Endothelial Piezo1 channel mediates mechano-feedback control of brain blood flow.

Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O2 and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia-neuronal activity-to-vascular response-the mechanical consequences of hyperemia have gone largely unexplored. Piezo1 is an endothelial mechanosensor that senses hyperemia-associated forces. Using genetic mouse models and pharmacologic approaches to manipulate endothelial Piezo1 function, we evaluated its role in blood flow control and whether it impacts cognition. We provide evidence of a built-in brake system that sculpts hyperemia, and specifically show that Piezo1 activation triggers a mechano-feedback system that promotes blood flow recovery to baseline. Further, genetic Piezo1 modification led to deficits in complementary memory tasks. Collectively, our findings establish a role for endothelial Piezo1 in cerebral blood flow regulation and a role in its behavioral sequelae.

Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential.

Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N-nitrosamine drug substance-related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin-converting enzyme inhibitors, identified by the suffix "pril," have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. N-nitroso ramipril and N-nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α-position were non-genotoxic in the in vivo liver comet assay and non-mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non-mutagenic and non-carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for N-nitroso ramipril and N-nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar "pril" NDSRIs.

Estimation of 100 m root zone soil moisture by downscaling 1 km soil water index with machine learning and multiple geodata.

Root zone soil moisture (RZSM) is crucial for agricultural water management and land surface processes. The 1 km soil water index (SWI) dataset from Copernicus Global Land services, with eight fixed characteristic time lengths (T), requires root zone depth optimization (Topt) and is limited in use due to its low spatial resolution. To estimate RZSM at 100-m resolution, we integrate the depth specificity of SWI and employed random forest (RF) downscaling. Topographic synthetic aperture radar (SAR) and optical datasets were utilized to develop three RF models (RF1: SAR, RF2: optical, RF3: SAR + optical). At the DEMMIN experimental site in northeastern Germany, Topt (in days) varies from 20 to 60 for depths of 10 to 30 cm, increasing to 100 for 40-60 cm. RF3 outperformed other models with 1 km test data. Following residual correction, all high-resolution predictions exhibited strong spatial accuracy (R ≥ 0.94). Both products (1 km and 100 m) agreed well with observed RZSM during summer but overestimated in winter. Mean R between observed RZSM and 1 km (100 m; RF1, RF2, and RF3) SWI ranges from 0.74 (0.67, 0.76, and 0.68) to 0.90 (0.88, 0.81, and 0.82), with the lowest and highest R achieved at 10 cm and 30 cm depths, respectively. The average RMSE using 1 km (100 m; RF1, RF2, and RF3) SWI increased from 2.20 Vol.% (2.28, 2.28, and 2.35) at 30 cm to 3.40 Vol.% (3.50, 3.70, and 3.60) at 60 cm. These negligible accuracy differences underpin the potential of the proposed method to estimate RZSM for precise local applications, e.g., irrigation management.

Repeat pulmonary vein isolation and anterior line ablation using a novel point-by-point pulsed-field ablation system.

BACKGROUND: Pulsed-field ablation (PFA) is a nonthermal energy source for ablation of cardiac arrhythmias. This study investigated the prospective outcomes of a novel PFA generator in conjunction with a commercially available, contact force-sensing, focal ablation catheter. OBJECTIVE: The purpose of this study was to assess the feasibility, safety, and lesion characteristics of point-by-point PFA in consecutive patients undergoing repeat ablation of atrial fibrillation (AF). METHODS: The study involved reisolation of pulmonary veins (PVs) with electrical reconnection and the creation of an anterior line (AL) in patients with anterior substrate or durable pulmonary vein isolation (PVI). RESULTS: In 24 patients (46% female; mean age 67 ± 10 years; 67% persistent AF), successful reisolation of 27 of 27 reconnected PVs (100%) was performed. In 19 patients, AL ablation was performed, with bidirectional block in 16 (84%), median ablation time 26 [21, 33] minutes, and first-pass bidirectional block in 13 patients (68%). Acute AL reconduction occurred in 8 of 19 patients (42%). Among these 8 patients, a subsequent sustained block of the AL was achieved in 5 (63%). Ultra-high-density electroanatomic mapping revealed homogeneous but relatively large low-voltage areas in the ablated regions. Median procedural, left atrial dwell, and fluoroscopy times were 100 [90, 109] minutes, 83 [75, 98] minutes, and 10 [8, 13] minutes, respectively. No major or minor complications occurred. CONCLUSION: This study demonstrated feasibility, acute efficacy, and safety of point-by-point PFA for repeat PVI and AL ablation. Further studies are warranted to assess the long-term durability and comparison with established ablation methods.

