OMB No. 0925-0001 and 0925-0002 (Rev. 10/2021 Approved Through 01/31/2026)

BIOGRAPHICAL SKETCH

EDUCATION/TRAINING

A. Personal Statement

I am a Professor of Pediatrics and Preventive Cardiologist whose clinical research interests are focused on understanding the etiology and physiology of the rising tide of cardiometabolic risk and the barriers to heart-healthy behavioral change that can mitigate risk. My current research interest is on the role of synergistic activity and dietary micro and macronutrient upgrades for optimal lipid metabolism, insulin regulation, and total body weight and weight distribution. I have worked in several institutions serving large minority populations, the University of California Benioff San Francisco and Children’s Hospital Oakland and now Children’s National Hospital in Washington DC. My involvement in the Bay Area in the development and clinical trials of nutrient-rich supplements in adolescents and adults spanning a wide BMI range demostrated a favorable impact on lipid metabolism and weight distribution after only 2 weeks in healthy individuals that takes longer to emerge in those who present at CMR with chronic inflammation. Lipoprotein subspecies analyses, metabolomics, and particularly lipidomics (notably nutrient-sensitive sphingolipid ceramides at the interface between immunity vs inflammation), have yielded early insight into the temporal and physiologic underpinnings of this observation. This work has underscored the importance of specific lipidomic sphingolipids that reside on high density lipoprotein (HDL) that prove critical for optimal lifelong innate immunity and cardiometabolic health, beginning in utero. I hypothesized and demonstrated association between dysfunctional HDL and COVID-19 severity in youth as well as with autoimmune rheumatic heart disease in Kampala, Uganda, demonstrating far reaching implications of lipid metabolism for child health. These basic research findings strengthen my commitment to advancing mechanistic understandings of the power of nutrtition to favorably move metabolism. My expertise is well-suited to lead this proposal aimed at elucidating putative connections between nutrients missing from the standard American diet and targeted peptides indicative of intestinal health, and lipid metabolism. I strongly support open data access to promote transparency, reproducibility and collaborative science practices.

Ongoing and recently completed projects I would like to highlight include:

U01 NHLBI Pediatric Heart Network

McCrindle (PI), Role: Site PI

7/01/18-6/30/23 (with no cost extension for internally funded ancillary research project for which I am PI)

Dyslipidemia of Obesity Intervention in Teens (Ancillary: Metabolomic Signature of Pitavastatin in DO IT)

NIH NIDDK 1R01DK131217

Ritchie (PI), Role: Co-I

7/1/23 – 6/30/28       

Milk Type in Toddlers Trial (Milk-TOT)

B. Positions, Scientific Appointments, and Honors

Positions and Scientific Appointments

Honors

C. Contribution to Science

1. Investigating the role of scavenger receptor in inflammation: My early basic science research characterized the role of redox regulation for a then newly described gene involved in the earliest manifestations of atherogenesis, the class A scavenger receptor (SRA). This receptor is a principal site of entry for oxidized cholesterol in macrophage foam cell development, and exhibits high levels of expression in monocyte to macrophage differentiation. Because activated macrophages generate free radicals, I initiated investigations that delineated the role of redox sensitive transcriptional pathways in SRA receptor up-regulation. My work identified oxidized LDL, the class A scavenger receptor ligand, as a physiologic agonist for monocyte differentiation and the induction of its own receptor. These basic science studies underscored the two-edged inflammatory potential of oxidized lipoproteins in heart disease. Free radicals, by virtue of their toxicity, stimulate the body’s armamentarium of antioxidant and anti-inflammatory defenses. Together, this work served to reinforce a commitment to better understand clinical factors relevant to both the generation of vascular oxidative stress and defense.
   1. Mietus-Snyder M, Friera A, Glass CK, Pitas RE. Regulation of scavenger receptor expression in smooth muscle cells by protein kinase C: a role for oxidative stress. Arterioscler Thromb Vasc Biol. 1997 May;17(5):969-78.
   2. Mietus-Snyder M, Glass CK, Pitas RE. Transcriptional activation of scavenger receptor expression in human smooth muscle cells requires AP-1/c-Jun and C/EBPbeta: both AP-1 binding and JNK activation are induced by phorbol esters and oxidative stress. Arterioscler Thromb Vasc Biol. 1998 Sep;18(9):1440-9.
   3. Mietus-Snyder M, Gowri MS, Pitas RE. Class A scavenger receptor up-regulation in smooth muscle cells by oxidized low density lipoprotein. Enhancement by calcium flux and concurrent cyclooxygenase-2 up-regulation. J Biol Chem. 2000 Jun 9;275(23):17661-70.

