Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

Abstract

The significant reduction in 'ischemic time' through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

Keywords: coronary microvascular obstruction; extracellular matrix; left ventricular remodeling; primary percutaneous coronary intervention; remote ischemic conditioning.

Figure 1

Schematic representation of the different mechanisms involved in the development of post-STEMI LVR. ECM: extracellular matrix; iLVEDV: indexed left ventricular end-diastolic volume; LVR: left ventricular remodeling; STEMI: ST elevation myocardial infarction; miRs: micro-RNAs; IL: interleukin; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor-α; Ly6c: lymphocyte 6 cytotoxic; TGF-β: tumor growth factor-β; MMPs: metalloproteinases; TIMPs: tissue inhibitor of metalloproteinases. ↑ indicates an increase; ↓ indicates a decrease.

Figure 2

Principal effects of pharmacological therapies and mechanical interventions on pathophysiological determinants of post-STEMI LVR. LVR: left ventricular remodeling; STEMI: ST elevation myocardial infarction; RAAS: renin angiotensin aldosterone system; SAC/VAL: sacubitril/valsartan; PCSK9: proprotein convertase subtilisin/kexin type 9; Gp IIb IIIa; glycoprotein IIb IIIa; RIPer-C: remote ischemic perconditioning; RIPost-C: remote ischemic post-conditioning; miRs: micro-RNAs. ↑ indicates an increase; ↓ indicates a decrease.

Figure 3

Scheme for a reasoned multitarget therapeutic strategy against post-STEMI LVR, in the ‘pre-PCI’ and ‘during-pPCI’ phases. On the left side of the picture, the timing of conventional pharmacological therapy for STEMI patients is described, in the ‘pre-PCI’ and ‘during-pPCI’ phases, according to the European Society of Cardiology (ESC) guidelines. Each pharmacological indication is identified with its own class of recommendation and level of evidence. On the right side of the picture, perspective pharmacological therapies and mechanical interventions in order to further improve protection against post-STEMI LVR according to precise timing are listed. PCSK9 inhibitors, liraglutide, and RIPer-C should be administered in the ‘pre-PCI’ phase, whereas thrombus aspiration (especially in patients with high glycemic values) and adenosine (in case of no-reflow phenomenon) should be used in the ‘during-pPCI’ phase. STEMI: ST elevation myocardial infarction; pPCI: primary percutaneous intervention; LVR: left ventricular remodeling; PCSK9: proprotein convertase subtilisin/kexin type 9; RIPer-C: remote ischemic perconditioning; ASA: acetylsalicylic acid; UFH: unfractioned heparin; Gp IIb IIIa: glycoprotein IIb IIIa.

Figure 4

Scheme for a reasoned multitarget therapeutic strategy against post-STEMI LVR in the ‘post-pPCI’ phase. In this picture, the timing of conventional pharmacological therapy for STEMI patients, in the ‘post-pPCI’ phase is described, according to the European Society of Cardiology (ESC) guidelines. Each pharmacological indication is identified with its own class of recommendation and level of evidence. In the gray rectangles, the perspective pharmacological therapies (ARNI, liraglutide, glifozins) and mechanical interventions (RIPost-C) in order to further improve protection against post-STEMI LVR according to precise timing are identified. STEMI: ST elevation myocardial infarction; pPCI: primary percutaneous intervention; LVR: left ventricular remodeling; ARNI: angiotensin receptor neprilysin inhibitor; RIPost-C: remote ischemic post-conditioning; PCSK9: proprotein convertase subtilisin/kexin type 9; ARBs: angiotensin receptor blockers; MRAs: mineralocorticoid receptor antagonists; DAPT: dual anti-platelet therapy; ASA: acetylsalicylic acid; LVEF: left ventricular ejection fraction.