Results may help surgeons determine when and how to treat heart attacks.
While reperfusion can restore cardiac function, such sudden infusions of oxygen can also further injure severely depleted regions of the heart.

“It’s a double–edged sword,” says Anthony McDougal, a graduate student in MIT’s Department of Mechanical Engineering. “The rapid return of oxygen is necessary for the heart to survive, but it could also overwhelm the heart.”

Now McDougal has developed a model that predicts a single heart cell’s response to dwindling supplies of oxygen. Specifically, it evaluates a cell’s ability to keep producing ATP and stay alive, even as it is increasingly deprived of oxygen.

The model is a first step in predicting whether reperfusion techniques will aid or further harm a depleted heart. It may also help to determine the optimal amount of oxygen to apply, given the degree of a heart’s deterioration.

“Part of the reason we’re interested in reperfusion is we’re not sure what is the timescale during which we can reintroduce the oxygen,” McDougal says. “If the tissue has been oxygen–deprived longer, you run into more risk of oxygen damaging the tissue. That becomes more of a problem as you try to address these issues, especially in rural locations that might have less access to hospitals.”

The results were published in the Journal of Biological Chemistry. McDougal’s co–author and advisor is C. Forbes Dewey, emeritus professor of mechanical engineering and biological engineering.

McDougal and Dewey sought to trace the metabolic, energy–producing conditions within a heart cell as it is progressively deprived of oxygen. While some scientists have explored this through various cellular models, most of those models have been limited to short timescales, around one to two minutes after healthy cells have been deprived of oxygen.

“We decided to see what is the state of the cell up to the moment of reperfusion. How is it faring, and what are the main pieces to consider when you begin to reperfuse it?” McDougal says.

McDougal identified 32 general molecular species involved in separate chain reactions to produce ATP. Once he compiled all the equations into the model, McDougal ran more than 200 simulations, to see how a cell’s total ATP production changed as each ATP–producing reaction adapted to various levels of oxygen over various lengths of time.

Surprisingly, the model’s simulations show that heart cells can continue generating ATP, even with oxygen levels as low as 10 percent of the optimal concentration in healthy cells..

As oxygen supplies plummet to around 10 percent, these oxygen–dependent reactions produce less and less ATP. That’s when anaerobic “backup” processes come online. For example, the molecular species creatine phosphate combines with an enzyme to cleave its phosphate group, attaching it to ADP to form more ATP. When reserves of creatine phosphate run low, a cell’s glycogen steps in to fill its role, maintaining ATP levels.

In short, the team found that, even though oxygen may be severely limited, cardiac cells appear to dig deep into their energy arsenals to maintain ATP levels and keep themselves alive.

However, eventually, as oxygen approaches zero, even backup reserves shut down, causing levels of ATP to crash – a point of no return for a fatigued cell. Interestingly, McDougal observed an intermediate stage, in which a heart cell’s ATP levels drop but have not yet crashed.

It is therefore essential to know just the right amount of oxygen to introduce to ischemic portions of the heart that are in such precarious states. For instance, in some cases, rather than introducing a rush of oxygen directly to a depleted region, Dewey says scientists might consider introducing small amounts of oxygen to the newly opened vessel.