2. Understanding Insulin Resistance: Growing interest in clinical interventions that might attenuate the redox sensitive expression of atherogenic genes has led to deep commitment to understanding the power of food to favorably move metabolism towards insulin sensitivity and cardiometabolic health. I began working with the laboratory of Bruce Ames at the Children’s Hospital Oakland Research Institute (CHORI) on a 15 yr collaboration with the USDA nutrition research laboratory in Albany CA to better understand the role of comprehensive nutrient supplementation on insulin resistance and metabolism Significant improvements in lipid metabolism, with HDL at the leading edge of change, were seen in only 2 wk in lean participants, but only begin to emerge after 2 mo in persons with obesity and inflammation. Mechanistic work to understand these observations has revealed links between heart-healthy nutrition, sphingolipid metabolism, ceramide lipotoxicity and immunity. Only 10 days of dietary fructose reduction significantly lowers toxic lipidomic metabolites in association with improved insulin sensitivity and decreased hepatic de novo lipogenesis. The putative importance of HDL, carrier of beneficial sphingolipid 1 phosphate, a point-counterpoint to toxic ceramide accumulation that proved functional in innate immunity is illustrated in the association found between HDL subspecies, HDL function, and the severity of COVID-19 infections in youth.
   1. Mietus-Snyder M, Shigenaga MK, Suh JH, Shenvi SS, Lal AA, McHugh T, Olson D, Lilienstein J, Krauss RM, Gildengoren G, McCann JC, and Ames BN. A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial. FASEB J. 2012 Aug;26(8):3515-27. 22549511
   2. Mietus-Snyder M, Narayanan N, Laine-Graves K, McCann J, Krauss, RM, Shigenaga M, McHugh T, Ames BN, and Suh JH. Randomized nutrient bar supplementation improves exercise-associated changes in plasma metabolome in adolescents and adult family members at cardiometabolic risk. PLoS One. 2020 Oct 20;15(10):e0240437. https://pubmed.ncbi.nlm.nih.gov/33079935/
   3. Olson, E, Olson E, Suh JH, Schwarz J-M, Noworolski SM, Jones GM, Barber JR, Erkin-Cakmak A, Mulligan K, Lustig RH, and Mietus-Snyder M. Effects of isocaloric fructose restriction on ceramide levels in children with obesity and metabolic syndrome: relation to hepatic de novo lipogenesis and insulin sensitivity. Nutrients. 2022;14(7):1432. https://doi.org/10.3390/nu14071432
   4. Mietus-Snyder M, Suslovic W, Delaney M, Playford MP, Ballout RA, Barber JR, Otvos JD, DeBiasi RL, Mehta NM and Remaley AT. Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity. Frontiers in Cardiovascular Medicine. 2022:9.

