Joint Cardioprotective Effect of Vitamin C and Other Antioxidants against Reperfusion Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention

Abstract

Percutaneous coronary intervention (PCI) has long remained the gold standard therapy to restore coronary blood flow after acute myocardial infarction (AMI). However, this procedure leads to the development of increased production of reactive oxygen species (ROS) that can exacerbate the damage caused by AMI, particularly during the reperfusion phase. Numerous attempts based on antioxidant treatments, aimed to reduce the oxidative injury of cardiac tissue, have failed in achieving an effective therapy for these patients. Among these studies, results derived from the use of vitamin C (Vit C) have been inconclusive so far, likely due to suboptimal study designs, misinterpretations, and the erroneous conclusions of clinical trials. Nevertheless, recent clinical trials have shown that the intravenous infusion of Vit C prior to PCI-reduced cardiac injury biomarkers, as well as inflammatory biomarkers and ROS production. In addition, improvements of functional parameters, such as left ventricular ejection fraction (LVEF) and telediastolic left ventricular volume, showed a trend but had an inconclusive association with Vit C. Therefore, it seems reasonable that these beneficial effects could be further enhanced by the association with other antioxidant agents. Indeed, the complexity and the multifactorial nature of the mechanism of injury occurring in AMI demands multitarget agents to reach an enhancement of the expected cardioprotection, a paradigm needing to be demonstrated. The present review provides data supporting the view that an intravenous infusion containing combined safe antioxidants could be a suitable strategy to reduce cardiac injury, thus improving the clinical outcome, life quality, and life expectancy of patients subjected to PCI following AMI.

Keywords: antioxidants; cardioprotection; ischemia-reperfusion; percutaneous coronary intervention; vitamin C.

Figure 1

Molecular mechanisms of the deleterious effects of myocardial reperfusion injury and proposed target of combined antioxidant therapy: Apaf1, apoptosis protease-activating factor-1; ARE, antioxidant response element; CAT, catalase; Cyt C, cytochrome c; DFO, deferoxamine; DMT1, divalent metal transporter 1; GPX, glutathione peroxidase; GSH, reduced glutathione; GSSG, oxidized glutathione; KEAP1, Kelch-like ECH-associated protein 1; LTCC, L-type calcium channel; LOH, lipid alcohols; NAC, N-acetyl-L-cysteine; NCOA4, nuclear receptor coactivator 4; Nrf2, nuclear factor-erythroid 2-related factor 2; NOX, reduced nicotinamide adenine dinucleotide phosphate oxidase; PUFA, polyunsaturated fatty acids; ROS, reactive oxygen species; SOD, superoxide dismutase; Tf, transferrin; TfR1, transferrin receptor protein 1; Vit C, vitamin C; XO, xanthine oxidase.

Figure 2

Molecular structure of vitamin C.

Figure 3

Mechanism of Vit C uptake and its effects in the cell: Reduced form of Vit C is transported through sodium-dependent transporter (SVCT2) and oxidized form, dehydroascorbic acid (DHA), is transported through GLUT4. Inside the cell, DHA is reduced back to Vit C. Vit C increases levels of tetrahydrobiopterin (BH4), levels which are a cofactor for endothelial nitric oxide synthase (eNOS) coupling and important for nitric oxide (NO) synthesis. AA, ascorbic acid; BH4, tetrahydrobiopterin; DHA, dehydroascorbic acid; eNOS, endothelial nitric oxide synthase; GLUT 4, type 4 glucose transporter; GPX, glutathione peroxidase; NO, nitric oxide; SVCT2, sodium-dependent vitamin C transporter 2; Vit E, α-tocopherol: Vit E^., α-tocopheroxyl radical.

Figure 4

Molecular structure of α-tocopherol.

Figure 5

Molecular structure of N-acetylcysteine.

Figure 6

Molecular structure of deferoxamine mesylate.

Figure 7

Molecular structures of two polyphenols: quercetin (A) and resveratrol (B).