Tracking down the causes of heart failure – Marta Vigil-Garcia

In the “From the lab to…” series, we highlight our team’s scientific expertise by providing the spotlight to colleagues who have recently published their research. For our first edition we learn about the research and background of Life Science Consultant, Marta Vigil-Garcia, PhD. Marta’s background is in cardiovascular research, and her recent publication identifies new potential therapeutic targets for the treatment of cardiac disease.

“A unique thing about the heart is that the majority of cardiomyocytes (heart cells) lose their ability to divide after birth”

Heart failure is a disease of our time, but it is known since ancient times. It is believed that the oldest identified case of heart failure is from remains discovered in a plundered tomb in the Valley of the Queens. The remains date back over 3500 years and are now housed in the Egyptian museum in Turin, Italy. Today, heart failure is considered a global health priority, and it affects over 26 million people worldwide.

Heart failure is a chronic, progressive condition in which the heart muscle is unable to pump enough blood to meet the body’s needs for blood and oxygen. Basically, the heart can’t keep up with its workload. What does this mean? Heart cells (cardiomyocytes) start to fail and die, leading to a progressive cardiomyocyte loss and formation of scar tissue.

Current heart failure therapies are mainly directed at managing the symptoms of the patients, and/or heart transplantation to prevent sudden cardiac death. For the last decade, many successful stories of the development of drug therapies that can reverse heart failure have fallen short, because many novel therapies failed to offer benefits, or raised safety concerns (i.e. hypotension). A major unmet need in drug development is the ability to identify the underlying disease drivers that could be targeted by a new therapeutic agent.

The centre-point of their research involved the isolation of heart cells (cardiomyocytes) from a mouse model of cardiac hypertrophy. Then, through gene expression analysis of failing cardiomyocytes, they were able to identify an activated genetic program relevant for human heart failure. Figure adapted from Vigil-Garcia et al., 2020.

Facing the challenges of academic research

Our team member Marta, co-authored the study “Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling”, published recently in Cardiovascular Research. The research, performed at the Hubrecht Institute, Utrecht, identified a set of new genes that could serve as potential therapeutic targets in heart failure patients.

The study used a state-of-the-art cell isolation method to collect cardiomyocytes and consequently perform cardiomyocyte-specific RNA sequencing. This technique allowed the researchers to identify which genes were being actively transcribed in this specific cell type. Thus, it was possible to study failing cardiomyocytes to find the active genetic proponents of the disease.

Marta described how isolating the cardiomyocytes presented a technical challenge, due to the characteristics of these cells: “It is very challenging to isolate cardiomyocytes. The heart cells can easily break during lab processing and therefore can have an impact on the final data. You need to make sure you have a lot of quality checks and of course, you must treat your cells very well!”

“Data analysis day” … the return of a big data set is a momentous occasion

While reflecting on some of the most exciting moments of her PhD study, Marta talks of a moment many researchers await with eager anticipation, the return of the sequencing data: “A special time during my research was when we sent our RNA sequencing samples for analysis, and waited for the data to come back. We then have a full data set to conduct analyses on, find new targets, and understand what’s going on. You must see what you can take out of the data and translate that into biology and use it to design and conduct new experiments that can further your research.”

By analysing the sequencing data, Marta and her collaborators identified a specific gene programme activated in the mouse hearts containing previously undescribed genes. To investigate the relevance of this genetic program, they used induced-pluripotent stem cell (iPSC) – derived cardiomyocytes and heart failure samples from patients. They showed that the identified genetic program (in mice), is also conserved in humans.

Differentiating iPSCs to cardiomyocytes is an elaborate and lengthy process, which requires diligent care and attention. “Another aspect of this research was the personal challenge to use iPSCs, as differentiating these into cardiomyocytes is very extensive. For example, you need to go into the lab on weekends, so it is very time consuming and it does not always work. You have to treat the cells very well… they are your little babies!”  Marta says, describing the challenge of using iPSCs.

Finally, at the end of the study they identified a metabolic enzyme that plays an important role in glucose metabolism. By identifying relevant genes in worsening the condition of the heart, we can develop new therapies that minimize the loss of cardiomyocytes and/or reverse the adverse remodelling processes in the diseased heart.

“The moment you submit the paper is very exciting, also I enjoyed presenting in conferences, meeting people and networking. Talking with people working in similar subjects can be weird, because there are so few people working within the same specific subject as you at an academic level. It is nice to be able to communicate with and understand peers researching similar subjects.”

Transitioning from research to working at Catalyze

Lastly, we asked Marta how her experiences of scientific research continue to support her in her role as a Life Sciences Consultant: “With my background I can understand the clients and their scientific ideas faster. I think that my experience in the academic environment helps me to connect better with professors, or CEOs that have also been in that environment and have a research background.”

Working at Catalyze, she says, is about something bigger — a shared love of science and its value to society: “We love science, in the way that we, generally, like what science does. By working at Catalyze we can help the scientific world move forward from a different perspective”.

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