3. Lipid Metabolism in Children: Work with lipoprotein subspecies analyses and mass spectroscopy metabolomics have informed my views on lipid metabolism and helped me hone insights to the importance of nutrition and lifestyle in activation of global peroxisome proliferating-activated receptor (PPAR) transcriptional regulators integral role to vascular health, energy metabolism, adipogenesis, lipid storage and transport, as well as innate immunity. Multiple independent lines of evidence suggest that the progressive dyslipidemia, insulin resistance, vascular dysfunction, and cardiovascular risk associated with age can be either delayed or accelerated as a function of lifestyle choices and medications that either activate or repress these central PPAR regulators. I have continued to advance mechanistic understanding of the prevalent and highly atherogenic dyslipidemia of obesity, a condition often managed in adults with pharmacologic PPAR activators, but importantly very sensitive to lifestyle. I helped advance understanding among general pediatric and preventive pediatric cardiology peers of the prevalence and correlates of this atherogenic dyslipidemia in youth with pilot data from the HEALTHY study in a middle school population, and I initiated secondary analyses supporting a predictive association of small and medium, but not large low density lipoprotein particles on vascular stiffness in the Malmo longitudinal adult cohort. These findings strengthened a successful protocol for a transdisciplinary multisite Dyslipidemia of Obesity Intervention in Teens (DO IT!) trial funded by the NHLBI Pediatric Heart Network to evaluate the role of statins in improving vascular health. I am site PI for this study at Children’s National and am pursuing associated ancillary studies to advance our understanding of the role of statins (known for pleiotropic effects on PPAR regulation) on lipid metabolism and risk of diabetes in youth burdened with obesity and insulin resistance.
   1. Mietus-Snyder M, Krauss RM. Lipid metabolism in children and adolescents: Impact on vascular biology. J Clin Lipidol. 2008 Jun;2(3):127-37.
   2. Kavey RE, Mietus-Snyder M. Beyond cholesterol: the atherogenic consequences of combined dyslipidemia. J Pediatr. 2012 Dec;161(6):977-9.
   3. Mietus-Snyder M, Drews KL, Otvos JD, Willi SM, Foster GD, Jago R, Buse JB. Low-density lipoprotein cholesterol versus particle number in middle school children. J Pediatr. 2013 Aug;163(2):355-62.
   4. Hartz J, Krauss RM, Gottsater M, Melander O, Nilsson P, Mietus-Snyder M.  Lipoprotein particle predictors of arterial stiffness after 17 years of follow up: the Malmö Diet and Cancer Study. Int J Vasc Med. Pub online 2020, Apr. 28.

4. Early and effective lifestyle interventions reduce the risk of the dyslipidemia and CMR across the lifespan. However, lifestyle change is underutilized and difficult to implement in the clinical realm due to time constraints on clinicians and lack of self-efficacy in patients. Fewer than 1% of American children and adolescents have a diet that meets recommended guidelines. Two thirds of American youth are sedentary, increasing the CMR of poor nutrition. Knowing that the DC public and public charter school wellness policy was falling short of full implementation, particularly among the most socioeconomically disadvantaged, I reasoned that medical student health mentors could partner with schools to deliver a mentored behavioral change intervention during school lunch and recess to model healthy nutrition and activity behaviors, effectively increasing health couseling face time without imposing on school academic time. Together with medical student leadership, Kid POWER (KiPOW^TM) was designed and we are encouraged by its success and reproducibility in geographically and demographically distinct Title 1 schools in DC and southern California with favorable outcomes for student BMI and fitness. Now in its 12^th year, favorable impacts on participating volunteer medical student health behaviors and their self-efficacy to counsel future patients on lifestyle change are also evident (this manuscript in preparation). Finally, I recently chaired a translational Scientific Statement for the American Heart Association that explores interrelated ‘omic’ fields of research in cardiometabolic risk vs health (the epigenome, microbiome, metabolome, lipidome, and inflammasome). Early biomarkers of promise in each domain are identified and connections to mitochondrial function underscored that may mediate the favorable responses emerging in these promising omic biomarkers to a heart-healthy lifestyle, notably to nutritional interventions.
   1. Narayanan N, Nagpal N, Zieve H, Vyas A, Tatum T, Ramos M, Team Kid Power!™; McCarter R Jr, Taylor Lucas C, Mietus-Snyder M.  A Replicable, School-based Intervention Using Health Mentor Face-time to Help Address Child Obesity by Strengthening School Wellness Policy. CDC J Chronic Disease. 2019;16:E154.

1. 2. Mietus-Snyder M, Chair, Marma-Perak A, Co-chair, Cheng C, Hayman LL, PhD, Haynes N,   Meikle PJ, Shah SH, Suglia SF, on behalf of the Council on Lifestyle and Cardiometabolic Health; the Council on Arteriosclerosis, Thrombosis and Vascular Biology; and the Council on CV and Stroke Nursing. Next Generation, Modifiable Cardiometabolic Biomarkers: Mitochondrial adaptation and metabolic resilience. A Scientific Statement from the American Heart Association. Circulation. 2023 Nov 28;148(22):1827-1845.

Complete List of Published Work in MyBibliography:    https://www.ncbi.nlm.nih.gov/myncbi/michele.mietus-snyder.1/bibliography/public/