“Cases from the Mountains”, Medical Grand Rounds with Dr. John Ryan
Nolan Breault, MSc Candidate (TMED)
A hallmark of early-stage disease is the presence of any number of undifferentiated symptoms. Depending on the illness, these can include headaches, coughing, and other forms of discomfort. While such symptoms are oftentimes little cause for concern, their persistence may signal that something more serious is at play. For pulmonary hypertension patients, one of the defining early symptoms is dyspnea, a shortness of breath that reduces one’s ability to engage in everyday aerobic activities.
Last Thursday’s Medical Grand Rounds was delivered by Dr. John Ryan, an internationally-renowned physician-scientist from the University of Utah who runs a dyspnea clinic dedicated to early diagnosis and treatment of pulmonary hypertension (PH). Dr. Ryan’s clinic is one of few that specializes in both cardiovascular and pulmonary diagnostics, seeking to shorten the delay between symptom onset and treatment that so often worsens long-term outcomes (1). Indeed, for Dr. Ryan, “no dyspnea is good dyspnea”.
Rounds consisted of an exploration of noteworthy referrals from Dr. Ryan’s practice. This included an example of Eisenmenger’s syndrome, which is a severe form of PH associated with congenital heart disease and large unrepaired shunts, a case of central cyanosis stemming from dietary silver intake, and an instance of unresolved patent ductus arteriosus (2). In each of these cases, Dr. Ryan discussed the diagnostic criteria and techniques employed to accurately assess his patients. These frequently consist of echocardiography and right heart catheterization, allowing for precise observation of the structure and function of the heart. In advanced cases of PH, echocardiography readily reveals an enlargement of the heart’s right ventricle, indicating increased strain on the tissue that later culminates in right-sided heart failure and death. Right heart catheterization serves as an invasive but critical tool for assessing hemodynamics to aid in PH diagnosis.
Outside of his clinical time, Dr. Ryan has written extensively about the physiology, genetics, and biochemistry of PH. Recent, high-impact publications revolve around the role of mitochondrial dynamics in the disease’s pathogenesis, particularly with respect to the activities of dynamin-related protein 1 (DRP1) and mitofusin-2. Dr. Ryan has assisted in showing that DRP1 activity is enhanced in PH and allows for a dysregulation in cell division of vascular smooth muscle cells, leading to an obstruction of blood flow and an increase in pressure (3,4). Further, a downregulation in the activity of mitofusin-2, which counteracts DRP1’s role in cell division, has also been implicated in the onset of disease (5). These findings have formed the basis of a new direction for PH therapeutics that function through disease regression as opposed to symptom management.
Following the conclusion of Dr. Ryan’s presentation, he engaged the class in an enthusiastic discussion of issues in modern healthcare accessibility and lay media representation, as well as how he navigated critical junctures in his career thus far. For the former, Dr. Ryan identified that many of his referrals came from rural communities, where historically a multitude of barriers such as poor coverage by health insurance, geographic distance, and distrust of medical institutions often leads patients to avoiding care. Dr. Ryan cited a few key areas of improvement in recent years that are supporting the delivery of healthcare to such communities, such as increasingly portable diagnostic tools like echocardiograms and growing amounts of medical information online. He elaborated by saying that patient empowerment, in this instance provided by the ability to educate oneself, is a key step towards improving accessibility but must be guided to ensure the accuracy of information. This theme was further highlighted by a discussion of the recent rise in popularity of electronic cigarettes, or “vapes”, which are marketed as a healthier alternative to traditional cigarettes but present a new public health concern by way of industrial evolution that exceeds the rate of research (6). In closing, Dr. Ryan transitioned to give the career advice of pursuing what one is most skilled at and recognizing that success most often comes from opportunity and meeting the right people at the right time, with the caveat that it takes hard work to be given such opportunities and to be placed next to “the right people”.
For the members of TMED 801, Rounds with Dr. Ryan provided insight into the clinical complexities that can arise out of undifferentiated symptoms such as dyspnea. Our later discussion came with perspective on contemporary healthcare issues and professional decision-making. On behalf of the class, I’d like to thank Dr. Ryan for sharing with us his time, expertise, and enthusiasm for work that extends the bounds of clinical knowledge.
1. Brown, L., M., Chen, H., Halpern, S., Taichman, D., McGoon, M. D., Farber, H. W., et al. Delay in Recognition of Pulmonary Arterial Hypertension. https://doi.org/10.1378/chest.10-1166 Chest [Internet]. 2011 Mar 10 [cited 2021 Oct 17];140(1):19-26. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198486/
2. Wood, P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. https://doi.org/10.1136/bmj.2.5099.755 Br Med J[Internet] 1958 Sept 27 [cited 2021 Oct 17]; 2:755. Available from: https://www.bmj.com/content/2/5099/755
3. Marsboom, G., Toth, P., Ryan, J. J., Hong, Z., Wu, X., Fang, Y., et al. Dynamin-Related Protein 1-Mediated Mitochondrial Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells and Offers a Novel Therapeutic Target in Pulmonary Hypertension. https://doi.org/10.1161/CIRCRESAHA.111.263848 Circ Res [Internet] 2012 Apr 17 [cited 2021 Oct 17];110:1484-1497. Available from: https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.111.263848
4. Sharp, W., Fang, Y., Han, M., Zhang, H. J., Hong, Z., Banathy, A., et al. Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. https://doi.org/10.1096/fj.12-226225 FASEB J [Internet] 2013 Sept 27 [cited 2021 Oct 17];28:316-326. Available from: https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.12-226225
5. Ryan, J. J., Marsboom, G., Fang, Y., Toth, P., Morrow, E., Luo, N., et al. PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. https://doi.org/10.1164/rccm.201209-1687OC American Journal of Respiratory and Critical Care Medicine [Internet] 2013 Feb 1 [cited 2021 Oct 17];187:865-878. Available from: https://www.atsjournals.org/doi/full/10.1164/rccm.201209-1687OC
6. Morris, P., Ference, B., Jahangir, E., Feldman, D., Ryan, J. J., Bahraml, et al. Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic Cigarettes: Clinical Perspectives From the Prevention of Cardiovascular Disease Section Leadership Council and Early Career Councils of the American College of Cardiology. JACC [Internet] 2015 Sept 22 [cited 2021 Oct 17];66(12):1378-1391. Available from: https://www.jacc.org/doi/abs/10.1016/j.jacc.2015.07.037