Año: 2024

Identification of Genetic Loci Associated With Intracerebral Hemorrhage Using a Multitrait Analysis Approach

Muiño E, Carcel-Marquez J, Llucià-Carol L et al. Neurology. 2024 Oct 22;103(8):e209666. doi: 10.1212/WNL.0000000000209666. Epub 2024 Sep 19.PMID: 39298701

https://pubmed.ncbi.nlm.nih.gov/39298701/

Background and Objetives: Genome-wide association studies (GWASs) have only 2 loci associated with spontaneous intracerebral hemorrhage (ICH): APOE for lobar and 1q22 for nonlobar ICH. We aimed to discover new loci through an analysis that combines correlated traits (multi-trait analysis of GWAS [MTAG]) and explore a gene-based analysis, transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH providing potential therapeutic targets.

Methods: Weuse the published MTAG of ICH (patients with spontaneous intraparenchymal bleeding) and small-vessel ischemic stroke. For all ICH, lobar ICH, and nonlobar ICH, a pairwise MTAG combined ICH with traits related to cardiovascular risk factors, cerebrovascular diseases, or Alzheimer disease (AD). For the analysis, we assembled those traits with a genetic correlation ≥0.3. A new MTAGcombining multiple traits was performed with those traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior-probability of model 3 (GWAS-pairwise) ≥0.6. We perform TWAS and PWAS that correlate the genetic component ofexpression or proteinlevels withthe genetic componentofa trait. We use the ICH cohort from UK Biobank as replication.

Results: For all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half of them were women. Replication cohort: 700 ICH and 399,717 controls. Novel loci were found only for all ICH (the trait containing lobar and nonlobar ICH), combining data of ICH and small vessel stroke, white matter hyperintensities volume, fractional anisotropy, mean diffusivity, and AD. We replicated 6 SNPs belonging to 2q33.2 (ICA1L, β = 0.20, SE = 0.03, p value = 8.91 × 10−12), 10q24.33 (OBFC1, β = −0.12, SE =0.02, p value = 1.67 ×10−8), 13q34 (COL4A2, β = 0.02, SE = 0.02, p value = 2.34 × 10−11), and 19q13.32 (APOC1, β =−0.19, SE =0.03, p value = 1.38 × 10−12; APOE, β = 0.21, SE = 0.03, p value = 2.70 × 10−11; PVRL2:CTB-129P6.4, β = 0.15, SE = 0.03, p value = 1.38 × 10−8); 2 genes (SH3PXD2A, Zscore = 4.83, p value = 6.67 × 10−7;andAPOC1, Z-score: = 5.11, p value = 1.60 × 10−7); and ICA1L transcript (Z-score = 6.8, p value = 9.1 × 10−12) and protein levels (Z-score = −5.8, p value = 6.7 × 10−9).

Funding: This work was supported by grants from the Institutode SaludCarlosIII (PI11/0176),Generaci´on Project,Maestro Project (PI18/01338), INVICTUS+ network, RICORSICTUS (RD21/0006/0006) together with Next-Generation EU funds that finance the actions of the Recovery and ResilienceMechanism,andtheEpigenesisProject(Marat´ode TV3),FEDERfunds, iBioStrokeproject(AC19/00106).E. Muiño is supportedby aR´ıoHortegaContract (CM18/00198) from the Instituto de Salud Carlos III. E. Muiño is supported by the Juan Rod´es contract (JR23/00045) from Instituto de Salud Carlos III. C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). M. Lled´os is supported by a PFIS Contract (Contratos Predoctorales de Formaci´on en Investigaci´on en Salud) from the Instituto de Salud Carlos III (FI19/00309). I. Fern´andez-Cadenas (CP12/03298) is supported by a research contract from Miguel Servet Program from the Instituto de Salud Carlos III.

Mediterranean Diet Prior to Ischemic Stroke and Potential Circulating Mediators of Favorable Outcomes

María Castañón-Apilánez, Carmen García-Cabo, Cristina Martin-Martin et al. Nutrients. 2024 Sep 23;16(18):3218.doi: 10.3390/nu16183218.. PMID: 39339817

