Enzyme released by cardiac mast cells during heart attack contributes to arrhythmia

In times of cardiac crisis, mast cells in the heart secrete a powerful enzyme, renin, that indirectly triggers dangerous arrhythmias, according to a team of researchers at the Weill Medical College of Cornell University in New York City.

The finding, reported in this month's issue of the Journal of Clinical Investigation, follows up on the team's recent breakthrough discovery that local cardiac mast cells produce renin. Experts had previously assumed that renin was secreted primarily by the kidneys.

"Now we've discovered that mast cell renin is released locally during heart attack or other acute cardiac events. This may help explain why the heart is especially prone to arrhythmias at these times," said study senior researcher Dr. Roberto Levi, Professor of Pharmacology at Weill Cornell Medical College.

Inhibiting local renin production might prove a valuable new means of preventing these dangerous heart rhythms, he added.

According to Dr. Levi, renin produced by local mast cells triggers cardiac arrhythmia via a series of biochemical steps.

"One of renin's big jobs as an enzyme is to break down a large-molecule protein called angiotensinogen into a smaller molecule, called angiotensin 1," he explained.

Angiotensin 1 is then converted to the active angiotensin 2, which has strong links to high blood pressure -- in fact, widely used drugs called "angiotensin converting enzyme (ACE) inhibitors" work by reducing angiotensin's hypertensive effects.

But angiotensin's impact on cardiac arrhythmias has been less clear.

"It now appears that angiotensin 2 -- formed by renin released from local mast cells -- triggers the release of massive amounts of a neurochemical, called norepinephrine, from nerves within the heart," said the study's other senior author, Dr. Randi Silver, Associate Professor of Physiology and Biophysics at Weill Cornell.

"In such high amounts, norepinephrine disrupts normal cardiac rhythms," she said. "In our experiments, the most common result was a type of arrhythmia called ventricular fibrillation."

Cardiac mast cells appear to produce high levels of renin during periods of cardiac stress, such as during heart attack.

In their experiments, the Weill Cornell team tracked the heart rhythms of guinea pigs and mice that underwent ischemia and reperfusion -- the sometimes damaging rush of blood back to the heart that occurs during heart attack in vessels blocked by atherosclerosis.

"We noticed a liberation of renin into the coronary effluent that we didn't see under normal conditions. This was associated with angiotensin formation and generation of arrhythmias," Dr. Levi said. "However, if we stabilized the animal's cardiac mast cells and prevented this renin release, we successfully prevented the arrhythmia."

The finding suggests that drugs that inhibit the release of renin by local mast cells could protect heart patients from abnormal heart rhythms.

"Our labs work at the basic science level, so research into pharmaceuticals would need to move to the clinical setting," Dr. Silver said. "But it does look promising."

The findings could also have implications for the treatment of non-acute conditions such as heart failure.

"Patients with chronic conditions such as angina may be releasing small but significant amounts of renin -- and therefore, angiotensin -- all the time," Dr. Levi said. "We know that long exposure to angiotensin can induce the kind of fibrosis (thickening) that leads to enlarged and stiffened hearts and heart failure. So, lowering angiotensin via local renin inhibition might help prevent those conditions, too."

This work was supported by grants from the National Institutes of Health.

Co-authors include lead researcher Dr. Christina J. Mackins, Dr. Seiichiro Kano, Dr. Nahid Seyedi, Dr. Ulrich Schaefer, Alicia C. Reid, and Takuji Machida -- all of Weill Cornell Medical College.

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