Right Ventricular Metabolic Dysregulation after Surgery for Heart Failure

Kamrouz Ghadimi, MD, MHSc, FAHA, credits his IARS Mentored Research Award in 2020, and the formal training he received through the Duke Clinical Research Institute, and Duke SOM’s Clinical Research Training Program with propelling his career and research forward. This initial research project, “Right Ventricular Metabolic Dysregulation after Surgery for Heart Failure,” set out to determine the role of dysregulated fatty acid oxidation (FAO) in cardiometabolic pathways that underlie right ventricular dysfunction and failure after operations that surgically treat left heart failure with reduced ejection fraction. Leveraging a unique biospecimen dataset, the study outcomes indicated for the first time that cardiometabolic pathways and biomarkers, including FAO intermediate metabolites, were involved in early right heart failure. Now an Associate Professor of Anesthesiology and Critical Care and Director of the Clinical Research Unit for the Department for the Duke University Health System, Dr. Ghadimi oversees a multitude of prospective clinical and translational research protocols, helps shape research policy and operations within his department, and contributes to shaping the research environment within Duke University School of Medicine and Duke Health at large. Additionally, he provides oversight of the biospecimen repository for his department, which now houses more than 120,000 samples that were contributed by patients from multiple clinical trials over the years, and actively participates in their health system-wide precision health initiative, called OneDukeGen. Below, he recalls his research journey, how his IMRA-funded study impacted patient care and the specialty of anesthesiology and his hopes for the future of anesthesia research.

1. What is your current position? How long have you been in this position? What was your role when you were first funded by IARS?

I am currently an Associate Professor of Anesthesiology and Critical Care and Director of the Clinical Research Unit for the Department. I have served in this role since January 1, 2022. In this role, I oversee a multitude of prospective clinical and translational research protocols, help shape research policy and operations within our department, and contribute to shaping the research environment within Duke University School of Medicine and Duke Health at large. My role also includes oversight of the biospecimen repository for our department, which now houses more than 120,000 samples that were contributed by patients from multiple clinical trials that were coordinated through our department over the years, and I actively participate in our health system-wide precision health initiative, called OneDukeGen.

This is in addition to my role as a trialist, and clinically, in my direct service to patients as a cardiac anesthesiologist and intensivist in the cardiothoracic surgical operating rooms and ICU.

The IMRA helped to not only develop and propel me through my translational research platform through creation of a biospecimen repository associated with a single center clinical trial that I designed and led, but also it helped me to acquire formal training in clinical research, epidemiology, and research operations that now is helpful in directing the CRU and in conducting broader, programmatic, multicenter investigations.

2. What drew you to academic anesthesiology and to your particular area of research? Has your research subject area evolved since the award?

During my anesthesiology residency, I was exposed to the cardiac operating rooms and ICU environments, my Program Director and Chair was a cardiac anesthesiologist and good human being. I learned a lot from him regarding the importance of mentorship and paying it forward. From there, I did a two-year fellowship at the University of Pennsylvania, and the exposure I had in that multidisciplinary environment, along with phenomenal mentorship as well, congealed for me a career in academic anesthesiology.

3. What was the goal of your initial research project? Was it met?

The initial goal of my proposal was to determine the role of dysregulated fatty acid oxidation (FAO) in cardiometabolic pathways that underlie right ventricular dysfunction and failure after operations that surgically treat left heart failure with reduced ejection fraction. We determined, for the first time, in a unique biospecimen dataset that was leveraged by implementing the original parent trial, that there were cardiometabolic pathways and biomarkers, including FAO intermediate metabolites, that were involved in early right heart failure. We also took this project a step further and evaluated unbiased proteomics to identify proteins that could potentially be modified to mitigate early right heart failure after these operations. We also generated a clinical-molecular predictive model in our small sample that can be further validated in a larger cohort. One unique aspect of this biospecimen repository was the collaboration that I developed with our cardiac surgeons, who were willing to biopsy the right ventricular myocardium during left ventricular assist device (LVAD) implant surgery. This led to the discovery of key metabolites present in RV myocardium that could explain why some patients develop early right heart failure related to pulmonary hypertension while others did not.

4. How did your findings impact patient care?

The overall parent trial had a direct impact on patient care by providing new actionable knowledge in support of the use of inhaled epoprostenol (arginine analogue) as a cost-effective alternative to nitric oxide in major cardiac surgery (LVAD implant and Heart Transplant) and in noncardiac surgery (lung transplantation) for important outcomes (clinicaltrial.gov identifier NCT03081052).

5. How did your research impact the field of anesthesiology?

Nitric oxide and inhaled epoprostenol have been used for decades and small trials or observational data seemed to suggest similar effects regarding hemodynamic endpoints, such as lowering of pulmonary vascular resistance or increase in cardiac index. However, large, powered, clinical trials with more robust explanatory methodology to determine each individual medication impact on key outcomes in this population were lacking. Important understanding underlying mechanisms that could be modified by the vasoreactive response to inhaled pulmonary vasodilation were also an unmet need. The latter was especially important to the IMRA because a proportion of patients that received inhaled pulmonary vasodilators did not display changes in their PVR. These non-responders interestingly had a higher incidence of early RHF and thus were a key cohort to unlocking the mechanistic underpinnings of pressure induced RHF.

6. How did the award affect your research/professional trajectory?

The IMRA was pivotal to propelling my career and my research in parallel, which is essentially how the career development plan was composed: each research aim had a corresponding CDP aim. My ability to serve as the PI on the parent trial and to become a trialist and clinical research operations leader was predicated on my ability to obtain formal training through the Duke Clinical Research Institute and Duke SOM’s Clinical Research Training Program, which culminated in a Master in Health Sciences in Clinical Research. My ability to identify baseline pathways that could be modified by inhaled agents was dependent on my ability to develop a biospecimen repository with complete sample provenance and governance (knowing where the samples are stored, how they are stored, and how to access them to be sure they are correctly paired with clinical patient data). And finally developing a clinical-molecular predictive model in early RHF development hinged on the ability to understand how predictive models were created clinically to then incrementally add biomarkers through bioinformatics and computation biology. I learned a tremendous amount from mentors and advisors to be able to lead a research program that includes biostatisticians that can aide in trial design and bioinformaticians that can systematically process multi-level omics data to generate meaningful results that provide molecular explanations for what we might observe clinically in our trial work. Combining biospecimens with clinical trials may provide some insight into why otherwise negative results (no differences) between interventional groups in large trials may actually have subpopulations that benefit from study interventions.

7. How do you feel about having received the IARS Mentored Research Award?

I am very fortunate to have received this award and am extremely thankful to the IARS board, my Chair, division chief, mentors, advisors, collaborators, and CRTP instructors. It takes a village to make this happen, and it could not happen without the institutional environment that I am fortunate to be a part of.

8. What is something that someone would be surprised to learn about you?

My pathway to academic anesthesiology was not a straight line. I initially matched into urology and admittedly my exposure to anesthesiology was quite limited during medical school. It was not until my surgical intern year that I spent most of my rotations in the surgical and neurosurgical ICUs, that I learned that anesthesiologists could become intensivists and made a switch to clinical anesthesiology.

9. What is your vision for the future of anesthesia research?

This is a great question. I think as a specialty we have done a wonderful job in ensuring research is prioritized and remains mission critical for advancing our specialty forward. Developing research fellowships to provide dedicated time to commit to specialized, formal training, research projects, and the development of mentorship/advisory teams for young PIs, seems to be the logical direction that many academic programs are headed towards.