https://pubmed.ncbi.nlm.nih.gov/39339817/

Abstract: Background/Objectives. A Mediterranean diet (MD) has been associated with neuroprotective effects. We aimed to assess the MD’s association with stroke prognosis and the potential mediators involved. Methods. Seventy patients with acute anterior circulation ischemic stroke were included. Dietary patterns were evaluated using the MEDAS scale, a food-frequency questionnaire, and a 24 h recall. Circulating biomarkers including insulin resistance (HOMA index), adipokines (resistin, adiponectin, leptin), choline pathway metabolites (TMAO, betaine, choline), and endothelial progenitor cells (EPCs) were measured. Early neurological improvement (ENI) at 24 h, final infarct volume, and functional outcome at 3 months were assessed. Results. Adherence to MD and olive oil consumption were associated with a lower prevalence of diabetes and atherothrombotic stroke, and with lower levels of fasting glycemia, hemoglobinA1C, insulin resistance, and TMAO levels. Monounsaturated fatty acids and oleic acid consumption correlated with lower resistin levels, while olive oil consumption was significantly associated with EPC mobilization. Multivariate analysis showed that higher MD adherence was independently associated with ENI and good functional prognosis at 3 months. EPC mobilization, lower HOMA levels, and lower resistin levels were associated with ENI, a smaller infarct volume, and good functional outcome. Conclusions. MD was associated with better prognosis after ischemic stroke, potentially mediated by lower insulin resistance, increased EPC mobilization, and lower resistin levels, among other factors.

Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) through RICORS-ICTUS (RD21/0006/0022, PI18/01096, CM19/00235, INT19/00075) by means of NextGenerationEU funds, which support the actions of the Mecanismo de Recuper-ación y Resiliencia (MRR)/PRTR 

 

The mitochondrial Na+/Ca2+ exchanger NCLX is implied in the activation of hypoxia-inducible factors

Carmen Choya-Foces , Elisa Navarro , Cristóbal de Los Ríos et al. Redox Biol. 2024 Nov:77:103364. doi: 10.1016/j.redox.2024.103364. PMID: 39341036.

https://pubmed.ncbi.nlm.nih.gov/39341036/

Abstract: Eukaryotic cells and organisms depend on oxygen for basic living functions, and they display a panoply of adaptations to situations in which oxygen availability is diminished (hypoxia). A number of these responses in animals are mediated by changes in gene expression programs directed by hypoxia-inducible factors (HIFs), whose main mechanism of stabilization and functional activation in response to decreased cytosolic oxygen concentration was elucidated two decades ago. Human acute responses to hypoxia have been known for decades, although their precise molecular mechanism for oxygen sensing is not fully understood. It is already known that a redox component, linked with reactive oxygen species (ROS) production of mitochondrial origin, is implied in these responses. We have recently described a mechanism by which the mitochondrial sodium/calcium exchanger, NCLX, participates in mitochondrial electron transport chain regulation and ROS production in response to acute hypoxia. Here we show that NCLX is also implied in the response to hypoxia mediated by the HIFs. By using a NCLX inhibitor and interference RNA we show that NCLX activity is necessary for HIF-α subunits stabilization in hypoxia and for HIF-1-dependent transcriptional activity. We also show that hypoxic mitochondrial ROS production is not required for HIF-1α stabilization under all circumstances, suggesting that the basal cytosolic redox state or other mechanism(s) could be operating in the NCLX-mediated response to hypoxia that operates through HIF-α stabilization. This finding provides a link between acute and medium-term responses to hypoxia, reinforcing a central role of mitochondrial cell signalling in the response to hypoxia.

Funding: This research has been financed by grants from the Spanish Government (partially funded by the European Union ERDF “A way of making Europe” and Next GenerationEU): RedoxStroke (RTI2018- 094203-B-I00), excellence network RED2018-102576-T, NCLRedoX (PID2021-124688OB-I00), NCLXtroke (PDC2022-133246-I00),
PID2021-125986OB-I00 and PID2022-139936OA-I00 from AEI (MICIU/ AEI/10.13039/501100011033); PI15/00107, PI22/00362 and RICORSICTUS (RD21/0006/0009) from Instituto de Salud Carlos III (ISCIII) and fellowships IJC2020-042679-I (MICIU) and RYC2022-036516-I (MICIU) to P.H.-A. from AEI and FPU18/03475 to C.C.-F. from MICIU, and by a grant from the Fundacion ´ Domingo Martínez.

A dual colorimetric-electrochemical microfluidic paper-based analytical device for point-of-care testing of ischemic strokes

