TMED Student Showcase: the FRIDA Study and Preclinical Investigation of Mitochondrial Fission Diseases

Written by Abhishek Shastry, MSc Candidate, TMED 801 Student

On March 2nd, audience members at this week’s Medical Grand Rounds had the opportunity to hear from Kiera Liblik and Nolan Breault, two Translational Medicine (TMED) graduate students whose exceptional research was showcased for Department of Medicine staff and students. Kiera, under the supervision of Dr. Amer Johri, is a medical student who completed her MSc while being enrolled in the undergraduate medical program at Queen’s University. Nolan is a second-year MSc student completing his studies under the supervision of Dr. Stephen Archer.
 

Kiera presented her work regarding the Female Risk factors for post-Infarction Depression and Anxiety (FRIDA) study. Ischemic heart disease has a higher 5-year mortality rate in females compared to males, and several female-specific risk factors contribute to this disparity[1]. Female patients may also be at an elevated risk for depression and anxiety outcomes after they have experienced a cardiac event[2]. However, the relationship between various CVD risk factors and their association with depression and anxiety in female patients is unclear. In addition, the specific risk of these outcomes in subgroups of female patients is unknown.
 

To investigate these questions, a pilot study  was implemented[3]. Kiera explained that female patients had higher depression and anxiety scores post-ACS. In addition, loneliness and low socioeconomic status were found to be risk factors anxiety, whereas unemployment in female participants was a large predictor of both anxiety and depression. Kiera and her colleagues to further investigate and collect data regarding what subgroups within this female patient population were disproportionately affected by ACS events.
 

In a larger study investigating cardiovascular risk factors, Kiera found that female patients with a history of diabetes had higher anxiety, and interestingly that a history of ACS was actually protective for anxiety – Kiera that although this data may seem contrary to her previous findings, a diagnosis of ACS may give patients more sureness about their condition, thus reducing anxiety. One of the most important findings from this study, similar to the pilot study, was that low social support was a large predictor of depression.
 

Nolan presented his research regarding abnormal mitochondrial fission in hyperproliferative diseases. Pulmonary arterial hypertension (PAH) is a group of progressive diseases that involve dysfunction of pulmonary artery smooth muscle cells (PASMCs). This dysfunction leads to a narrowing of the blood vessels, ultimately increasing the pulmonary artery pressure. A greater medial enlargement of blood tissues caused by uncontrolled, elevated cell division has been identified as a large cause of PAH, which can result in cardiac failure and death[4].
 

Mitochondria, the powerhouse of the cell, are responsible for producing energy for the cell. Mitochondria can fuse and fission (divide). An increased amount of mitochondrial fission has been associated with cell division, through a mechanism regulated by the Dynamin-related Protein 1 (DRP1)[5]. In PAH, Drp1 is overexpressed; PAH research aims to find inhibitors for this protein, so that increased fission – and therefore the hyperproliferation of cells – can be mitigated. Nolan seeked to investigate Dripitor and compound 6, inhibitors of Drp1.
 

Nolan showed that Dripitor inhibited fission and reduced cell proliferation in the A549 non-small cell lung cancer cell (NSCLC) line, as well as in PAH PASMCs, both of which exhibit a hyperproliferative phenotype. Apoptosis was also increased by Dripitor administration, which helps maintain normal levels of cell growth. Nolan noted that Dripitor was highly specific for Drp1. To study what effect this inhibitor has in vivo, rats with PAH were given Dripitor. Nolan found that the thickness of pulmonary arteries was reduced and that rat hearts were remodelled, which allowed them to function better. Most importantly, pulmonary arterial pressure was improved after Dripitor treatment, along with other measures including pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE), Cardiac Index (CI), and pulmonary vascular resistance (PVR).
 

After their presentations, Kiera and Nolan met with the TMED students to discuss various aspects of their projects, including their projects benefitted patients, how their work is represented in the lay press and considers Equity, Diversity, Inclusivity and Indigeneity initiatives, and their academic and career journeys within the TMED program. Kiera discussed current strategies to strategies to mitigate mental health outcomes in female patients, and Nolan discussed the field of mitochondrial medicine and current paradigms for PAH treatments. As this discussion was unique in that TMED students showcased their work to other TMED students, Kiera and Nolan discussed how they managed to successfully work in fast-paced research environments and recommendations for their fellow TMED students.
 

On behalf of the TMED class, I would like to thank Kiera and Nolan for their presentations and discussions.
 

References

1.         Sabbag, A, et al. (2017). Sex Differences in the Management and 5-Year Outcome of Young Patients (<55 Years) with Acute Coronary Syndromes. The American Journal of Medicine, 130(11), 1324.e15-.e22. https://doi.org/https://doi.org/10.1016/j.amjmed.2017.05.028

2.         Cheok, F, et al. (2003). Identification, course, and treatment of depression after admission for a cardiac condition: rationale and patient characteristics for the identifying depression as a comorbid condition (IDACC) project. American Heart Journal, 146(6), 978-84. https://doi.org/https://doi.org/10.1016/S0002-8703(03)00481-2

3.         Liblik, K, et al. (2021). THE FRIDA PILOT STUDY (FEMALE RISK FACTORS FOR POST-INFARCTION DEPRESSION AND ANXIETY). Canadian Journal of Cardiology, 37(10), S17. https://doi.org/10.1016/j.cjca.2021.07.045

4.         Lai, Y-C, et al. (2014). Pulmonary Arterial Hypertension. Circulation Research, 115(1), 115-30. https://doi.org/10.1161/CIRCRESAHA.115.301146

5.         Hu, C, et al., Drp1-Dependent Mitochondrial Fission Plays Critical Roles in Physiological and Pathological Progresses in Mammals. International Journal of Molecular Sciences. 2017 (10.3390/ijms18010144).