Grupos de investigación

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19587

Browse

Now showing 1 - 20 of 190

Fibroblast Growth Factor 23 as a Prognostic Biomarker in Post-Myocardial Infarction Outcomes: Influence of Renal Function and Its Modulation by Klotho.
(WILEY, 2026-02-17) Vázquez-Sánchez, Sara; Blasco, Ana; Polo-Salguero, Marina; Mourino-Álvarez, Laura; Gil-Fernández, Marta; Corbacho-Alonso, Nerea; Navarro-García, José Alberto; Mercado-García, Elisa; González-Lafuente, Laura; Rodríguez-Sánchez, Elena; González-Moreno, Daniel; Pérez-Gómez, Alberto; Matutano, Andrea; Vázquez, Jesús; López, Juan Antonio; Fernández-Velasco, María; Barderas, María G; Ruiz-Hurtado, Gema
Elevation of FGF23 (fibroblast growth factor 23) and decreased Klotho levels have been associated with various cardiovascular and renal diseases. However, the combined study of the FGF23-Klotho axis in ischemic heart disease remains elusive. We analyzed the associations between circulating FGF23 and Klotho levels with cardiac and renal parameters, as well as mortality outcomes following myocardial infarction (MI). Cardiac tissue from patients with ischemic heart disease and a post-MI mouse model were analyzed to assess myocardial FGF23 expression. Proteomic analysis was performed to examine myocardial pathways activated by FGF23 and regulated by Klotho. We observed an inverse correlation between circulating levels of FGF23 and Klotho in patients after MI. Elevated plasma FGF23 levels were particularly associated with ST-segment-elevation MI and cardiac dysfunction, including reduced left ventricular ejection fraction, prolonged corrected interval, and higher Killip-Kimball classification of cardiac risk, identifying FGF23 as a potential prognostic marker of overall and cardiac-related mortality. In contrast, systemic Klotho levels were reduced in patients with ST-segment-elevation MI but did not correlate with mortality. In cardiac tissue, ischemic injury significantly upregulated FGF23 expression. Although Klotho prevented FGF23-induced proteomic alterations, it did not inhibit cardiac FGF23 overexpression in the post-MI model. FGF23 represents a promising biomarker for mortality and cardiac dysfunction in patients with MI. Although Klotho does not appear to be a reliable predictor of mortality after MI, its cardioprotective properties suggest a role in modulating FGF23-driven metabolic, structural, and proliferative processes in the myocardium.
Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress.
(OXFORD UNIV PRESS, 2022-12-29) González-Amor, María; García-Redondo, Ana B; Jorge, Inmaculada; Zalba, Guillermo; Becares, Martina; Ruiz-Rodríguez, María J; Rodríguez, Cristina; Bermeo, Hugo; Rodrigues-Díez, Raquel; Rios, Francisco J; Montezano, Augusto C; Martínez-González, Jose; Vázquez, Jesús; Redondo, Juan Miguel; Touyz, Rhian M; Guerra, Susana; Salaices, Mercedes; Briones, Ana M
Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.
Early renal and vascular damage within the normoalbuminuria condition.