A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS.

A20 is a ubiquitin-modifying protein that negatively regulates NF-κB signaling. Mutations in A20/TNFAIP3 are associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (ECs) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. A20ΔCNS-EC mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the blood-brain barrier (BBB) was not impaired, we observed a strong activation of CNS-ECs in these mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We discovered ICOSL to be expressed by A20-deficient CNS-ECs, which we found to function as adhesion molecules. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20ΔCNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in WT mice. In addition, blocking of ICOSL on primary mouse brain microvascular ECs impaired the adhesion of T cells in vitro. Taken together, we propose that CNS EC-ICOSL contributes to the firm adhesion of T cells to the BBB, promoting their entry into the CNS and eventually driving neuroinflammation.

Correlation of systolic and diastolic blood pressure with echocardiographic phenotypes of cardiac structure and function from three German population-based studies.

Arterial hypertension is considered a risk factor for the development of heart failure. Here we investigate cross-sectional associations of systolic and diastolic blood pressure with subtle functional and morphological changes of left ventricular echocardiographic parameters representing early dysfunction in three representative German population-based studies. We assessed 26,719 individuals without symptomatic heart failure from the Hamburg City Health Study (HCHS, n = 7396, derivation cohort), the Gutenberg Health Study (GHS, 14,715, validation cohort) and the Study of Health in Pomerania (SHIP, 4608, validation cohort). Multivariable linear regression analyses with systolic and diastolic blood pressure as continuous exposure variables were adjusted for common cardiovascular risk factors and antihypertensive medication. Both systolic and diastolic blood pressure were consistently associated with measures of left ventricular hypertrophy (ß per standard deviation (SD) for LV mass (g) and systolic blood pressure: 5.09 (p < 0.001); diastolic blood pressure: 2.29 (p < 0.001) in HCHS). Systolic blood pressure correlated with declining diastolic function (ß per SD for E/e': 0.29, p < 0.001 in HCHS) and diastolic blood pressure with declining systolic function (ß per SD for LVEF, in %: - 0.15; p = 0.041 in HCHS) in all cohorts. Pending further validation, our results from three independent German population samples suggest differential effects of systolic versus diastolic blood pressure on left ventricular structure and function.

The infrastructure of electrophysiology centers impacts the management of cardiac tamponade-Results from a national survey.

BACKGROUND: Although electrophysiological (EP) centers have institutional standards, evidence on management of cardiac tamponade is lacking. AIM AND METHODS: A physician-based survey was conducted by sending out questionnaires to all hospitals in Germany performing EP procedures. To evaluate the infrastructure of EP centers and the impact of center volume and onsite cardiac surgery on the management of cardiac tamponade, the results of the survey were analyzed for low-volume (0-250 procedures per year), mid-volume (250-500 procedures), and high-volume (>500 procedures) centers, as well as for centers with and without onsite cardiac surgery. RESULTS: A total of 341 centers were identified and 189/341 (55%) returned data sets were analyzed. Most types of EP procedures are performed across all kinds of centers. Ablation of ventricular tachycardia (VT) is concentrated in higher volume centers and in centers with onsite cardiac surgery. None of the participating low-volume centers and only 13% of centers without onsite cardiac surgery responded to performing epicardial VT ablation. Irrespective of center volume and onsite cardiac surgery, neither body mass index nor age was reported to be an exclusion criterion for ablation procedures. Higher volume centers and centers with onsite cardiac surgery more often have dedicated EP laboratories and EP-nursing teams. Also, differences regarding periprocedural safety precautions and management of cardiac tamponade were found for low-, mid-, and high-volume centers, as well as for centers with and without onsite cardiac surgery. CONCLUSION: While center volume and onsite cardiac surgery do not impact patient selection, there are differences in ablation spectrum, infrastructure, periprocedural safety precautions, and treatment of tamponade.

Acute lesion extension following pulmonary vein isolation with two novel single shot devices: Pulsed field ablation versus multielectrode radiofrequency balloon.

