Researchers debut practice of monitoring mitochondria to predict, prevent cardiac arrest

New technology developed by researchers at Boston Children’s Hospital in conjunction with Cambridge-based Pendar Technologies has the ability to monitor oxygen levels in human tissue and predict cardiac arrest in heart patients, a study published in Science Translational Medicine reports.

Co-leader of the study John N. Kheir, MD, and colleagues at Boston Children’s Heart Center developed the pen-sized device in an effort to monitor the amount of oxygen a body—and the heart in particular—receives in real time. Currently, tissue oxygenation is measured largely through mixed venous saturation (SvO2), which is successful but requires repeated blood draws, which can be dangerous in already-unstable heart disease patients. SvO2 also can’t determine whether or not organ tissues are receiving sufficient oxygen for optimal performance.

“This is an important area for us, clinically, as we take care of vulnerable patients during and after major cardiac surgeries,” Kheir said in an email. “We are always looking for ways to better monitor our patients in critical care, especially to predict a problem before it results in an event like cardiac arrest. Even a few minutes more warning gives the healthcare team time to be proactive instead of reactive, and that could have a major impact on outcomes.”

Pendar CEO and co-corresponding author on the study Daryoosh Vakhshoori, PhD, and Kheir’s team worked to develop a device that would monitor oxygen levels in the mitochondria, the power centers of cells that process energy. When the body isn’t receiving enough oxygen, as is the case in patients with impaired breathing or circulation issues, the efficiency of the mitochondria is likewise compromised.

Using technology known as resonance Raman spectroscopy (RRS), the researchers are able to quantify the amount of oxygen reaching cells’ mitochondria, and can be alerted to oxygen shortages that could result in serious conditions like cardiac arrest. Although Vakhshoori said Pendar has been studying RRS for some time now, primarily focusing on hemoglobin oxygenation in the blood, doctors haven’t been able to predict when someone’s heart will cease to function until now. According to the study, because the heart has an impressive ability to compensate for low-oxygen conditions, it’s been hard to tell how severe the problem is until the heart stops. Echocardiograms and monitoring blood pressure can only go so far in predicting these outcomes.

“Current metrics only provide surrogate measures of tissue injury or ischemia,” Kheir said. “In contrast, monitoring the mitochondrion using RRS provides a continuous readout of how satisfied the mitochondrion is with its substrate provision. Not only can this provide continuous information, but the readout of the ‘danger zone’ value was independent of the cause of the insult.”

When cells run out of oxygen, Kheir’s research stated, the equilibrium of the organism is changed. Electrons accumulate in mitochondrial proteins like hemoglobin, myoglobin and mitochondrial cytochromes, causing an energy shift that can kill cells or shut down mitochondria.

Using RRS, Kheir and colleagues measured oxygen flow with a metric known as 3RMR (the resonance Raman reduce mitochondrial ratio), which uses light readings to assess mitochondrial function and oxygen levels. Using a custom-built, 441-nm single-mode laser, they could see how light scattered across mitochondrial proteins, indicating how many electrons were on those proteins and if those levels were dangerous. The information was processed with a complex, unique algorithm developed by the authors.

Researchers tested the technology in both test rats and pigs. In rats, scientists discovered lower levels of oxygen in the heart directly correlated with higher levels of 3RMR. After measuring cell activity during 10 minutes of low-oxygen exposure, the study’s authors found that 3RMR spikes of more than 40 percent predicted reduced heart contractility and cardiac arrest. These results were overwhelmingly accurate, at 95 percent specificity and 100 percent sensitivity.

Vakhshoori said this was when the team saw a breakthrough.

“It was gratifying to find that for our model of cardiac hypoxia, the 3RMR measurement almost perfectly predicted impending cardiac failure, with no false positives,” he said. “The fact that 3RMR outperformed the hemoglobin or myoglobin oxygen saturation as well as tPO2 and ejection fraction measurements demonstrated that we are really getting to where the oxygen is utilized.”

Researchers also simulated congenital heart surgery in a pig and determined how satisfied the heart was with its supply of oxygen—something that’s never been done before.

Kheir and colleagues’ spectroscopic system successfully detected changes in mitochondrial redox state in vivo, the authors wrote, within as little as two to three minutes. In the study, the authors called the technique a “new paradigm to assess the adequacy of oxygen delivery to a tissue.”

“We were able to visualize cellular energetics in real-time, identifying the time when the myocardium is so energy deficient that it cannot function properly,” Kheir said. “This may be an early warning marker of problems following coronary artery surgery, or eventually a way to monitor myocardial oxygen delivery after surgery in the ICU. In the future, monitoring other organs in the same way will be possible, such as during organ transplantation or microvascular surgery.”

The researchers said next steps include determining the range of normal 3RMR level in healthy myocardium, monitoring organoids and engineered tissues non-invasively for their mitochondrial activities and continuing to work with Pendar to develop promising technology.