Author + information
- Guiomar Mendieta, MD, MS,
- Soumaya Ben-Aicha, MS,
- Laura Casani, DVM, PhD,
- Lina Badimon, PhD@lbadimon,
- Manel Sabaté, MD, PhD and
- Gemma Vilahur, PhD∗ ()
- ↵∗Cardiovascular ICCC Program, Research Institute-Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Avenida S. Antoni María Claret 167, 08025 Barcelona, Spain
Targeting the inhibition of ischemic damage to limit cardiac post–myocardial infarction (MI) injury is an insufficiently explored therapeutic strategy. Instead, research efforts have mainly focused on therapeutic strategies directed at limiting cardiac damage triggered during reperfusion, but with limited success (1). We have previously shown that 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-Co-AR) inhibition by simvastatin administration just before reperfusion significantly reduces reperfusion injury in swine (2). However, whether inhibition of HMG-Co-AR early during ischemia could limit ischemic lesion progression had not yet been investigated. In this study, we investigated whether an early pharmacoprotective intervention by intravenous HMG-Co-AR inhibition with a modified atorvastatin preparation during coronary occlusion could detain the advancement of ischemic injury and mitigate the progression of MI damage before reperfusion.
Ischemia was induced during 90 min in regular-chow fed pigs (n = 14) by closed-chest left anterior descending coronary artery balloon occlusion, as previously described (3). After 15 min of ischemia, animals were allocated (randomly and blindly) to receive an intravenous infusion of a modified atorvastatin preparation (0.5 mg/kg) or vehicle. The impact of the treatment in the presence of comorbidities (high low-density lipoprotein cholesterol) was evaluated in swine fed a Western-type diet during 10 days before MI induction, following the same protocol afterward (n = 14). Blood samples were taken before ischemia induction and at 30, 60, and 90 min thereafter. To detect acute damage and quantify the degree of ischemic injury accurately, we chose a multimarker approach, measuring ischemia-modified albumin, cardiac fatty acid binding protein, and myoglobin, which have been previously validated in published reports (4). The Institutional Animal Care and Use Committees (CEEA-IR), the European Directive 2010/63/EU, and the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines reviewed and approved the experimental procedures.
The variation among group means (time periods and animal groups) was evaluated using the parametric analysis of variance test, followed by the post hoc Scheffé’s comparison method. A p value <0.05 was considered significant.
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 (Figure 1). Intravenous administration of atorvastatin also reduced the 3 markers of ischemic damage in the presence of hypercholesterolemia (total cholesterol: ≈305 mg/dl; p < 0.05 vs. control; data not shown).
This study is the first to demonstrate that intravenous statin administration at the onset of ischemia significantly mitigates the progression of ischemic injury, as measured by an attenuated rise of acute cardiac ischemia biomarkers. Through the inhibition of HMG-CoAR, statins reduce low-density lipoprotein cholesterol levels and decrease cardiovascular morbidity and mortality. Beyond their lipid-lowering effects, statins have direct cardioprotective and vasculoprotective properties that explain their beneficial effects in the acute phase of MI (5). To evidence the full-blown effects of isoprenoid blockade on the basis of the pharmacokinetics of statins and the clinical scenario of patients needing immediate cardioprotection (in the ambulance or before percutaneous coronary intervention), we speculated on the use of statins at the earliest point during ischemia, and this required intravenous use of a modified statin preparation.
A significant and sustained reduction of ischemic injury in treated animals was evidenced through the attenuated rise of cardiac ischemia biomarkers, which remained at significantly lower levels than in vehicle-administered pigs even after 90 min of ischemia onset. It is worth emphasizing that these cardiovascular benefits were achieved both in normocholesterolemic and hypercholesterolemic animals, although cardiovascular risk factors, such as dyslipidemia, have shown to impair the response to multiple cardioprotective interventions (5).
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.
Please note: The authors thank the Generalitat of Catalunya (Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat, 2017 SGR 1480) and the Fundación Investigación Cardiovascular-Fundación Jesus Serra for their continuous support. The authors gratefully acknowledge the valuable help and support of M.A. Canovas, P. Catalina, O. García, J. Moreno, F.J. Rodriguez, and M. Pescador with animal handling and for the proper conduct of all the experimental work. This work was supported by the Fundació Investigació Marato TV3 (#20154310), Plan Nacional de Salud (PGC2018-094025-BI00 and SAF2016-76819-R) from the Spanish Ministry of Science and Innovation and funds FEDER “Una Manera de Hacer Europa”; the Spanish Society of Cardiology (Beca FEC Investigación Básica/2016); and CIBERCV. Dr. Vilahur has received grants from the Fundació Investigació Marato TV3 (#20154310), Plan Nacional de Salud (PGC2018-094025-BI00) from the Spanish Ministry of Science and Innovation and funds FEDER “Una Manera de Hacer Europa,” and from the Spanish Society of Cardiology (Beca FEC Investigación Básica/2016); and is the holder of the patent that includes the use of statins for intravenous administration. Dr. Badimon has received grants from Plan Nacional de Salud (SAF2016-76819-R) from the Spanish Ministry of Science and Innovation and funds FEDER “Una Manera de Hacer Europa” and from CIBERCV; and is the holder of the patent that includes the use of statins for intravenous administration. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation
- Ibanez B.,
- Heusch G.,
- Ovize M.,
- Van de Werf F.
- Vilahur G.,
- Cubedo J.,
- Casani L.,
- et al.
- Ferdinandy P.,
- Hausenloy D.J.,
- Heusch G.,
- Baxter G.F.,
- Schulz R.