Myocardial infarct size is a key determinant of cardiac mortality to the point that infarct reduction strategies are fundamental to its contemporary management, particularly for acute ST-elevation myocardial infarction (STEMI). Minimizing infarct size in acute STEMI is not only dependent on restoring patency of an occluded coronary vessel as soon as possible, but also minimizing myocardial damage from reperfusion injury (ie, the double-edged sword of restoring perfusion). The major factors thought to contribute to reperfusion injury include oxidative stress, intracellular calcium overload, mitochondrial permeability transition pore opening, rapid restoration of physiological pH, and inflammation. Therapeutic strategies intervening in these pathophysiological pathways have been variable, with some showing significant clinical benefits; however; none have been shown to impact major adverse coronary events.
A Novel Combination
N-acetylcysteine (NAC) is a sulfhydryl donor that has two major potential beneficial effects in STEMI: (1) potentiation of the hemodynamic, anti-inflammatory and platelet anti-aggregative effects of nitroglycerin (NTG) in restoring coronary perfusion, and (2) free radical scavenging properties that may minimize oxidative stress. Previous human studies have demonstrated that NAC combined with NTG reduced the development of myocardial infarction in patients with severe unstable angina. Furthermore, in thrombolytic-treated STEMI patients, the combination reduced oxidative stress with a trend toward more rapid ST segment resolution and better preservation of left ventricular function. These studies justified the need for a randomized placebo-controlled study design of NAC/NTG in STEMI patients undergoing PCI –the N-AcetylCysteine in Acute Myocardial infarction (NACIAM) trial.
The NACIAM trial was a randomized, double-blind, placebo-controlled, multicenter study comparing intravenous NTG alone with combined intravenous NAC/NTG, initiated within the emergency department, in acute STEMI patients referred for primary PCI. The study demonstrated a 33% relative reduction (5.5% absolute reduction) in cardiac MRI-assessed infarct size in the NAC-treated patients. In addition, intravenous NAC administration was associated with improved myocardial salvage, more rapid resolution of chest pain, a favorable in-hospital safety profile, and smaller cardiac MRI-assessed infarct size at 3 months post-STEMI.
Further research involving the early use of NAC/NTG therapy is required to determine the mechanisms responsible for the reduced infarct size and evaluate the impact of this therapy on clinical outcomes. Further analysis of the NACIAM data is being undertaken to understand the relative contribution of NAC to infarct size reduction, in relation to its effect on potentiating NTG and its free radical scavenging properties. A large multicenter clinical outcome study assessing the composite endpoint of death and readmission with re-infarction/heart failure is also being contemplated. In the meantime, the NACIAM trial serves as an important advance in acute STEMI management, demonstrating that the early use of agents with coronary vasodilating, anti-platelet, and free radical scavenging properties may reduce infarct size.
Pasupathy S, Ravella R, Grover S, et al. Early use of N-acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction reduces myocardial infarct size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]). Circulation. 2017;136:894-903. Available at http://circ.ahajournals.org/content/136/10/894.
Stone G, Selker H, Thiele H, et al. Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J Am Coll Cardiol. 2016;67:1674-1683.
Hausenloy D, Yellon D. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;12:92-100.
Horowitz J, Antman E, Lorell B. Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation. 1983;68:1247-1253.
Loscalzo J. N-Acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. J Clin Invest. 1985;76:703-708.
Horowitz J, Henry C, Syrjanen M, et al. Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. Circulation. 1988;77:787-794.
Arstall M, Yang J, Stafford I, et al. N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction. safety and biochemical effects. Circulation. 1995;92:2855-2862.