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Exercise Prevents Aortic Stiffness by Modulating Neuro-Immune Interaction, Jae Min Cho, PhD, and Team Find 

Artery stiffness is a key risk factor for high blood pressure, heart failure, and organ damage, but many questions remain about how and why it develops. One major mystery involves the outer layer of the aorta — known as the adventitia — and the nerves and immune cells within it. Now, post-doctoral scholar Jae Min Cho, PhD, along with a team of scientists from Tzung K. Hsiai, MD, PhD's cardiovascular bioengineering lab, and Mark W. Chapleau, PhD, at the University of Iowa, has made progress thanks to a new study in mice that shows how habitual exercise can influence the interactions between nerve and immune cells in the adventitia to reduce aortic stiffening. The team also demonstrated that regular exercise can prevent this interaction and, consequently, aortic stiffness. An article about their work was published on April 30 in Circulation Research.

The experiments showed how exercise reduces the interaction between sympathetic nerves and a specific group of immune cells, macrophages in the aortic adventitia, leading to lower inflammation and communication with the extracellular matrix-producing fibroblasts, which decreases arterial elasticity. The team utilized the well-recognized angiotensin II infusion model to simulate the arterial stiffness. It demonstrated increased sympathetic nerve fibers in the adventitia, causing them to release excess norepinephrine and activate the beta-2 adrenergic receptors on circulating macrophages in the adventitia. Exercise countered the effects of angiotensin II in the mouse models.

“Overall, our results show that exercise prevents aortic stiffness by mitigating the neuro-immune interaction in the aortic adventitia,” Dr. Cho said.

He and the team’s next plan is to study how exercise affects interactions between vasculature and the immune system, focusing on mechanosensitive pathways and spatial transcriptomic profiling to translate their findings into a clinical trial. They feel fortunate to be able to carry out their work in the UCLA Department of Medicine. “The DoM provides a highly collaborative and interdisciplinary environment ideal for this research. It brings together experts in the cardiovascular physiology, immunology, and neuroscience fields that are the central axis of our study of neuroimmune regulation of vascular stiffness,” Dr. Cho added. “The department also offers access to cutting-edge technologies, such as single-cell sequencing, advanced imaging, and animal models, which are critical for our work.” 

Congratulations to all on your exciting progress!

Activation of Key Estrogen Receptor Could Fight Metabolic Disease

While a growing body of research has suggested that reduced activity of estradiol — a form of estrogen — is linked to obesity and insulin resistance, it was unclear exactly what the hormone was doing in cells and tissues that was so important to metabolic health, especially in men. A new study led by corresponding author Andrea Hevener, PhD and first author Zhenqi Zhou, PhD, scientists and professors of medicine in the division of endocrinology, offers some answers: Dr. Hevener and his team found that the expression of a gene called Esr1 in the muscle is critical for mitochondrial function and metabolic health in male mice, and that tissue-selective activation of the receptor that the gene encodes, estrogen receptor alpha (ERa), can fight metabolic-related disease in both male and female mice.

A journal article describing the study was published May 5 in Cell Reports Medicine. In it, Dr. Hevener explained how his team used mouse models that either had muscle-specific loss or gain of Esr1 to show that the gene promotes mitochondrial DNA replication and health in a way that is important to metabolic function and insulin action in skeletal muscle. Additionally, genetically altered male and female mice in which human ERa was over-expressed maintained their metabolic health even when they were fed a diet designed to induce metabolic disease. Their mitochondria also adapted better to exercise than control animals.

“Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes,” the researchers wrote in their paper.

To Drs. Hevener and Zhou, the DoM provides a uniquely interdisciplinary environment that facilitates the kind of collaboration required to make discoveries that could have a big impact on patients.

“The DoM also offers access to cutting-edge core facilities, robust mentorship, and a culture that encourages cross-disciplinary innovation — all of which are essential for advancing my research goals and for generating impactful findings with clinical relevance,” Dr. Hevener said.

Dr. Hevener’s team included DoM faculty and post-doctoral scholars from the divisions of endocrinology, geriatrics and cardiology. Congratulations to all on an impressive paper! 

Adding an Intranasal Drug to Tuberculosis Regimen Speeds Up Cure in Mice, UCLA Researchers Find 

Tuberculosis is one of the deadliest infectious diseases but can take as long as six to eight months to cure — a protracted timeline that contributes to the development of permanent organ damage and drug resistance. Scientists in the lab of Marcus A. Horwitz, MD have been working hard to shorten the time it takes to eliminate the disease; back in 2019, they identified a novel oral four-drug regimen that could cut the time to cure tuberculosis in a mouse model by around 85% to just three weeks. Now, they’ve trimmed that time once again to as little as a week and a half by delivering additional doses two of the drugs intranasally.

