For people who initially¹ survive a heart attack, a significant cause of death in the next few days is cardiac rupture²（破裂） -- literally³, bursting of the heart wall. A new study by University of Iowa researchers pinpoints⁴ a single protein as the key player in the biochemical cascade⁵（层叠，喷流） that leads to cardiac rupture. The findings, published Nov. 13 as an Advance Online Publication (AOP) of the journal Nature Medicine, suggest that blocking the action of this protein, known as CaM kinase, may help prevent cardiac rupture and reduce the risk of death.

After a heart attack, the body produces a range of chemicals that trigger biological processes involved in healing and repair. Unfortunately, many of these chemical signals can become "too much of a good thing" and end up causing further damage often leading to heart failure and sudden death.

"Two of the medicines that are most effective for heart failure are beta-blockers, which block the action of adrenaline（肾上腺素） , and drugs that block the angiotensin receptor," explains Mark E. Anderson, M.D., Ph.D., UI professor and head of internal medicine and senior study author. "The third tier of therapy is medication that blocks the action of aldosterone."

Aldosterone levels increase in patients following a heart attack, and higher levels of the hormone⁶ are clearly associated with greater risk of death in the days immediately following a heart attack.

Increased aldosterone（醛固酮） levels also are associated with a burst of oxidation in heart muscle, and in 2008, Anderson's team showed that oxidation activates⁷ CaM kinase. Anderson's research has also shown that CaM kinase is a lynchpin in the beta-blocker and angiotensin pathways.

"We wondered if aldosterone might somehow work through CaM kinase and, if it did, could some of the benefits of aldosterone blockers be attributed to effects on CaM kinase?" Anderson says.

Anderson's team, including co-first authors Julie He, a student in the UI Medical Scientist Training Program; Mei-Ling Joiner, Ph.D.; Madhu Singh, Ph.D.; Elizabeth Luczak, Ph.D.; and Paari Swaminathan, M.D., devised a series of experiments in mice to investigate how elevated levels of aldosterone damage heart muscle after a heart attack and how Cam kinase（激酶） is involved.

The experiments confirmed that aldosterone increases the amount of oxidized, and therefore, activated⁸ CaM kinase in heart muscle. Mice given excess aldosterone, mimicking⁹ levels seen in human patients, were twice as likely to die after a heart attack as mice that were not given extra aldosterone (70 percent vs. 35 percent), and the cause of death was heart rupture.

Importantly, any treatment that reduced the amount of oxidized CaM kinase or otherwise inhibited¹⁰ CaM kinase activity lowered the risk of cardiac rupture and death in the mice.

Interestingly, the researchers found that activated CaM kinase prompted heart muscle cells to produce an enzyme¹¹ called MMP9 that is implicated¹² in heart rupture.

"Although there are many sources of this enzyme, our study showed that heart muscle itself is actually making this protein too and is acting¹³ against its own self-interest in doing so," Anderson says. "We don't know why it happens, but inhibiting¹⁴ CaM kinase can prevent it."

The MMP9 enzyme is involved in remodeling the "matrix" that surrounds heart cells. This matrix, which acts like mortar¹⁵ between cells, is constantly being broken down and rebuilt. In hearts that rupture after heart attack this remodeling process becomes excessive, weakening the matrix to the point that it ruptures¹⁶.