(LIPPINCOTT WILLIAMS & WILKINS, 2021-11-01) Santiago-Hernandez, Aranzazu; Martin-Lorenzo, Marta; Martínez, Paula J; Gómez-Serrano, María; Lopez, Juan Antonio; Cannata, Pablo; Esteban, Vanesa; Heredero, Angeles; Aldamiz-Echevarria, Gonzalo; Vázquez, Jesús; Ruiz-Hurtado, Gema; Barderas, Maria G; Segura, Julian; Ruilope, Luis M; Alvarez-Llamas, Gloria
A continuous association between albuminuria and cardiorenal risk exists further below moderately increased albuminuria ranges. If only based in albumin to creatinine ratio (ACR) higher than 30 mg/g, a significant percentage of individuals may be out of the scope for therapeutic management. Despite epidemiological outcomes, the identification of biochemical changes linked to early albuminuria is underexplored, and normoalbuminuric individuals are usually considered at no risk in clinical practice. Here, we aimed to identify early molecular alterations behind albuminuria development. Hypertensive patients under renin-angiotensin system (RAS) suppression were classified as control, (ACR < 10 mg/g) or high-normal (ACR = 10-30 mg/g). Urinary protein alterations were quantified and confirmed by untargeted and targeted mass spectrometry. Coordinated protein responses with biological significance in albuminuria development were investigated. Immunohistochemistry assays were performed in human kidney and arterial tissue to in situ evaluate the associated damage. A total of 2663 identified proteins reflect inflammation, immune response, ion transport and lipids metabolism (P value ≤ 0.01). A1AT, VTDB and KNG1 varied in high-normal individuals (P value < 0.05), correlated with ACR and associated with the high-normal condition (odds ratio of 20.76, 6.00 and 7.04 were found, respectively (P value < 0.001)). After 12 months, protein variations persist and aggravate in progressors to moderately increased albuminuria. At tissue level, differential protein expression was found in kidney from individuals with moderately increased albuminuria and atherosclerotic aortas for the three proteins, confirming their capacity to reflect subclinical organ damage. Early renal and vascular damage is molecularly evidenced within the normoalbuminuria condition.
Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center.
(EDICIONES DOYMA, 2021-02) López-Sainz, Ángela; Hernandez-Hernandez, Aitor; Gonzalez-Lopez, Esther; Domínguez, Fernando; Restrepo-Cordoba, Maria Alejandra; Cobo-Marcos, Marta; Gómez-Bueno, Manuel; Hernandez-Perez, Francisco Jose; Oteo, Juan Francisco; Mirelis, Jesus G; Cavero, Miguel Angel; Moñivas, Vanessa; Mingo Santos, Susana; de Haro-Del Moral, F Javier; Krsnik, Isabel; Salas, Clara; Bornstein, Belén; Briceño, Ana; López, Juan Antonio; Vázquez, Jesús; Alonso-Pulpón, Luis; Segovia, Javier; Garcia-Pavia, Pablo
Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.
Aging Induces Hepatic Oxidative Stress and Nuclear Proteomic Remodeling in Liver from Wistar Rats.
(MDPI, 2021-09-27) Bárcena, Brenda; Salamanca, Aurora; Pintado, Cristina; Mazuecos, Lorena; Villar, Margarita; Moltó, Eduardo; Bonzón-Kulichenko, Elena; Vázquez, Jesús; Andrés, Antonio; Gallardo, Nilda
Aging is a continuous, universal, and irreversible process that determines progressive loss of adaptability. The liver is a critical organ that supports digestion, metabolism, immunity, detoxification, vitamin storage, and hormone signaling. Nevertheless, the relationship between aging and the development of liver diseases remains elusive. In fact, although prolonged fasting in adult rodents and humans delays the onset of the disease and increases longevity, whether prolonged fasting could exert adverse effects in old organisms remains incompletely understood. In this work, we aimed to characterize the oxidative stress and nuclear proteome in the liver of 3-month- and 24-month-old male Wistar rats upon 36 h of fasting and its adaptation in response to 30 min of refeeding. To this end, we analyzed the hepatic lipid peroxidation levels (TBARS) and the expression levels of genes associated with fat metabolism and oxidative stress during aging. In addition, to gain a better insight into the molecular and cellular processes that characterize the liver of old rats, the hepatic nuclear proteome was also evaluated by isobaric tag quantitation (iTRAQ) mass spectrometry-based proteomics. In old rats, aging combined with prolonged fasting had great impact on lipid peroxidation in the liver that was associated with a marked downregulation of antioxidant genes (, , and ) compared to young rats. Besides, our proteomic study revealed that RNA splicing is the hepatic nuclear biological process markedly affected by aging and this modification persists upon refeeding. Our results suggest that aged-induced changes in the nuclear proteome could affect processes associated with the adaptative response to refeeding after prolonged fasting, such as those involved in the defense against oxidative stress.
Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.
(NATURE PORTFOLIO, 2021-05-11) de la Fuente-Alonso, Andrea; Toral, Marta; Alfayate, Alvaro; Ruiz-Rodríguez, María Jesús; Bonzón-Kulichenko, Elena; Teixido-Tura, Gisela; Martínez-Martínez, Sara; Méndez-Olivares, María José; López-Maderuelo, Dolores; González-Valdés, Ileana; Garcia-Izquierdo, Eusebio; Mingo, Susana; Martín, Carlos E; Muiño-Mosquera, Laura; De Backer, Julie; Nistal, J Francisco; Forteza, Alberto; Evangelista, Arturo; Vázquez, Jesús; Campanero, Miguel R; Redondo, Juan Miguel
Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Titin cleavage in living cardiomyocytes induces sarcomere disassembly but does not trigger cell proliferation.
(Elsevier, 2026-05-15) Pricolo, Maria Rosaria; López-Unzu, Miguel A; Vicente, Natalia; Morales-López, Cristina; Huerta-López, Carla; Pérez-Franco, Wendy; Dumitru, Andra C; Peña-Peña, Jorge; Espinosa, Francisco M; Sanchez, Mateo I; Garcia, Ricardo; Silva-Rojas, Roberto; Torres, Miguel; Herrero-Galán, Elías; Alegre-Cebollada, Jorge
Adult mammalian hearts have limited regenerative capacity due to the inability of cardiomyocytes to proliferate, a major clinical hurdle in contemporary cardiology. The presence of highly organized, contractile sarcomeres has long been considered an impediment for cardiomyocyte division. Indeed, sarcomere disassembly is a crucial step to complete the cell cycle in the few situations where cardiomyocytes have been observed to proliferate. However, whether sarcomere disassembly can per se trigger cell cycle re-entry remains unknown, a possibility that we have tested here. In this study, we have engineered a system to induce sarcomere disassembly in living murine cardiomyocytes based on the specific cleavage of the structural protein titin by tobacco etch virus protease. Although isolated neonatal cardiomyocytes with disassembled sarcomeres remain viable and retain low-amplitude contractile activity, our results show no evidence of increased cardiomyocyte proliferation in targeted cells, as indicated by the analyses of markers of DNA synthesis and cytokinesis. We obtain equivalent results when titin is cleaved in cardiomyocytes stimulated with mitogenic factors in vitro and in the adult myocardium in vivo. These findings suggest that the removal of sarcomere structural barriers is necessary, but not sufficient, for cardiomyocyte proliferation, which implies that additional factors are required for cardiomyocytes to undergo cell division.
Best Paper of the Year 2024.
(SPRINGER, 2025-02) Mukherjee, Rupak; Lara-Pezzi, Enrique
Polygenic risk for white matter hyperintensities is associated with early cerebrovascular events partly through hemodynamic measures in cognitively unimpaired middle-aged and older adults with low cardiovascular risk.
