17 Apr Heart Responds To Stress of Cardiac Surgery By Clearing Damaged Mitochondria and Making New Ones
MedicalResearch.com Interview with:
Dr. Roberta Gottlieb
Roberta Gottlieb, MD
Director of Molecular Cardiobiology
Professor of Medicine
Cedars-Sinai Heart Institute
Cedars-Sinai
Los Angeles, California
MedicalResearch.com: What is the background for this study?
Response: Most heart surgeries involve stopping the heart and relying upon a machine to oxygenate the blood and pump it to the rest of the body, a procedure called cardiopulmonary bypass. The heart is typically cooled, which further reduces metabolic demand. During this time, the heart is without a blood supply to provide oxygen and nutrients, but near the end of the procedure, the heart is re-started and blood flow is restored. This period of ischemia followed by reperfusion can injure the heart muscle, much like what happens during a myocardial infarction, or heart attack.
It has been shown that the degree of injury at the time of surgery (measured by the release of cardiac enzymes) is associated with mortality at 30 days and risk of heart failure within 3 years. For that reason, it is important to understand the cellular and molecular events that occur in the heart muscle during cardiac surgery so that we can decrease ischemia/reperfusion injury.
MedicalResearch.com: What are the main findings?
Response: In this study, we obtained small biopsies of the heart at the beginning and end of the surgery. The biopsies are taken from a section of the heart that is normally trimmed during the surgery in order to place the cardiopulmonary bypass tubing. We had previously reported that the process of autophagy is activated during surgery. Autophagy is a cellular recycling program that breaks down intracellular organelles and protein aggregates in order to provide building blocks for energy production or new protein synthesis. In the present study, we asked if mitochondria — the powerhouses of the cell — were targets of autophagy. We found that indeed, mitochondria were tagged for destruction through autophagy.
We also found evidence of damage to mitochondrial DNA, likely related to ischemia/reperfusion injury. What was very surprising was that there was strong evidence of cellular activity to make new mitochondria, a very energy-demanding process. It seems unusual to expend energy making new mitochondria when the heart is so severely stressed by ischemia and reperfusion associated with surgery; yet this phenomenon was observed in almost every one of the patients studied.
We found that this process did not involve new gene expression but instead relied on pre-existing mRNAs that were then pressed into service to make new proteins that were needed for the mitochondria. We do not yet know if this response is a helpful adaptation for the heart or if it is a feature of ischemia/reperfusion injury, and we do not yet know whether the mitochondrial DNA damage we observed will be repaired over time or if that damage is associated with subsequent risk of heart failure.
MedicalResearch.com: What should readers take away from your report?
Response: The heart responds to the stress of ischemia and reperfusion with a complex and tightly coordinated program to clear damaged mitochondria and make new ones. Interestingly this program strongly resembles what occurs in squirrels as they emerge from winter torpor (hibernation). They also use stored mRNA to make new mitochondria at a time when the animal has very little remaining in the way of energy stores. Thus, this process appears to be an evolutionarily conserved response to severe stress. More work is needed, however, to understand whether this program, when activated in the ischemic human heart, is helpful or harmful.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: We plan to investigate the mechanisms involved, using animal models, and to test drugs that can enhance or suppress this response, in order to gain insight into ways to help the human heart.
MedicalResearch.com: Is there anything else you would like to add?
Response: We would like to acknowledge the support of the National Institutes of Health (NIH), which made this research possible, as well as support from the Dorothy and E. Phillip Lyon Chair in Molecular Cardiology and the American Heart Association. The NIH award numbers were P01 HL112730, R01 HL132075 and R01 HL103859.
We would also like to express our appreciation to the team of surgeons and investigators at Beaumont Hospital in Dearborn Michigan that collected these important samples. This work was performed with approval of the Human Subjects Committees at both institutions. As the tissue is ordinarily discarded in the routine course of surgery, informed consent was not required and no patient identifying information was collected. The information we were able to gain from these tissue samples is invaluable and we extend our appreciation to the patients from whom it was obtained.
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Citation:
JCI Insight. 2017 Feb 23;2(4):e89303. doi: 10.1172/jci.insight.89303.
Mitophagy and mitochondrial biogenesis in atrial tissue of patients undergoing heart surgery with cardiopulmonary bypass.
Andres AM1, Tucker KC1, Thomas A1, Taylor DJ1, Sengstock D2, Jahania SM2, Dabir R2, Pourpirali S1, Brown JA3, Westbrook DG3, Ballinger SW3, Mentzer RM Jr1, Gottlieb RA1.
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Last Updated on April 17, 2017 by Marie Benz MD FAAD