magnetic resonance imaging.

BACKGROUND: Identification of increased pulmonary capillary wedge pressure (PCWP) by right heart catheterization (RHC) is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF). Recently, cardiovascular magnetic resonance (CMR) imaging estimation of PCWP at rest was introduced as a non-invasive alternative. Since many patients are only identified during physiological exercise-stress, we hypothesized that novel exercise-stress CMR-derived PCWP emerges superior compared to its assessment at rest. METHODS: The HFpEF-Stress Trial prospectively recruited 75 patients with exertional dyspnea and diastolic dysfunction who then underwent rest and exercise-stress RHC and CMR. HFpEF was defined according to PCWP (overt HFpEF ≥15 mmHg at rest, masked HFpEF ≥25 mmHg during exercise-stress). CMR-derived PCWP was calculated based on previously published formula using left ventricular mass and either biplane left atrial volume (LAV) or monoplane left atrial area (LAA). RESULTS: LAV (rest/stress: r = 0.50/r = 0.55, p < 0.001) and LAA PCWP (rest/stress: r = 0.50/r = 0.48, p < 0.001) correlated significantly with RHC-derived PCWP while numerically overestimating PCWP at rest and underestimating PCWP during exercise-stress. LAV and LAA PCWP showed good diagnostic accuracy to detect HFpEF (area under the receiver operating characteristic curve (AUC) LAV rest 0.73, stress 0.81; LAA rest 0.72, stress 0.77) with incremental diagnostic value for the detection of masked HFpEF using exercise-stress (AUC LAV rest 0.54 vs stress 0.67, p = 0.019, LAA rest 0.52 vs stress 0.66, p = 0.012). LAV but not LAA PCWP during exercise-stress was a predictor for 24 months hospitalization independent of a medical history for atrial fibrillation (hazard ratio (HR) 1.26, 95% confidence interval 1.02-1.55, p = 0.032). CONCLUSION: Non-invasive PCWP correlates well with the invasive reference at rest and during exercise stress. There is overall good diagnostic accuracy for HFpEF assessment using CMR-derived estimated PCWP despite deviations in absolute agreement. Non-invasive exercise derived PCWP may particularly facilitate detection of masked HFpEF in the future.

Evidence for interictal blood-brain barrier dysfunction in people with epilepsy.

OBJECTIVE: Interictal blood-brain barrier dysfunction in chronic epilepsy has been demonstrated in animal models and pathological specimens. Ictal blood-brain barrier dysfunction has been shown in humans in vivo using an experimental quantitative magnetic resonance imaging (MRI) protocol. Here, we hypothesized that interictal blood-brain barrier dysfunction is also present in people with drug-resistant epilepsy. METHODS: Thirty-nine people (21 females, mean age at MRI ± SD = 30 ± 8 years) with drug-resistant epilepsy were prospectively recruited and underwent interictal T1-relaxometry before and after administration of a paramagnetic contrast agent. Likewise, quantitative T1 was acquired in 29 people without epilepsy (12 females, age at MRI = 48 ± 18 years). Quantitative T1 difference maps were calculated and served as a surrogate imaging marker for blood-brain barrier dysfunction. Values of quantitative T1 difference maps inside hemispheres ipsilateral to the presumed seizure onset zone were then compared, on a voxelwise level and within presumed seizure onset zones, to the contralateral side of people with epilepsy and to people without epilepsy. RESULTS: Compared to the contralateral side, ipsilateral T1 difference values were significantly higher in white matter (corrected p < .05), gray matter (uncorrected p < .05), and presumed seizure onset zones (p = .04) in people with epilepsy. Compared to people without epilepsy, significantly higher T1 difference values were found in the anatomical vicinity of presumed seizure onset zones (p = .004). A subgroup of people with hippocampal sclerosis demonstrated significantly higher T1 difference values in the ipsilateral hippocampus and in regions strongly interconnected with the hippocampus compared to people without epilepsy (corrected p < .01). Finally, z-scores reflecting the deviation of T1 difference values within the presumed seizure onset zone were associated with verbal memory performance (p = .02) in people with temporal lobe epilepsy. SIGNIFICANCE: Our results indicate a blood-brain barrier dysfunction in drug-resistant epilepsy that is detectable interictally in vivo, anatomically related to the presumed seizure onset zone, and associated with cognitive deficits.