Grupos de investigación

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

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Anthracycline cardiotoxicity: role of metabolic vulnerability induced by cardiac pressure overload.
(OXFORD UNIV PRESS, 2026-01-13) Galán-Arriola, Carlos; Pérez-Camargo, Daniel; Jorge, Inmaculada; Bautista, Víctor; Ayaon-Albarrán, Ali; Pérez-Martínez, Claudia; de Molina-Iracheta, Antonio; Cádiz, Laura; Medina-Hernández, Danielle; Caballero-Henares, Carlos; Lopez-Martín, Gonzalo J; Vázquez, Jesús; Ochala, Julien; Fuster, Valentin; Sánchez-González, Javier; Ibáñez, Borja
Hypertension and valvular heart disease, both associated with left ventricular (LV) pressure overload, increase the risk of anthracycline cardiotoxicity. While epidemiologically established, the underlying mechanisms remain unclear, precluding identification of therapeutic targets. Two-month-old Yucatan pigs (males and females) underwent aortic banding to induce LV pressure overload or no operation. After 4 months, animals received a low-risk cumulative dose of doxorubicin (5 weekly 1 mg/kg intravenous injections) or vehicle, generating four groups: (i) healthy controls (no LV overload, no doxorubicin), (ii) Dox (doxorubicin, no LV overload), (iii) Banding (B: LV overload, no doxorubicin), and (iv) B + Dox (LV overload plus doxorubicin). Cardiac function, structure, and metabolism were assessed over 8 months by cardiac magnetic resonance, magnetic resonance spectroscopy, and hybrid positron emission tomography/computed tomography. At study end, proteomics and mitochondrial structure and function were analysed. Complementary in vivo and ex vivo studies examined the mechanistic role of energetic imbalance. LV overload increased LV mass (P < .0001) and ejection fraction (P = .0081), with compensatory metabolic changes (drop in phosphocreatine (P = .022)). Low-risk Dox alone altered myocardial metabolism (increased glucose uptake, P = .014) but preserved cardiac function. In pigs with pre-existing LV pressure overload, doxorubicin increased mortality (P < .0001 vs all other groups), reduced left ventricular ejection fraction (LVEF) (P < .0001), increased fibrosis, and impaired mitochondrial respiration (P = .032). In HL-1 cardiomyocytes, reducing energy demand with mavacamten rescued cell viability under combined doxorubicin and hypertrophic stress. LV pressure overload increases myocardial susceptibility to anthracycline cardiotoxicity by inducing a high-energy-demand state. Anthracycline treatment, even at a low-risk dose, disrupts compensatory mechanisms in the pressure-overloaded heart, rapidly leading to cardiac dysfunction and heart failure. Preventive strategies targeting this metabolic vulnerability are urgently needed for patients with extant LV pressure overload (e.g. hypertension or valvular heart disease) who are undergoing anthracycline therapy.
Administration of Single or Repeated Doses of CDCs in a Swine Model of Reperfused Myocardial Infarction: Magnetic Resonance and Proteomics Evaluation.
(MDPI, 2025-11-22) de Pedro, María Ángeles; Báez-Díaz, Claudia; Jorge, Inmaculada; Vázquez-Lopez, Fátima; Torrescusa-Bermejo, Axiel; Martinez-Fernandez, Beatriz; Pulido, María; López, Esther; Vázquez, Jesús; Sánchez-Margallo, Francisco M; Crisostomo, Veronica
Some studies report better outcomes in cell therapy for myocardial infarction (MI) with repeated administrations. We aimed to elucidate the potential differences in terms of cardiac function and protein expression after one or three doses of cardiosphere-derived cells (CDCs) in a porcine MI model. CDCs were isolated from swine cardiac explants, cultured in cardiomyocyte growth medium (CGM), and prepared for administration. Pigs surviving a 90 min balloon occlusion of the mid-left anterior descending coronary artery (LAD) were randomly allocated to receive vehicle (CON), one (D1), or three (D3) doses of 30 × 10 CDCs via the infarct-related coronary artery. Cardiac function was assessed with magnetic resonance at baseline and 10 weeks. Programmed electrical stimulation to study arrhythmogenicity was performed at 10 weeks. High-throughput quantitative proteomic analysis of infarcted tissue was performed to identify biological processes based on protein abundance changes between groups. No significant differences were found between the three groups for any cardiac function parameter at 10 weeks. No increase in ventricular tachycardia inducibility was seen in treated groups. However, gene ontology and topological analyses revealed potentially beneficial molecular adaptations. Upregulation of GYS1, AGL, and GBE1 indicated an increase in glycogen biosynthesis and energy availability, while an increase in ANK2, along with hub proteins ALB and TRAP1, suggested cardioprotective effects. Furthermore, the increase in remodeling-related proteins, including EPHA4, PODN, and ALPK3, pointed to favorable structural adaptation following infarction. In conclusion, the intracoronary administration of single or repeated doses of 30 × 10 CDCs to a porcine reperfused MI model shows only slight differential improvement in both cardiac function and protein profile in this experimental setting, thus presenting limited translational potential.
Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
(NATURE PORTFOLIO, 2025-12) Ramírez-Pardo, Ignacio; Campanario, Silvia; Chavda, Bhakti; Santiago-Fernández, Olaya; Flández, Marta; Grima-Terrén, Mercedes; Cisneros, Andrés; Calls-Cobos, Aina; Itzhak, Daniel N; Ngo, Bryan; Janaki-Raman, Sudha; Kantz, Edward D; Ortet, Laura; Diaz, Antonio; Lindenau, Kristen; Doménech-Fernández, Julio; Gómez-Cabrera, Mari Carmen; Camafeita, Emilio; Vázquez, Jesús; Martinez-Vicente, Marta; Serrano, Antonio L; Perdiguero, Eusebio; Isern, Joan; Cuervo, Ana Maria; Muñoz-Cánoves, Pura
Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.
Pro-regenerative fingerprints identified in a sub-population of adult mouse cardiomyocytes by integrative single-cell proteomics.
(BioMed Central, 2026-05-22) Marín-Vicente, Consuelo; Villa Del Campo, Cristina; Calvo, Enrique; Rodríguez, Jose Manuel; Sierra, Rocío; Martín-Salamanca, Sandra; Torroja, Carlos; Végvári, Akos; Zubarev, Roman A; Torres, Miguel; Vázquez, Jesús
Recent advances in instrument sensitivity and sample preparation techniques are significantly improving the ability to study the heterogeneity of cell populations at the single-cell level by mass spectrometry-based proteomics. Integrating multiple layers of cellular data offers additional and yet unexplored insights in single-cell proteomics. In regenerative research, cardiomyocyte proliferation driven by the overexpression of the Myc transcription factor has been described, however, it has not yet been investigated at single-cell resolution. By using an optimized adult cardiomyocytes isolation procedure from mouse models and taking advantage of the integrative capabilities of the iSanXoT application, we are able to minimize batch effects and cell size-related biases, obtain quantitative subcellular compartment information and detect protein alterations within subcellular compartments, as it had not yet been defined for this methodology. This approach enhances data quantification accuracy and facilitates biological interpretation. We show that the Myc transcription factor switches the expression profile of metabolic enzymes and expands a subpopulation of adult cardiomyocytes with a pro-regenerative signature. We demonstrate that different layers of information can properly pattern the proteomic phenotype of single-cells. The analysis of single-cardiomyocyte data with the integrative statistical framework of iSanXoT provided important clues to understand the impact of Myc transcription factor in provoking different immaturity and pro-regenerative signatures in adult mouse cardiomyocytes. The cellular heterogeneity exerted by mouse cardiomyocytes upon Myc overexpression demonstrates the relevance of conducting regenerative studies at the single-cell level for precisely defining the amplitude of this response in the heart.
Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
(NATL ACAD SCIENCES, 2026-04-07) García-Domínguez, Esther; García-Domínguez, Cristina; Cabrera-Alarcón, José Luis; Muñoz-Hernández, María Del Mar; Hernansanz-Agustín, Pablo; Curtabbi, Andrea; Domenech-Fernandez, Julio; Calvo, Enrique; Vázquez, Jesús; Serrano, Antonio L; Muñoz-Cánoves, Pura; Olaso-González, Gloria; Enríquez, José Antonio; Gómez-Cabrera, María Carmen
Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.