(FRONTIERS MEDIA SA, 2025) Genius, Patricia; Rodríguez-Fernández, Blanca; Minguillon, Carolina; Brugulat-Serrat, Anna; Huguet, Jordi; Esteller, Manel; Sudre, Carole H; Cortés Canteli, Marta; Tristão-Pereira, Catarina; García Lunar, Inés; Navarro, Arcadi; Gispert, Juan Domingo; Vilor-Tejedor, Natalia
White matter hyperintensities (WMH) are a hallmark of cerebrovascular disease. They are often found in middle-aged individuals and are associated with a greater risk of stroke and vascular dementia. Although traditional cardiovascular risk factors are linked to WMH, some individuals with low vascular risk according to conventional scales still show WMH burden, suggesting an increased vulnerability. This study aimed to elucidate the biological mechanisms underlying the presence of WMH in cognitively unimpaired (CU) middle-aged and older individuals with low cardiovascular risk. We included 1,072 CU participants from the ALFA study with a low cardiovascular risk profile for late-life dementia (CAIDE-I score 9). We defined a multi-stage exploratory study design to reveal the potential biological pathways driving WMH in the study sample. First, we estimated the genetic predisposition to WMH using polygenic scoring (PRS) and used this score as a predictor of: (a) WMHV as a subclinical quantitative measure of global and regional WMH burden and (b) pathological WMH levels (pathological: Fazekas score 2), as a qualitative measure of clinically relevant WMH. Covariate-adjusted Spearman's rank correlation tests evaluated the association between the PRS and regional and global WMH volumes (WMHV), while a logistic regression model was performed to explore the association with pathological WMH. Second, group-stratified partial correlations (CAIDE-specific factors) were explored to identify homogeneous groups with persistent genetic associations with WMH, beyond the presence of cardiovascular risk factors. Third, an enrichment analysis of the PRS-annotated genes unveiled the biological mechanisms leading to WMH burden. Finally, based on the enrichment analysis, we examined the role of cardiometabolic traits as biomarkers of WMHV. Genetic predisposition to WMH was associated with larger global and regional WMHV after adjusting for age and sex, specifically in frontal areas. In this group, larger WMHV were associated with poorer executive function. Group-stratified analyses showed significant correlations particularly among older participants, those with hypercholesterolemia and those with lower educational attainment. Gene-set enrichment involved vascular, neuronal and cellular pathways, and blood pressure measurements partially mediated the association between the genetic risk for WMH and the actual WMHV. These findings support a polygenic contribution to cerebrovascular burden and nominate cardiac function as a biological link along the heart-brain axis. While the PRS is not yet clinically actionable, our results propose and prioritize hemodynamic monitoring as an early, testable intervention in genetically susceptible individuals, to help prevent cerebrovascular damage and downstream cognitive impairment in healthy participants with low cardiovascular risk profile.
A high-fat diet nutritional intervention reprograms cardiac metabolism and improves systolic function in a pig model of heart failure with reduced ejection fraction.
(SPRINGER, 2026-03-27) Galán-Arriola, Carlos; Pérez-Camargo, Daniel; Ferrarini, Alessia; Mastrangelo, Annalaura; Higuero-Verdejo, María Isabel; López-Martín, Gonzalo Javier; Devesa, Ana; Gutiérrez, Rocío Villena; Fernández-Tocino, Miguel; Díaz-Guerra, Anabel; Montero-Cruces, Lourdes; Carnero, Manuel; Fernández-Jiménez, Rodrigo; Fuster, Valentin; Sánchez-González, Javier; Ibáñez, Borja
Most forms of heart failure are characterized by a metabolic switch from the use of fatty acids to glucose as the main fuel source for ATP generation in the myocardium. Whether metabolic reprogramming is a therapeutic target remains controversial. In this study, heart failure with reduced ejection fraction (HFrEF) and metabolic switch (i.e., increased myocardial glucose uptake) was induced in pigs by generating viable dysfunctional myocardium secondary to progressive coronary artery stenosis. Pigs (n = 19) were then randomized to a high-fat diet (HFD, chow diet supplemented with 20% lard) or control diet (no supplementation) for two months. Pre- and post-nutritional treatment contrast-enhanced cardiac magnetic resonance (CMR) and FDG-PET/CT studies were performed. Hearts were then harvested for further analysis. LVEF significantly improved in pigs receiving the 2-month HFD (38% [33, 43] to 54% [47, 62], p = 0.036) but remained unchanged in control-diet pigs (36% [35, 45] to 41% [38, 43], p = 0.24). HFD-fed pigs had a smaller extent of fibrosis after the dietary intervention (late gadolinium enhancement 0.45% LV [0.17, 1.67] vs 6.23 [5.54, 9.57], p = 0.0047). On FDG-PET, a reversion of the metabolic reprogramming in the LAD-dysfunctional myocardium was observed only in HFD-fed pigs (0.46 counts [0.21, 0.65] vs 1.80 [1.53, 2.83], p = 0.016). Transmission electron microscopy of explanted hearts revealed less fragmented mitochondrial and a lower lipid droplet density in cardiomyocytes from HFD-fed pigs (38 per 10 µm3 [34, 50] vs 96 [78, 124], p = 0.022), and this was accompanied by increased expression of genes involved in fatty acid metabolism and downregulation of genes encoding glucose import proteins. In conclusion, in a large animal model of HFrEF secondary to myocardial dysfunction with a metabolic switch, a nutritional intervention based on HFD feeding was associated with a cardiac metabolic restoration of fatty acid substrate use, restoration of cardiomyocyte lipid trafficking and significantly improved systolic function.
