Gemma Arderiu, Teresa Padró, María Borrell-Pages, and Lina Badimon
Cardiovascular Research (2025) 00, 1–13
Methods and Results: Hypercholesterolemic pigs underwent a first AMI (90-min coronary balloon occlusion). During ongoing ischaemia, animals received IV-atorva or vehicle. Forty days later, animals underwent RE-AMI and were sacrificed on Day 43. All animals remained on p.o. atorvastatin and a high-cholesterol diet from the first AMI until sacrifice. Serial CMR analysis was performed on Day 3 postAMI, prior- (Day 40) and post-RE-AMI (Day 43). No differences were detected in oedema formation in both animal groups during AMI and RE-AMI. Gadolinium DE-CMR revealed smaller infarcts in IV-atorva-treated animals at index event at 3 and 40 days postAMI compared to vehicle-administered pigs (P < 0.05). CMR analyses post-RE-AMI revealed smaller infarcts in the animals treated with IV-atorva at index event than in the vehicle-administered pigs. These IV-atorva at index event benefits were associated with higher left ventricular (LV) ejection fraction and normal LV wall motion in the jeopardized myocardium at RE-AMI (P < 0.05 vs. vehicle). The scar region of RE-AMI of animals treated with IV-atorva at index event showed reduced cardiac inflammatory infiltrate, apoptosis and senescence activation, and increased reparative fibrosis and neovessel formation vs. vehicle-administered pigs. Animals treated with IV-atorva at index event also showed lower C-reactive protein and higher interleukin-10 plasma levels in the setting of RE-AMI.
Conclusion: The cardioprotection afforded by IV-atorva administration during an index-AMI event shows a legacy effect attenuating myocardial damage and preserving cardiac contractile function upon RE-AMI. The potential benefits of this intravenous approach should be tested in the clinical setting.
Lina Badimon, Guiomar Mendieta, and Gemma Vilahur.Lina Badimon, Guiomar Mendieta, and Gemma Vilahur.
European Heart Journal (2023) 44, 2332–2334
The scientific understanding of the mechanism of action of statins, beyond their cholesterol-lowering properties, has grown considerably over the last years. The benefits of their pleiotropic effects have been attributed to the inhibition of isoprenylation, an effect that can be attained at different levels depending on the type and pharmacokinetic profile of the statin in use. Statin inhibition of mevalonate synthesis prevents isoprenoid intermediate synthesis, including farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). These intermediates serve as important lipid attachments for the post-translational modification of intracellular small G-proteins such as Ras, Rho, and Rac and their downstream effectors. Inhibition of these GTP proteins may be an important mechanism contributing to the pleiotropic effects of statins. Target cellular and molecular points far beyond LDL lowering-mediated effects have been identified and the statin doses required are higher than those for lipid lowering in chronic CV disease (CVD) prevention.
Recent experimental studies in a pre-clinical animal model have demonstrated that the heart is best protected against ischaemia through the administration of an intravenous formulation of modified atorvastatin given during ischaemia and prior to revascularization. However, this novel strategy needs to be proven in human studies.
Guiomar Mendieta, Soumaya Ben‑Aicha, Manuel Gutiérrez, Laura Casani, Monika Arzanauskaité, Francesc Carreras, Manel Sabate, Lina Badimon and Gemma Vilahur.
J Am Coll Cardiol 2020;75:1386–402
Objectives: This study compared the cardioprotective effects of intravenous statin administration during myocardial infarction (MI) with oral administration immediately post-MI in pigs.
Methods: Hypercholesterolemic pigs underwent MI induction (90 min of ischemia) and were kept for 42 days. Animals were distributed in 3 arms (A): A1 received an intravenous bolus of atorvastatin during MI; A2 received an intravenous bolus of vehicle during MI; and A3 received oral atorvastatin within 2 h post-MI. A1 and A3 remained on daily oral atorvastatin for the following 42 days. Cardiac magnetic resonance analysis (days 3 and 42 post-MI) and molecular/histological studies were performed.
Results: At day 3, A1 showed a 10% reduction in infarct size compared with A3 and A2 and a 50% increase in myocardial salvage. At day 42, both A1 and A3 showed a significant decrease in scar size versus A2; however, A1 showed a further 24% reduction versus A3. Functional analyses revealed improved systolic performance in A1 compared with A2 and less wall motion abnormalities in the jeopardized myocardium versus both groups at day 42. A1 showed enhanced collagen content and AMP-activated protein kinase activation in the scar, increased vessel density in the penumbra, higher tumour necrosis factor alpha plasma levels and lower peripheral blood mononuclear cell activation versus both groups.
Conclusions: Intravenous administration of atorvastatin during MI limits cardiac damage, improves cardiac function, and mitigates remodelling to a larger extent than when administered orally shortly after reperfusion. This therapeutic approach deserves to be investigated in ST-segment elevation MI patients.
Also listen to this manuscript’s audio summary by Editor-in-Chief Dr Valentin Fuster on JACC.org.
Also see the Editorial Comment: Statins Make a Difference in Acute Myocardial Infarction. A Revival
Andrea Baehr, Rabea Hinkel, Christian Kupatt.
Guiomar Mendieta, Soumaya Ben‑Aicha, Laura Casani, Lina Badimon, Manel Sabate, Gemma Vilahur.
