First person – Saba Naghipour

Saba Naghipour

How would you explain the main findings of your paper to non-scientific family and friends?

Trimethylamine-N-oxide (TMAO) is a chemical your gut bacteria can create when you eat certain foods like meat, fish, dairy and eggs. It is now believed that when this chemical gets too high in your blood that your risk of heart disease is increased, but we don't really understand how or why. In particular, the impact this chemical has on the heart’s ability to pump blood or produce chemical energy is poorly understood.

Our new research shows that short exposures of this chemical to the heart are enough to lower the blood pressure generated by the heart, an effect that also lowers how much blood the heart itself receives. Interestingly, we also demonstrate a paradox; that is, the heart's ability to create chemical energy is increased an unhealthy amount. This is like slamming the accelerator of a car and pushing the rev-counter well into the red zone; you might get to where you need faster, but at the cost of engine integrity and damage. When we look deeper into how the proteins of the heart may be influenced, they agree with the findings that more energy is being produced despite lowering the heart's ability to work.

These are really interesting findings, as we show, for the first time, that exposure of this chemical to your heart for a short time frame is enough to decrease the heart's role as a blood pump, whilst also overactivating and stressing the heart's energy power plant.

What are the potential implications of these results for your field of research?

We demonstrate that acute exposure of TMAO in a Langendorff perfused mouse heart within a concentration range that covers elevations observed in various disease states can depress left ventricular pressure development, an effect that also decreases coronary flow. We also show that acute TMAO exposure to the myocardium can stress the mitochondria into an ‘overdrive’ phenotype. Given that TMAO is thought to be linked to cardiovascular disease (CVD), the implications of these findings are that acute elevations, often observed post-prandially in response to animal food products, may also be impacting the cardiovascular system. As such, repeated elevations over a chronic period may be increasing the risk of CVD development. Thus, TMAO may serve as a suitable target in the prevention or treatment of CVD, either via drug targeting or with dietary intake adjustment.

What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?

The main advantage of using a Langendorff perfusion apparatus is that it allows us to measure ex vivo activity in a working heart and manipulate it for our experimental design. We can infuse drugs in a dose–response manner, as we do so in the following experiment, we can perform pressure–volume loops, we can conduct ischaemia/reperfusion studies, and we can perform reactive hyperaemia studies to investigate coronary reserve. Conversely, given that this is performed ex vivo, we cannot come back at a later period to re-assess cardiac function in the same heart, which would be more useful when studying the heart’s ability to recover long term from ischaemia/reperfusion damage.

The Oroboros Oxygraph-2k system that we also use in this study is useful given its high resolution and flexibility to perform and dictate experiments to your judgement. However, its throughput is its drawback, given that each machine can only assess two samples, whereas other systems, though they are limited with their protocol designs, can run many more samples at once.

What has surprised you the most while conducting your research?

Our main surprise from this work concerns the overactivation of mitochondrial respiration in the heart in response to TMAO. Previous studies have demonstrated that chronic exposure to TMAO can decrease mitochondrial respiration in the heart, a result we were also anticipating in this study. Conversely, we demonstrated that acute exposure increased mitochondrial respiration into an ‘overdrive’ phenotype. The data thus imply that TMAO stresses the mitochondria into this overdrive phenotype, and with prolonged exposure this would result in the depressed respiration phenotype that others have previously shown with chronic exposure.

What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?

Research funding is always an incredibly large road bump in the pathway of research. Lack of funding means that rather than being able to design an elaborate experiment to address a big research question, we are forced to design an experiment within our lab budget that can address part of the question, and compromises are thus made. For example, male animals are only used in experiments to save money, whereas ideally both sexes would be used. Additionally, more funding allows for greater data to be generated, which in the absence of, some part of the research story may have otherwise been lost and unrealised. To solve this problem, there needs to be a shift in funding towards basic research again, as discoveries made here are what produce viable targets and studies for the clinical setting to further investigate. Furthermore, the premise of using successful grant track records to win further grants allows funded labs to continually stay funded, whilst those who have been without a grant for some time struggle to acquire one to fund their work; this is unfair. Perhaps there needs to be less emphasis on grant track records in the acquisition of further ones.

What changes do you think could improve the professional lives of scientists?

I believe a healthier work–life balance (whatever that actually is) would immensely improve the professional lives of scientists. I have found that in recent years, academics, scientists and PhD students are buried under a tonne of administrative paperwork, and, as such, have their time, energy and focus taken away from their research, which should be their main focus. How this will actually be achieved I believe depends on who is trying to be relieved from their excess workload; a lab manager put in place to take the pressure off PhD students from taking care of the lab, or a grant writer to remove the burdens of academics and PIs. For myself personally, the hours spent chasing up quotes and tech companies, filling out forms for orders and ethics, and waiting on hold with various institutions, adds up to a significant amount of time, which, if was spent in the laboratory or with data analysis instead, would have been more productive for my research workflow.

What's next for you?

We wish to further pursue the findings from the present study. Notably, what is the time duration required for the cardiac mitochondria to go from this overdrive phenotype into the depressed function that others have observed, and what are the implications of chronic TMAO exposure in a healthy and diseased heart. Given that TMAO is found to be elevated in disease states, it is still unclear if it is a direct driver of disease or a new biomarker. We have previously published a review in which we speculate that it is a secondary driver of disease; that is, as a disease phenotype worsens, TMAO is accumulated and elevated in the blood past a pathogenic threshold that would then allow it to participate and drive the disease process too. Thus, it is of interest to us to investigate the role of TMAO in chronic metabolic diseases such as diabetes and obesity.