Dortez S, Pacheco M, Gasull T, Crevillen AG, Escarpa A. Lab Chip. 2024 Aug 9. doi: 10.1039/d4lc00398e. Online ahead of print. PMID: 39118539
Abstract: A novel microfluidic paper-based analytical device with dual colorimetric and electrochemical detection (dual μPAD) was developed for the assessment of transferrin saturation (TSAT) in samples from ischemic stroke patients. TSAT was calculated from the ratio between transferrin-bound iron, which was colorimetrically measured, and the total iron-binding capacity, which was electrochemically measured. To this end, a μPAD was smartly designed, which integrated both colorimetric and electrochemical detection reservoirs, communicating via a microchannel acting as a chemical reactor, and with preloading/storing capabilities (reagent-free device). This approach allowed the dual and simultaneous determination of both parameters, providing an improvement in the reliability of the results due to an independent signal principle and processing. The μPADs were validated by analyzing a certified reference material, showing excellent accuracy (Er ≤ 5%) and precision (RSD ≤ 2%). Then they were applied to the analysis of diagnosed serum samples from ischemic stroke patients. The results were compared to those provided by a free-interference method (urea-PAGE). Impressively, both methods exhibited a good correlation (r = 0.96, p < 0.05) and no significant differences were found between them (slope 1.0 ± 0.1 and the intercept 1 ± 4, p < 0.05), demonstrating the excellent accuracy of our approach during the analysis of complex samples from ischemic stroke patients, using just 90 μL of clinical samples and taking less than 90 min in comparison with the 18 hours required by the urea-PAGE approach. The developed fully integrated colorimetric-electrochemical μPAD is a promising ready to use reagent-free device for the point-of-care testing of TSAT, which can be used to assist physicians in the fast diagnosis and prognosis of ischemic strokes, where the decision-time is crucial for the patient’s survival.
Funding: This work has been financially supported by the TRANSNANOAVANSENS program from the Community of Madrid (P2018/NMT-4349) (A. E.), by the grant PID2020-118154GB-I00 funded by MCIN/AEI/10.13039/501100011033 (A. E.), by the NEURO-CHIP-CM program from the Community of Madrid (Y2020/NMT6312) (A. E.), by the RICORS RD21/0006/0024 (NextGeneration EU funding) and 2021SGR00925 (Agencia de gestio d’Ajuts Universitaris i de Recerca de Catalunya) (T. G.), and by the Spanish Ministry of Economy and Competitiveness (CTQ2017-86441-C2-1-R, FPI fellowship (S. D.)).

Atrial Imaging and Cardiac Rhythm in Cryptogenic Embolic Stroke: The ARIES Study

Rigual R,Castrejón-Castrejón S, Fernández-Gassó L et al. J Am Heart Assoc. 2024 Sep 3;13(17):e036236. doi: 10.1161/JAHA.124.036236. Epub 2024 Aug 29. PMID: 39206739.

https://pubmed.ncbi.nlm.nih.gov/39206739/

Abstract: BACKGROUND: Unknown cardioembolic sources are frequent causes of cryptogenic stroke. We analyzed the risk of atrial fibrillation (AF) or high burden of ectopic atrial activity (HBEA) in patients with cryptogenic stroke, assessing atrial function and 1- year outcomes. METHODS AND RESULTS: The ARIES (Atrial Imaging and Cardiac Rhythm in Cryptogenic Embolic Stroke) study is an observational study including patients with cryptogenic stroke. We analyzed the frequency of AF and HBEA (>3000 atrial ectopic beats/day or >2 bursts or atrial tachycardia between 3 beats and ≤30 seconds) in two 30- day Holter- ECGs, comparing advanced echocardiography signs of left atrial (LA) dysfunction according to rhythm: AF, HBEA, and normal sinus rhythm. We also evaluated 1- year stroke recurrence and mortality. The study included 109 patients; 35 (32.1%) patients had AF, 27 (24.8%) HBEA, and 47 (43.1%) normal sinus rhythm. Compared with those with normal sinus rhythm, patients with AF presented higher 2- dimensional and 3- dimensional LA indexed volumes (38.8±11.2 versus 27.3±11.8 mL/m2, and 50.6±17.2 versus 34.0±15.4 mL/m2, respectively, P<0.001), lower 3- dimensional LA ejection fraction (50±14.6 versus 62.7±11.8, P=0.001), LA reservoir strain (22.0±8.6 versus 30.4±10.5, P<0.001), and LA contraction strain (10.5±8.18 versus 17.1±7.5, P<0.001), remaining significant in multivariate analysis. Patients with HBEA showed higher LA indexed volumes and lower LA reservoir strain than patients with normal sinus rhythm only in univariate analysis. There were no differences in ischemic recurrence or mortality among the groups. CONCLUSIONS: Patients with cryptogenic stroke showed a high incidence of AF and HBEA. AF is strongly related to LA volume, LA function, and LA reservoir and contraction strain, whereas HBEA showed milder structural changes. Advanced LA echocardiography could help patient selection for long- term ECG monitoring in suspected cardiac sources.

Funding: This project has been supported by a grant from the Stroke Project of the Cerebrovascular Diseases Study Group of the Spanish Society of Neurology, funded by Daiichi- Sankyo. This work was also supported by RICORS (Redes de Investigación Cooperativa Orientadas a Resultados en Salud) network under grant RD21/0006/0012.