INTRODUCTION: Pulsed-field ablation (PFA) and the multielectrode radiofrequency balloon (RFB) are two novel ablation technologies to perform pulmonary vein isolation (PVI). It is currently unknown whether these technologies differ in lesion formation and lesion extent. We compared the acute lesion extent after PVI induced by PFA and RFB by measuring low-voltage area in high-density maps and the release of biomolecules reflecting cardiac injury. METHODS: PVI was performed with a pentaspline catheter (FARAPULSE) applying PFA or with the compliant multielectrode RFB (HELIOSTAR). Before and after PVI high-density mapping with CARTO 3 was performed. In addition, blood samples were taken before transseptal puncture and after post-PVI remapping and serum concentrations of high-sensitive Troponin I were quantified by immunoassay. RESULTS: Sixty patients undergoing PVI by PFA (n = 28, age 69 ± 12 year, 60% males, 39.3% persistent atrial fibrillation [AF]) or RFB (n = 32, age 65 ± 13 year, 53% males, 21.9% persistent AF) were evaluated. Acute PVI was achieved in all patients in both groups. Mean number of PFA pulses was 34.2 ± 4.5 and mean number RFB applications was 8.5 ± 3 per patient. Total posterior ablation area was significantly larger in PFA (20.7 ± 7.7 cm²) than in RFB (7.1 ± 2.09 cm²; p < .001). Accordingly, posterior ablation area for each PV resulted in larger lesions after PFA versus RFB (LSPV 5.2 ± 2.7 vs. 1.9 ± 0.8 cm², LIPV 5.5 ± 2.3 vs. 1.9 ± 0.8 cm², RSPV 4.7 ± 1.9 vs. 1.6 ± 0.5 cm², RIPV 5.3 ± 2.1 vs. 1.6 ± 0.7 cm,² respectively; p < .001). In a subset of 38 patients, increase of hsTropI was higher after PFA (625 ± 138 pg/mL, n = 28) versus RFB (148 ± 36 pg/mL, n = 10; p = .049) supporting the evidence of larger lesion extent by PFA. CONCLUSION: PFA delivers larger acute lesion areas and higher troponin release upon successful PVI than multielectrode RFB-based PVI in this single-center series.

Novel Radiofrequency Balloon Catheter　- Impact of Ablation Parameters on Single-Shot Isolation.

BACKGROUND: A novel multielectrode radiofrequency balloon (RFB) catheter has been released for pulmonary vein isolation (PVI).Methods and Results: In this observational study consecutive patients with drug-refractory paroxysmal or persistent atrial fibrillation (AF) undergoing first-time PVI were enrolled in 2 high-volume ablation centers. All procedures were conducted in conjunction with a 3D-mapping system. Clinical, procedural and ablation parameters were systematically analyzed. 105 patients (58% male; 52% paroxysmal AF, 68±11.3 years mean age, left atrial volume index 38.6±14.8 mL/m2) were included. 241/412 (58.5%) PVs were successfully isolated with a single shot (SS), with a time-to-isolation of 11.6±8 s. Total number of radiofrequency applications was 892 (mean 2.2/PV), resulting in successful isolation of 408/412 (99%) PVs at the end of the procedure. Mean electrodes' impedance drop was significantly higher in the SS-PVI compared with non-SS applications (21.5±6.6 vs. 18.6±6.5 Ohm). Concordantly, higher temperature rise was observed in the SS vs. non-SS applications (10.9±4.9℃ vs. 9.6±4.7℃). CONCLUSIONS: In this multicenter real-world study, mean impedance drop and temperature rise were associated with successful SS-PVI applying the novel RFB catheter. These parameters may help to guide efficient usage of the new RF balloon.

A novel saline-based occlusion tool allows for dye-less cryoballoon-based pulmonary vein isolation and fluoroscopy reduction.

Background: Cryoballoon (CB)- based pulmonary vein isolation (PVI) remains guided by fluoroscopy and dye. The novel saline injection-based occlusion tool allows for pulmonary vein (PV)-occlusion assessment without the need for dye injection. Aim: To compare KODEX-EPD guided CB-PVI using the novel saline injection-based workflow with conventional cryoablation for acute efficacy, fluoroscopy exposure and dye volume. Methods: Consecutive atrial fibrillation (AF)- patients undergoing CB-PVI in conjunction with KODEX-EPD (CryoEPD group) were analyzed. Patients undergoing conventional CB-PVI (Cryo group) in the same time period acted as controls. Results: One hundred forty patients [91/140 (65%) persistent AF] were studied. Seventy patients underwent CryoEPD procedures [64 ± 13 years, 21 (30%) female] and seventy patients underwent Cryo procedures [68 ± 10 years, 27 (39%) female].A total of 560 PVs were identified and successfully isolated. Mean procedure time was 66 ± 15 min for the CryoEPD group, and 65 ± 19 min for the Cryo group (p = 0.3). Fluoroscopy time (CryoEPD 6 ± 4 min; Cryo 13 ± 6 min, p < 0.001) and dose area product (CryoEPD 193 [111; 297] cGycm2; Cryo 381 [268; 614] cGycm2, p < 0.001) were lower in patients undergoing CryoEPD compared with Cryo procedures. No dye was needed in the CryoEPD group while 53 ± 18 ml dye per patient were administered for the Cryo group (p < 0.001). The overall complication rate was comparable between both groups (p = 0.5). Conclusion: KODEX-EPD guided AF-ablation enables dye-free CB-based PVI with reduced fluoroscopy exposure when compared to conventional CB-ablation, without differences in acute procedural outcomes or procedure duration.

