Scientists discover how a Decades-old Drug Reduces the Size of a Heart Attack

Left: Magnetic resonance imaging (MRI) of the heart of a patient after a heart attack. Right: key. 1: left ventricle, 2: left atrium, 3: right ventricle. The major heart muscle surrounds the left ventricle, and healthy muscle appears black on MRI. After an infarction, the necrotic portion of the heart appears white on MRI after injectino of a contrast agent. Credit: CNIC

Scientists at CNIC have discovered a new mechanism of action of metoprolol, a drug that can reduce the damage produced during a heart attack if administered early. Rapid administration of metoprolol during a heart attack directly inhibits the inflammatory action of neutrophils. The reduced inflammation translates into a smaller area of damaged tissue in the post-infarcted heart. The finding, published in Nature Communications, opens the way to new applications for this cheap, safe, and simple drug.

Acute myocardial infarction is a serious disease that affects more than 50 000 people a year in Spain. Treatment has advanced a great deal in recent years, especially in the extensive use of coronary angioplasty. Nevertheless, many heart attack survivors have seriously impaired heart function that limits their long-term health and generates major costs to the health system.

In noninfectious diseases, neutrophils mount an excessive response, and after a myocardial infarction these cells attack the heart, contributing to the long-term injury and impaired function. “In an infarction,” explained Dr. Ibañez, “the most important thing is to re-establish blood flow as soon as possible. But unfortunately, the incoming blood sets off an inflammatory process, started by neutrophils, that causes additional, permanent damage to the heart.” This additional damage due to blood flow restoration is known as reperfusion injury, and has been regarded as a necessary evil because it is essential to unblock the coronary artery rapidly.

Metoprolol is a beta-blocker that has been in clinical use for more than 30 years and costs less than €2 per dose, therefore of little commercial interest. In 2013, the METOCARD-CNIC clinical trial, led and coordinated by the same CNIC research team, showed that administration of metoprolol very early after an infarction reduces the size of the cardiac injury and improves long-term health. “Metoprolol stuns the blood neutrophils, altering their behavior and limiting their injurious inflammatory action on cardiac muscle,” explained Jaime García-Prieto. When coronary blood flow is re-established, neutrophils launch a complex and organized inflammatory reaction, with negative consequences.

According to García-Prieto, “When neutrophils enter the infarcted heart tissue after the restoration of blood flow, they act disproportionately, inducing the death of cells that, while weakened, have survived the infarction.” As Andrés Hidalgo, CNIC scientist and expert on neutrophils, explained, “Neutrophil tissue invasion is intimately related to their interactions with platelets. Metoprolol blocks these interactions, drastically limiting the number of neutrophils arriving in the infarcted tissue.” Moreover, impeding neutrophil invasion also prevents the formation of blood-cell aggregates that block the microcirculation in the post-infarction heart.
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