{"id":12727,"date":"2017-07-24T08:07:46","date_gmt":"2017-07-24T08:07:46","guid":{"rendered":"http:\/\/revoscience.com\/en\/?p=12727"},"modified":"2017-07-24T08:07:46","modified_gmt":"2017-07-24T08:07:46","slug":"study-predicts-heart-cells-response-dwindling-oxygen","status":"publish","type":"post","link":"https:\/\/www.revoscience.com\/en\/study-predicts-heart-cells-response-dwindling-oxygen\/","title":{"rendered":"Study predicts heart cells\u2019 response to dwindling oxygen"},"content":{"rendered":"

Results may help surgeons determine when and how to treat heart attacks.\u00a0<\/strong><\/em><\/span><\/p>\n

\"\"
Graduate student Anthony McDougal has developed a model that predicts a single heart cell\u2019s response to dwindling supplies of oxygen.
Image: MIT News<\/figcaption><\/figure>\n

CAMBRIDGE, Mass. —\u00a0Time is of the essence when treating a patient undergoing a heart attack. Cardiac surgeons attempt to quickly stabilize the heart by applying reperfusion, a technique that restores oxygen to the heart by opening up blocked vessels with balloons and stents. While reperfusion can restore cardiac function, such sudden infusions of oxygen can also further injure severely depleted regions of the heart.<\/span><\/p>\n

\u201cIt\u2019s a double-edged sword,\u201d says Anthony McDougal, a graduate student in MIT\u2019s Department of Mechanical Engineering. \u201cThe rapid return of oxygen is necessary for the heart to survive, but it could also overwhelm the heart.\u201d<\/span><\/p>\n

Now McDougal has developed a model that predicts a single heart cell\u2019s response to dwindling supplies of oxygen. Specifically, it evaluates a cell\u2019s ability to keep producing ATP \u2014 a cell\u2019s primary fuel source \u2014 and stay alive, even as it is increasingly deprived of oxygen.<\/span><\/p>\n

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\u2019s deterioration.<\/span><\/p>\n

\u201cPart of the reason we\u2019re interested in reperfusion is we\u2019re not sure what is the timescale during which we can reintroduce the oxygen,\u201d McDougal says. \u201cIf 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.\u201d<\/span><\/p>\n

The results are published this month in the\u00a0<\/span>Journal of Biological Chemistry<\/a>.\u00a0<\/em>McDougal\u2019s co-author and advisor is C. Forbes Dewey, emeritus professor of mechanical engineering and biological engineering.<\/span><\/p>\n

Changes of heart<\/strong><\/span><\/p>\n

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.<\/span><\/p>\n

McDougal wanted instead to see how a heart cell changes over a much longer timescale, to understand how a patient\u2019s heart may evolve from the time it becomes oxygen-deprived to the point at which a patient may receive reperfusion.<\/span><\/p>\n

\u201cWe 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?\u201d McDougal says.<\/span><\/p>\n

The team focused on modeling the effect of declining oxygen supplies on the chemical reactions responsible for producing ATP in a heart cell.<\/span><\/p>\n

McDougal identified 32 general molecular species involved in separate chain reactions to produce ATP. He then looked through the scientific literature to find enzymatic equations that describe how each individual reaction works, including its dependence on oxygen. He then compiled the equations for all 32 reactions into one model.<\/span><\/p>\n

\u201cThere were a lot of cases where he had to estimate the reaction rates, because two different papers would have different results, based on different animal experiments or different conditions, and he had to work backward to try and normalize the results to see what biological relationships he could get out of them that were meaningful,\u201d Dewey says.<\/span><\/p>\n

Once he compiled all the equations into the model, McDougal ran more than 200 simulations, to see how a cell\u2019s total ATP production changed as each ATP-producing reaction adapted to various levels of oxygen over various lengths of time.<\/span><\/p>\n

Steady, steady, then a crash<\/strong><\/span><\/p>\n

Surprisingly, the model\u2019s 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.<\/span><\/p>\n

With healthy supplies of oxygen, ATP is produced via glycolysis, an aerobic process that requires oxygen to kick off a cascade of chemical reactions involving various molecular species, all ending in the healthy production of ATP. To release useful\u00a0 energy, the cell uses an enzyme to snap off a phosphate molecule from the three-phosphate ATP structure, leaving ADP (adenosine diphosphate) and using the single phosphate to feed various cellular activities.<\/span><\/p>\n

As oxygen supplies plummet to around 10 percent, these oxygen-dependent reactions produce less and less ATP. That\u2019s when anaerobic \u201cbackup\u201d 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\u2019s glycogen steps in to fill its role, maintaining ATP levels.<\/span><\/p>\n

\u201cGlycogen is just a big hair ball of glucose, and at a certain point, with even more pressure on ATP, the cell can pull individual glucose molecules off that hair ball and turn it into energy,\u201d McDougal says.<\/span><\/p>\n

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.<\/span><\/p>\n

However, eventually, as oxygen approaches zero, even backup reserves shut down, causing levels of ATP to crash \u2014 a point of no return for a fatigued cell. Interestingly, McDougal observed an intermediate stage, in which a heart cell\u2019s ATP levels drop but have not yet crashed.<\/span><\/p>\n

\u201cThese are your knife-edge cases, where any small perturbation to the cell could cause it to spiral and die, or come back and stay alive,\u201d McDougal says.<\/span><\/p>\n

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 so that it could slowly diffuse into the injured areas, without shock or harm. \u201cSome animal experiments suggest that this might be beneficial,\u201d Dewey says. \u201cWe now have a model that can begin to evaluate many new treatment methods, seeking ones that have exceptional promise.\u201d<\/span><\/p>\n

\u201cHopefully with time, we can create a better map of exactly how much oxygen to give, at what time point,\u201d McDougal adds.<\/span><\/p>\n

This research was initially supported, in part, by the Singapore-MIT Alliance program in Computational and Systems Biology.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

Results may help surgeons determine when and how to treat heart attacks.\u00a0 CAMBRIDGE, Mass. —\u00a0Time is of the essence when treating a patient undergoing a heart attack. Cardiac surgeons attempt to quickly stabilize the heart by applying reperfusion, a technique that restores oxygen to the heart by opening up blocked vessels with balloons and stents. […]<\/p>\n","protected":false},"author":6,"featured_media":12728,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26,17],"tags":[],"class_list":["post-12727","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicine","category-research"],"featured_image_urls":{"full":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0-150x150.jpg",150,150,true],"medium":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0-300x200.jpg",300,200,true],"medium_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"1536x1536":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"2048x2048":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"ultp_layout_landscape_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"ultp_layout_landscape":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"ultp_layout_portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",600,400,false],"ultp_layout_square":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",600,400,false],"newspaper-x-single-post":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"newspaper-x-recent-post-big":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",540,360,false],"newspaper-x-recent-post-list-image":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",95,63,false],"web-stories-poster-portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",639,426,false],"web-stories-publisher-logo":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",96,64,false],"web-stories-thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2017\/07\/MIT-Cardiac-Muscle_0.jpg",150,100,false]},"author_info":{"info":["Amrita Tuladhar"]},"category_info":"Medicine<\/a> Research<\/a>","tag_info":"Research","comment_count":"0","_links":{"self":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/12727","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/users\/6"}],"replies":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/comments?post=12727"}],"version-history":[{"count":0,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/12727\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media\/12728"}],"wp:attachment":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media?parent=12727"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/categories?post=12727"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/tags?post=12727"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}