Systematic Review of International Population Studies With Cardiac Magnetic Resonance and Genomics Research Data ("Imagenomics").
(Elsevier, 2026-02-20) Hesse, Kerrick; Aung, Nay; Petersen, Steffen E; Siripanthong, Bhurint; Captur, Gabriella; Yeo, Khung Keong; Friedrich, Matthias G; Jaddoe, Vincent W V; Dörr, Marcus; Pischon, Tobias; Bluemke, David A; Ibáñez, Borja; Fuster, Valentin; Chahal, C Anwar A; Khanji, Mohammed Y
Epidemiological population studies may include cardiac magnetic resonance (CMR)-derived phenotyping and large-scale genotyping, providing unprecedented level of detail to investigate novel gene-lifestyle-disease interactions. The systematic review presents high-level summaries and critically appraises contemporary challenges and biobank opportunities. The authors identified 17 relevant biobanks by searching "CMR," "genome" and "population study" on MEDLINE, EMBASE, and Web of Science 2025. Collectively, studies recruited ∼1 million participants with stored blood samples for extensive genomic analyses, of whom >180,000 have or will undergo CMR. Use of expansive personal data must safeguard participant confidentiality, encourage technological standardization, and champion inclusivity and sustainability. Application of genotypic and imaging-derived phenotypic information will be readily translatable to clinical practice through investigation of, among others, new therapeutic targets and highly sensitive and specific biomarkers. Imaging biobanks are accessible to researchers by application. This systematic review should inspire greater use and cross-collaboration and facilitate powerful discoveries in more heterogeneous population samples.
Timing of microglial ablation determines protection from tau-mediated neurodegeneration and cognitive decline.
(BioMed Central, 2026-04-10) Trigo-Alonso, Paula; Luengo, Enrique; Fernández-Mendivíl, Cristina; Viqueira, Lucía; García-Magro, Nuria; Del Sastre, Eric; Bernal, Juan Antonio; Negredo, Pilar; López, Manuela G
Targeting glycogen clearance to treat diabetic cardiomyopathy.
(Springer Nature, 2025-11) García-Quintáns, Nieves; Bernal, Juan A
Impact of dapagliflozin on key pathophysiological pathways underlying chronic heart failure progression: the DAPA-MODA biomarker study.
