| Title: |
Anthracycline cardiotoxicity: role of metabolic vulnerability induced by cardiac pressure overload |
| Authors: |
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 |
| Contributors: |
European Commission; Spanish Ministry of Science and Innovation; La Caixa; Red Madrileña de Nanomedicina en Imagen Molecular -Comunidad de Madrid; Instituto de Salud Carlos III; Ministerio de Ciencia; Innovación y Universidades; Pro CNIC Foundation; Severo Ochoa Center of Excellence; MICIN; AEI |
| Source: |
European Heart Journal ; ISSN 0195-668X 1522-9645 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2026 |
| Description: |
Background and Aims 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. Methods 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. Results 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. Conclusions 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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/eurheartj/ehaf1060 |
| DOI: |
10.1093/eurheartj/ehaf1060/66394973/ehaf1060.pdf |
| Availability: |
https://doi.org/10.1093/eurheartj/ehaf1060; https://academic.oup.com/eurheartj/advance-article-pdf/doi/10.1093/eurheartj/ehaf1060/66394973/ehaf1060.pdf |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.515D6EF5 |
| Database: |
BASE |