Coffee consumption and associations with blood pressure, LDL-cholesterol and echocardiographic measures in the general population.

Coffee, next to water the most widespread beverage, is attributed both harmful and protective characteristics concerning cardiovascular health. This study aimed to evaluate associations of coffee consumption with cardiac biomarkers, echocardiographic, electrocardiographic parameters and major cardiovascular diseases. We performed a cross-sectional analysis of 9009 participants of the population-based Hamburg City Health Study (HCHS), enrolled between 2016 and 2018 median age 63 [IQR: 55; 69] years. Coffee consumption was classified into three groups: < 3 cups/day (low), 3-4 cups/day (moderate), > 4 cups/day (high). In linear regression analyses adjusted for age, sex, body mass index, diabetes, hypertension, smoking, and additives, high coffee consumption correlated with higher LDL-cholesterol (ß = 5.92; 95% CI 2.95, 8.89; p < 0.001). Moderate and high coffee consumption correlated with lower systolic (ß = - 1.91; 95% CI - 3.04, - 0.78; p = 0.001; high: ß = - 3.06; 95% CI - 4.69, - 1.44; p < 0.001) and diastolic blood pressure (ß = - 1.05; 95% CI - 1.67, - 0.43; p = 0.001; high: ß = - 1.85; 95% CI - 2.74, - 0.96; p < 0.001). Different levels of coffee consumption did neither correlate with any investigated electrocardiographic or echocardiographic parameter nor with prevalent major cardiovascular diseases, including prior myocardial infarction and heart failure. In this cross-sectional analysis, high coffee consumption correlated with raised LDL-cholesterol levels and lower systolic and diastolic blood pressure. However, major cardiovascular diseases including heart failure and its diagnostic precursors were not associated with coffee consumption, connoting a neutral role of coffee in the context of cardiovascular health.

Association between Coffee Consumption and Brain MRI Parameters in the Hamburg City Health Study.

Despite associations of regular coffee consumption with fewer neurodegenerative disorders, its association with microstructural brain alterations is unclear. To address this, we examined the association of coffee consumption with brain MRI parameters representing vascular brain damage, neurodegeneration, and microstructural integrity in 2316 participants in the population-based Hamburg City Health Study. Cortical thickness and white matter hyperintensity (WMH) load were measured on FLAIR and T1-weighted images. Microstructural white matter integrity was quantified as peak width of skeletonized mean diffusivity (PSMD) on diffusion-weighted MRI. Daily coffee consumption was assessed in five groups (<1 cup, 1-2 cups, 3-4 cups, 5-6 cups, >6 cups). In multiple linear regressions, we examined the association between brain MRI parameters and coffee consumption (reference group <1 cup). After adjustment for covariates, 3-4 cups of daily coffee were associated with lower PSMD (p = 0.028) and higher cortical thickness (p = 0.015) compared to <1 cup. Moreover, 1-2 cups per day was also associated with lower PSMD (p = 0.022). Associations with WMH load or other groups of coffee consumption were not significant (p > 0.05). The findings indicate that regular coffee consumption is positively associated with microstructural white matter integrity and cortical thickness. Further research is necessary to determine longitudinal effects of coffee on brain microstructure.