(EDICIONES DOYMA SA, 2025-11-27) Martínez-Pina, Verónica; Bayés-Genís, Antoni; Nuñez, Julio; Riquelme-Pérez, Alejandro; Cebreiros-López, Iria; Morillas, Herminio; Cobo-Marcos, Marta; García-Pinilla, José M; Rodríguez-Palomares, Juan F; Dobarro, David; Restrepo-Córdoba, María A; González-Juanatey, José R; Zamorano, José L; Noguera-Velasco, José A; Pascual-Figal, Domingo A
Dapagliflozin improves clinical outcomes in patients with chronic heart failure (HF), irrespective of left ventricular ejection fraction. However, its effects on circulating biomarkers that reflect distinct pathophysiological pathways remain incompletely understood. DAPA-MODA is a prospective, multicenter, single-arm study that enrolled patients with stable chronic HF receiving optimized guideline-directed medical therapy, excluding sodium-glucose cotransporter-2 inhibitors. In a predefined biomarker substudy (n=156; 63.5% men; age 70.5±10.6 years; 67.9% with left ventricular ejection fraction > 40%), 11 biomarkers representing 5 key biological pathways (cardiac stress, inflammation, neurohormonal activation, congestion, and fibrosis) were measured at baseline, 1 month, and 6 months. At baseline, markers of myocardial stress were frequently elevated (NT-proBNP [95.5%] and MR-proANP [34.8%]), as was troponin for myocardial injury (73.5%). Inflammatory (IL-6 [40%], CRP [35%], GDF-15 [56%]) and neuro-endocrine stress (copeptin [43%]) markers were also commonly raised. In contrast, elevations in congestion (MR-proADM, CA-125) and fibrosis markers (ST2, PINP) were less frequent, reflecting diverse pathophysiological involvement. Dapagliflozin led to significant reductions in NT-proBNP and MR-proADM levels by 6 months. Reductions in MR-proANP, CRP, IL-6, copeptin, and PINP were confined to patients with elevated baseline levels. ST2 and CA-125 remained unchanged, while GDF-15 levels increased modestly. Dapagliflozin favorably modulates several key pathophysiological pathways involved in chronic HF progression, with differential effects among biomarkers by acting particularly on those that are elevated at baseline.
Titin-related familial dilated cardiomyopathy: factors associated with disease onset.
(OXFORD UNIV PRESS, 2025-12-22) Johnson, Renee; Fletcher, Robert A; Peters, Stacey; Ohanian, Monique; Soka, Magdalena; Smolnikov, Andrei; Abihider, Katherine E; Ackerman, Michael J; Ader, Flavie; Akhtar, Mohammed M; Amin, Ahmad S; Ashley, Euan A; Atherton, John J; Austin, Rachel; Baas, Annette F; Bagnall, Richard D; Ross, Samantha Barratt; Blouin, Jean-Louis; Brown, Emily E; Bundgaard, Henning; Cannie, Douglas; Chmielewski, Przemyslaw; Correnti, Gemma; Crespo-Leiro, Maria Generosa; Dal Ferro, Matteo; Dellefave-Castillo, Lisa M; Dominguez, Fernando; Dooijes, Dennis; Dybro, Anne M; Ed Demri, Youssef; El Hachmi, Mohamed; Escobar-Lopez, Luis; Foye, Sarah Jajesnica; Franaszczyk, Maria; Gigli, Marta; Lopez, Esther Gonzalez; Goudal, Adeline; Graw, Sharon; Guipponi, Michel; Haan, Eric; Haas, Jan; Hammersley, Daniel J; Hansen, Frederikke G; Hayward, Christopher S; Hey, Thomas Morris; Heymans, Stephane; Ho, Carolyn Y; Houweling, Arjan C; Ingles, Jodie; Ingrey, Angela; Jabbour, Andrew; James, Paul A; Jansweijer, Joeri A; Jongbloed, Jan D H; Keogh, Anne M; Larrañaga-Moreira, Jose M; Lekanne Deprez, Ronald H; Macciocca, Ivan; Macdonald, Peter S; Mansencal, Nicolas; Mansour, Julia; Martinez-Veira, Cristina; McDonough, Barbara; McGaughran, Julie; Medo, Kristen; Merlo, Marco; Michalak, Ewa; Monserrat, Lorenzo; Mountain, Helen; Muller, Steven