Glycative Stress Disrupts the Mitochondrial-Lysosome Axis and Promotes Geroconversion in Aging Cardiomyocytes.
(WILEY, 2026-03) Bou-Teen, Diana; Valiuska, Simonas; Miro-Casas, Elisabet; Rubeo, Chiara; Bonzon-Kulichenko, Elena; Nichtova, Zuzana; Fernandez-Sanz, Celia; Inserte, Javier; Rodriguez-Sinovas, Antonio; Benito, Begoña; Ródenas-Alesina, Eduard; Vázquez, Jesús; Ferreira-González, Ignacio; Ruiz-Meana, Marisol
Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more abundant, less acidic, and frequently loaded with lipofuscin. Notably, ~7% of cardiomyocytes showed proinflammatory senescence traits. In vitro, glycative stress in H9c2 myoblasts reproduced mitochondrial AGE buildup, dysfunction, and activation of the mitochondria-lysosome axis. However, AGE-modified mitochondria impaired lysosomal acidification and proteolysis, hindering mitophagic clearance and contributing to lipofuscin accumulation. This sequence of events ultimately led to proinflammatory senescence in a subset of cells. These findings identify mitochondrial AGE accumulation as a novel mechanism of sublethal nonsolved aging-associated stress that eventually triggers geroconversion in cardiomyocytes. This mechanism could facilitate the transition of the aging heart towards a failing phenotype.
Fibronectin-induced overactivation of αβ-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome.
(NATURE PORTFOLIO, 2026-07-06) Alarcón-Ruiz, Iván; Ruiz-Rodríguez, María Jesús; Martínez-Martínez, Sara; Toral, Marta; Martín-Bermejo, Noelia; Mateos-García, Sergio; Gil-Ruiz, Teresa; Herrero-Galán, Elías; Méndez-Olivares, María José; López-Maderuelo, Dolores; Gutiérrez-Martínez, Carolina; Clemente, Cristina; Clemente-Manteca, Alejandro; H-Alcántara, Alberto; Guala, Andrea; Evangelista, Arturo; Teixido-Tura, Gisela; Rodríguez-Puyol, Diego; Nistal, Juan Francisco; Alegre-Cebollada, Jorge; Vázquez, Jesús; Duarte, Juan; Redondo, Juan Miguel; Campanero, Miguel R
Thoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an αβ-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased αβ integrin and ILK expression. Disrupting FN assembly or inhibiting αβ, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of Ilk, or smooth muscle-specific deletion of Ilk reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-αβ-PI3K-PIP3-PDK1-ILK-AKT-NOS2 signaling cascade in MFS and support its causative role in human TAAD, highlighting its components as potential targets for therapeutic intervention.
Mitochondria directly interact with the nuclear pore complex.
(NATURE PORTFOLIO, 2026-06) Menendez-Montes, Ivan; Marin-Vicente, Consuelo; Mukherjee, Shibani; Ahmed, Mahmoud Salama; Gomez, Manuel Jose; Anene-Nzelu, Chukwuemeka George; Lee, Chang Jie Mick; Koslowski, Svenja; Solmonson, Ashley; Tassin, Tara; Ali, Shah R; Pessoa, Pedro; Elnwasany, Abdallah; Lam, Nicholas T; Thet, Suwannee; Calvo, Enrique; Cardoso, Alisson C; Pereira, Ana Helena M; Xiao, Feng; Wang, Ping; Mohamed, Asim; El-Feky, Hamed; Elghamry, Ahmed; Gancedo-Alonso, Gonzalo; Nguyen, Ngoc Uyen Nhi; Hsu, Ching-Cheng; Westfall, Aundrea K; DeBerardinis, Ralph; Foo, Roger Sik-Yin; Kinter, Michael; Pressé, Steve; Xing, Chao; Szweda, Luke; Aroumougame, Asaithamby; Sanchez-Cabo, Fatima; Enriquez, Jose Antonio; Torres, Miguel; Vazquez, Jesus; Sadek, Hesham A
Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes, which control pathways including redox and calcium homeostasis. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
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

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