3 Tesla magnetic resonance imaging in patients with cardiac implantable electronic devices: a single centre experience.

AIMS: Three Tesla (T) magnetic resonance imaging (MRI) provides critical imaging information for many conditions. Owing to potential interactions of the magnetic field, it is largely withheld from patients with cardiac implantable electronic devices (CIEDs). Therefore, we assessed the safety of 3T MRI in patients with '3T MRI-conditional' and 'non-3T MRI-conditional' CIEDs. METHODS AND RESULTS: We performed a retrospective single-centre analysis of clinically indicated 3T MRI examinations in patients with conventional pacemakers, cardiac resynchronization devices, and implanted defibrillators from April 2020 to May 2022. All CIEDs were interrogated and programmed before and after scanning. Adverse events included all-cause death, arrhythmias, loss of capture, inappropriate anti-tachycardia therapies, electrical reset, and lead or generator failure during or shortly after MRI. Changes in signal amplitude and lead impedance were systematically assessed. Statistics included median and interquartile range. A total of 132 MRI examinations were performed on a 3T scanner in 97 patients. Thirty-five examinations were performed in patients with 'non-3T MRI-conditional' CIEDs. Twenty-six scans were performed in pacemaker-dependent patients. No adverse events occurred during or shortly after MRI. P-wave or R-wave reductions ≥ 50 and ≥ 25%, respectively, were noted after three (2.3%) scans, all in patients with '3T MRI-conditional' CIEDs. Pacing and shock impedance changed by ± 30% in one case (0.7%). Battery voltage and stimulation thresholds did not relevantly change after MRI. CONCLUSION: Pending verification in independent series, our data suggest that clinically indicated MRI scans at 3T field strength should not be withheld from patients with cardiac pacemakers or defibrillators.

Pragmatic screening for heart failure in the general population using an electrocardiogram-based neural network.

AIMS: We aim to develop a pragmatic screening tool for heart failure at the general population level. METHODS AND RESULTS: This study was conducted within the Hamburg-City-Health-Study, an ongoing, prospective, observational study enrolling randomly selected inhabitants of the city of Hamburg aged 45-75 years. Heart failure was diagnosed per current guidelines. Using only digital electrocardiograms (ECGs), a convolutional neural network (CNN) was built to discriminate participants with and without heart failure. As comparisons, known risk variables for heart failure were fitted into a logistic regression model and a random forest classifier. Of the 5299 individuals included into this study, 318 individuals (6.0%) had heart failure. Using only the digital ECGs instead of several risk variables as an input, the CNN provided a comparable predictive accuracy for heart failure versus the logistic regression model and the random forest classifier [area under the curve (AUC) of 0.75, a sensitivity of 0.67 and a specificity of 0.69 for the CNN; AUC 0.77, a sensitivity of 0.63 and a specificity of 0.76 for the logistic regression; AUC 0.79, a sensitivity of 0.67 and a specificity of 0.72 for the random forest classifier]. CONCLUSIONS: Using a CNN build on digital ECGs only and requiring no additional input, we derived a screening tool for heart failure in the general population. This could be perfectly embedded into clinical routine of general practitioners, as it builds on an already established diagnostic tool and does not require additional, time-consuming input. This could help to alleviate the underdiagnosis of heart failure.

Predicting DNA-Reactivity of N-Nitrosamines: A Quantum Chemical Approach.

N-Nitrosamines (NAs) are a class of reactive organic chemicals that humans may be exposed to from environmental sources, food but also impurities in pharmaceutical preparations. Some NAs were identified as DNA-reactive mutagens and many of those have been classified as probable human carcinogens. Beyond high-potency mutagenic carcinogens that need to be strictly controlled, NAs of low potency need to be considered for risk assessment as well. NA impurities and nitrosylated products of active pharmaceutical ingredients (APIs) often arise from production processes or degradation. Most NAs require metabolic activation to ultimately become carcinogens, and their activation can be appropriately described by first-principles computational chemistry approaches. To this end, we treat NA-induced DNA alkylation as a series of subsequent association and dissociation reaction steps that can be calculated stringently by density functional theory (DFT), including α-hydroxylation, proton transfer, hydroxyl elimination, direct SN2/SNAr DNA alkylation, competing hydrolysis and SN1 reactions. Both toxification and detoxification reactions are considered. The activation reactions are modeled by DFT at a high level of theory with an appropriate solvent model to compute Gibbs free energies of the reactions (thermodynamical effects) and activation barriers (kinetic effects). We study congeneric series of aliphatic and cyclic NAs to identify trends. Overall, this work reveals detailed insight into mechanisms of activation for NAs, suggesting that individual steric and electronic factors have directing and rate-determining influence on the formation of carbenium ions as the ultimate pro-mutagens and thus carcinogens. Therefore, an individual risk assessment of NAs is suggested, as exemplified for the complex API-like 4-(N-nitroso-N-methyl)aminoantipyrine which is considered as low-potency NA by in silico prediction.