A; Murphy, Anne M; Murray, Brittney; Oates, Emily C; Ormondroyd, Elizabeth; Pachter, Nicholas; Paldino, Alessia; Palmyre, Aurélien; Pereira, Naveen L; Picard, Kermshlise C; Poplawski, Nicola; Prasad, Sanjay; Proukhnitzky, Julie; Pruny, Jean-Francois; Reant, Patricia; Richard, Pascale; Ronan, Anne; Sedaghat-Hamedani, Farbod; Semsarian, Christopher; Storm, Garrett; Stroeks, Sophie; Syrris, Petros; Taylor, Matthew R G; Thomson, Kate; Thompson, Tina; van Tintelen, J Peter; Vissing, Christoffer Rasmus; Waddell-Smith, Kathryn E; Wallis, Mathew; Zentner, Dominica; Arnott, Clare; Marian, Ali J; Oh, Jaewon; Fokstuen, Siv; James, Cynthia A; Barriales-Villa, Roberto; Meder, Benjamin; Wahbi, Karim; Giudicessi, John R; Parikh, Victoria N; Ware, James S; Piriou, Nicolas; Rooryck, Caroline; Lakdawala, Neal K; Mestroni, Luisa; Sinagra, Gianfranco; Elliott, Perry M; Watkins, Hugh; McNally, Elizabeth M; Charron, Philippe; van Spaendonck-Zwarts, Karin Y; Garcia-Pavia, Pablo; Peña-Peña, Maria Luisa; Mogensen, Jens; Christensen, Alex Hoerby; Bilińska, Zofia T; Rasmussen, Torsten B; Seidman, Jonathan G; Seidman, Christine E; Te Riele, Anneline S J M; Verdonschot, Job A J; Pinto, Yigal M; Christiaans, Imke; Fatkin, Diane
Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.
Abstract 4365441: The Prevalence of Clinical Atherosclerosis in Denmark
(Lippincott Williams & Wilkins (LWW), 2025-11-04) Hasselbalch, Rasmus; Kragh, Maja Valentin; Perez-Garcia, Carlos; Eldrup, Nikolaj; Fuster, Jose; Boettcher, Morten; Iversen, Kasper; Kofoed, Klaus; Ibanez, Borja; Bundgaard, Henning
Functional interplay between endothelial nitric oxide synthase and membrane type 1 matrix metalloproteinase in migrating endothelial cells.
(Elsevier, 2007-10-15) Genís, Laura; Gonzalo, Pilar; Tutor, Antonio S; Gálvez, Beatriz G; Martínez-Ruiz, Antonio; Zaragoza, Carlos; Lamas, Santiago; Tryggvason, Karl; Apte, Suneel S; Arroyo, Alicia G
Nitric oxide (NO) is essential for vascular homeostasis and is also a critical modulator of angiogenesis; however, the molecular mechanisms of NO action during angiogenesis remain elusive. We have investigated the potential relationship between NO and membrane type 1-matrix metalloproteinase (MT1-MMP) during endothelial migration and capillary tube formation. Endothelial NO synthase (eNOS) colocalizes with MT1-MMP at motility-associated structures in migratory human endothelial cells (ECs); moreover, NO is produced at these structures and is released into the medium during EC migration. We have therefore addressed 2 questions: (1) the putative regulation of MT1-MMP by NO in migratory ECs; and (2) the requirement for MT1-MMP in NO-induced EC migration and tube formation. NO upregulates MT1-MMP membrane clustering on migratory human ECs, and this is accompanied by increased degradation of type I collagen substrate. MT1-MMP membrane expression and localization are impaired in lung ECs from eNOS-deficient mice, and these cells also show impaired migration and tube formation in vitro. Inhibition of MT1-MMP with a neutralizing antibody impairs NOinduced tube formation by human ECs, and NO-induced endothelial migration and tube formation are impaired in lung ECs from mice deficient in MT1-MMP. MT1-MMP thus appears to be a key molecular effector of NO during the EC migration and angiogenic processes, and is a potential therapeutic target for NO-associated vascular disorders.
Cardiovascular toxicity of checkpoint inhibitors: review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity.