Basic Research in Cardiology (2020) 115:2
Proof-of-concept studies were carried out in mice and rats in which treatments or vehicle were administered 15 min after initiation of ischemia induced by permanent coronary ligation. Western-blot analyses revealed that in the ischemic myocardium of IV-atorva-treated pigs, RhoA was inactivated, phosphorylation of p53 and caspase-3 was reduced and AMPK was activated with the consequent regulation of the mTOR/raptor-signalling pathway. IV-atorva-treated rats showed, as compared to vehicle, a significant reduction (60%) in scar size assessed at 1 month by histological staining, and mice studies demonstrated the causal involvement of AMPK activation in IV-atorva mediated cardioprotective effects. We demonstrate in pigs and rodents that prompt intravenous treatment with atorvastatin during ischemia limits cardiac cell death and reduces infarct size through AMPK signalling.
Guiomar Mendieta, Soumaya Ben-Aicha, Laura Casani, Lina Badimon, Manel Sabaté, Gemma Vilahur
JACC VOL. 74, NO. 3, JULY 23, 2019:473 Letter
Intravenous administration of atorvastatin early after the onset of ischemia protects against ischemic damage. Indeed, at the 3 time points examined, atorvastatin significantly reduced ischemia-modified albumin, cardiac fatty acid binding protein, and myoglobin blood levels as compared with controls.
In conclusion, intravenous administration of statin in the early phase of ischemia induces fast-acting and long-standing cardioprotective effects in the swine model of MI. Indeed, its application in the context of acute coronary syndrome, particularly in the setting of ST-segment elevation MI on first medical contact, seems highly feasible. Further studies are warranted to provide improved cardioprotective benefits to patients with acute coronary syndrome.
Gemma Vilahur, Laura Casaní, Esther Pena, Xavier Duran, Oriol Juan-Babot, Lina Badimon.
Induction of RISK by HMG-CoA reductase inhibition affords cardioprotection after myocardial infarction. Atherosclerosis 206 (2009) 95–101.
Conclusions: HMG-CoA inhibition early after reperfusion activates RISK kinases, reduces the extent of damaged myocardium, and improves heart function.
Gemma Vilahur, Oriol Juan-Babot, Esther Peña, Blanca Oñate, Laura Casaní, Lina Badimon.
Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction. Journal of Molecular and Cellular Cardiology 50 (2011) 522–533. Results and Conclusions: Accordingly, leukocytes and macrophages are progressively recruited to the IM (P≤0.05). Ischemia up-regulates pro-fibrotic TGF-β that gradually rises collagen1-A1/-A3 mRNA with subsequent increase in total collagen fibrils and fibroblasts from 3 days-R onwards (P≤0.005). MMP-2 activity increases from ischemia to 3 days post-R (P≤0.05). We report that there is a timely coordinated cellular and molecular response to myocardial ischemia and R within the first 6 days after MI. In-depth understanding of the mechanisms involved in tissue repair is warranted to timely intervene and better define novel cardioprotective strategies.
Gemma Vilahur, Laura Casaní, Esther Peña, Oriol Juan-Babot, Guiomar Mendieta, Javier Crespo, Lina Badimon.
HMG-CoA reductase inhibition prior reperfusion improves reparative fibrosis post-myocardial infarction in a preclinical experimental model. International Journal of Cardiology 175 (2014) 528–538.
Conclusions: Acute HMG-CoA-reductase inhibition during total ischemia and prior reperfusion limits reperfusion injury and prolonged oral simvastatin treatment thereafter improves cardiac healing post-MI.
Alex Gallinat, Gemma Vilahur, Teresa Padró and Lina Badimon.
Network-Assisted Systems Biology Analysis of the Mitochondrial Proteome in a Pre-Clinical Model of Ischemia, Revascularization and Post-Conditioning. Int. J. Mol. Sci. 2022, 23, 2087. https://doi.org/ 10.
Lola Fernández Encinas, Nuria Lluch, Alan H B Wu, Juan Carlos Kaski, Lina Badimon, Judit Cubedo.
A Novel ELISA for the Quantification of Serum Levels of 2 Glycosylated Variants of Apolipoprotein J: Biomarkers for Myocardial Ischemia, The Journal of Applied Laboratory Medicine, Volume 8, Issue 5, September 2023, Pages 917–930.
Conclusions: The newly developed ELISAs to quantify ApoJ-GlycA2 and ApoJ-GlycA6 serum levels showed an acceptable analytical performance according to European Medicines Agency guidelines on bioanalytical method validation in terms of precision, accuracy, recovery, cross-reactivity, and stability.
Gemma Vilahur, Laura Casaní, Oriol Juan-Babot, José M. Guerra, Lina Badimon.
Infiltrated cardiac lipids impair myofibroblast-induced healing of the myocardial scar post-myocardial infarction. Atherosclerosis 224 (2012) 368-376.
Conclusion: Intramyocardial lipid accumulation impairs TGFb/TbRII/Smad2/3 signaling altering the fibrotic reparative process of the scar resulting in larger infarcts and cardiac dysfunction.
Gemma Vilahur, Judit Cubedo, Laura Casaní, Teresa Padró, Manel Sabaté-Tenas, Juan J. Badimon, and Lina Badimon.
Reperfusion-triggered stress protein response in the myocardium is blocked by post-conditioning. Systems biology pathway analysis highlights the key role of the canonical aryl-hydrocarbon receptor pathway. European Heart Journal (2013) 34, 2082–2093. Conclusion: Ischaemic post-conditioning improves cardiac function post-myocardial infarction and reduces reperfusion-induced cell damage by down-regulation of the AhR-signalling transduction pathway ultimately leading to infarct size reduction.