(DOYMA, 2023-11) Zatarain-Nicolás, Eduardo; Martín, Pilar; Márquez Rodas, Iván; Virizuela, Juan; Martín García, Ana; Mitroi, Cristina; Cosín Sales, Juan; Barrios, Vivencio; Sánchez-Cabo, Fátima; Ibañez, Borja; de Castro Carpeño, Javier; López Fernández, Teresa
Immune checkpoint inhibitors (ICI) have changed the prognosis of many tumors. However, concerning associated cardiotoxicity has been reported. Little is known about the real-life incidence-specific surveillance protocols or the translational correlation between the underlying mechanisms and the clinical presentation of ICI-induced cardiotoxicity. The lack of data from prospective studies led us to review the current knowledge and to present the creation of the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT), a prospective registry of patients receiving ICI that aims to examine the role of hsa-miR-Chr8:96, (a specific serum biomarker of myocarditis) in the early diagnosis of ICI-induced myocarditis. An exhaustive prospective cardiac imaging study will be performed before and during the first 12 months of treatment. The correlation between clinical, imaging, and immunologic parameters may improve our understanding of ICI-induced cardiotoxicity and enable simpler surveillance protocols. We assess ICI-induced cardiovascular toxicity and describe the rationale of the SIR-CVT.
T lymphocytes linking autoimmunity and cardiovascular disease in aging
(OAE PUBLISHING INC, 2025-05-30) Ortega-Sollero, Enrique; Ruíz-Fernández, Ignacio; Martín, Pilar
Aging alters the immune system, leading to immunosenescence characterized by impaired T cell functions. The balance between regulatory T cells and type 17 helper T (Th17) cells is crucial for maintaining peripheral immune homeostasis. Aging disrupts this balance, contributing to a systemic chronic proinflammatory environment that increases the prevalence of age-related diseases. The Treg/Th17 imbalance compromises self-tolerance, promoting autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Furthermore, chronic inflammation driven by aberrant T cell responses is a significant risk factor for the progression of cardiovascular diseases (CVD), including hypertension, atherosclerosis, myocardial infarction, and myocarditis. Autoimmune disorders further exacerbate the risk of CVD, which remains the leading cause of mortality among patients with autoimmune diseases. This review provides an in-depth analysis of the mechanisms driving Treg/Th17 imbalance during aging, highlighting its impact on immune homeostasis, autoimmunity, and cardiovascular health. It explores how inflammaging and T cell dysfunction contribute to diseases such as rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, and myocardial infarction, emphasizing shared pathways and therapeutic strategies to restore immune balance and mitigate chronic inflammation. Understanding these immune pathways highlights the therapeutic potential of restoring Treg/Th17 balance to restore immune tolerance and reduce chronic inflammation, thereby mitigating the onset and progression of these age-related conditions.
SILAC-based nuclear proteomics uncovers antitumor mechanisms of selenium nanoparticles with in vivo validation in a melanoma model
(Elsevier, 2025-09) Estevez, Hector; Garcia-Calvo, Estefania; Álvarez-Fernández Garcia, Roberto; Sanchez-Diaz, Raquel; Lazcano, Juan José; Martin, Pilar; Luque-Garcia, Jose L.
Chitosan-stabilized selenium nanoparticles (Ch-SeNPs) are promising agents for cancer therapy due to their unique physicochemical properties, including spherical morphology and uniform size distribution. This study investigates the molecular mechanisms underlying their antitumoral effects, with a focus on the nuclear proteome. Quantitative proteomic analysis revealed 343 nuclear proteins, 47 of which showed significant changes following Ch-SeNPs treatment. Key regulators such as CDK1 and CDC5 were implicated in cell cycle arrest and tumor suppression pathways. Ch-SeNPs also affected processes including mRNA metabolism and cytoskeleton organization. In addition, Ch-SeNPs significantly inhibited tumor growth in a murine melanoma model, supporting their therapeutic potential.

Browse

Recent Submissions