“Our results show that combining intranasal treatment with oral therapy can shorten the treatment time required to achieve relapse-free cure in mice,” said Bai-Yu Lee, PhD, a researcher in Dr. Horwitz’s lab and first author of an academic article on the study that published June 11 in the Journal of Infectious Diseases. “Since the results of drug treatment in the mouse model of pulmonary tuberculosis are fairly predictable of the results in humans, we anticipate that combining inhalational and oral routes for administration of anti-tuberculosis drugs will achieve more rapid and effective treatment of tuberculosis in humans.” 

The researchers’ short-course regimen consists of the drugs clofazimine, bedaquiline, pyrazinamide and delamanid. Knowing that bypassing the gastrointestinal tract might make their regimen more potent, they selected the strongest two drugs — bedaquiline and delamanid — and suspended them in Infasurf, an FDA-approved intranasal agent used to treat respiratory distress in newborns. To test out the approach, they treated one cohort of a tuberculosis mouse model with the oral regimen and the intranasal additions, and a second one with the original oral-only regimen. For comparison, they treated another group with the standard treatment for tuberculosis. The mice that received the lab’s treatment protocols were split into three groups that were treated for 1.5, 2 or 3 weeks, while the ones on the standard regimen were treated for 3.

All the mice were held for three months after completing treatment, at which point their lungs were assessed for the presence of the bacteria that causes tuberculosis. They used stringent criteria to define a “cure”: Mice with even one bacterium in their lungs were considered to have relapsed.

For the group that received the lab’s oral-only regimen, mice treated for 1.5 weeks had a 60% relapse rate at three months, compared to an 11% rate for the group that received the combined oral and intranasal treatment. In the mice treated for 2 weeks, none that were treated with either the intranasal-oral or oral-only treatments relapsed; in the group that was treated for 3 weeks, none of the mice that received the intranasal-oral regimen relapsed, and only 10% of the mice that received the oral-only regimen relapsed. In contrast, all of the mice that were on the standard protocol relapsed three months after treatment stopped.

The researchers plan to conduct additional experiments to see whether Infasurf might have influenced the treatment’s efficacy. They also hope to obtain funding to conduct research on their updated regimen in nonhuman primates — and ultimately industry partners who could help develop intranasal platforms for tuberculosis drugs, according to co-author Daniel L. Clemens, MD, PhD.

Dr. Lee sees the UCLA Department of Medicine is one of the world’s best places to conduct research on one of the world’s deadliest diseases.

“The DoM is actively engaged in treating patients with these infectious diseases both in the United States and abroad. Moreover, preclinical animal models must use highly virulent strains of tubercle bacilli to provide accurate information in therapeutic drug studies,” Dr. Lee explained. “The DoM has state-of-the-art Biosafety Level 3 facilities required for work with virulent tubercle bacilli and UCLA is able to provide the biosafety training necessary for our work.” 

Congratulations, team, on an outstanding study! 

Heart Health Biomarkers Predict Cancer Risk 

When one thinks about heart health, cancer may not be the first thing that comes to mind. However, a new study involving DoM faculty members Xinjiang Cai, MD, PhD, Karol Watson, MD, PhD and Eric Y. Yang, MD suggests that elevated cardiovascular biomarkers are linked to a higher risk of cancer, even in people who have neither heart disease nor cancer.

“From a preventive cardiology standpoint, these findings encourage a reevaluation of mildly elevated baseline cardiac biomarkers in asymptomatic individuals — levels that may have previously been overlooked for cancer association,” said Dr. Cai, who served as first author on a journal article describing the results that published June 16 in JACC: Advances. “While a cardiovascular workup remains essential to assess potential subclinical cardiac disease, our results suggest that clinicians should also consider broader implications, including the possibility of increased cancer risk.” 

Given that prevention is a key objective in both cancer and cardiovascular disease, the researchers wondered whether the same biomarkers that are used to detect subclinical heart disease, such as high-sensitivity cardiac troponin (hs-CTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), might also predict cancer risk. To investigate this link, they analyzed data from 6,244 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), which included adults between 45 to 84 years of age who did not have cardiovascular disease at the beginning of the study, which was conducted between 2000 and 2002. MESA investigators measured participants blood levels of hs-cTnT and NT-proBNP. 

The study subjects were followed for nearly 18 years. Using rigorous statistical analyses, the researchers showed that even very small increases in hs-cTnT and NT-proBNP strongly predicted those who would develop cancer in the future regardless of their initial health status. High levels of both proteins were linked to a greater chance of developing colon cancer, while higher levels of NT-proBNP alone were associated with a greater risk of lung cancer. The findings held true even after cardiovascular risk factors like smoking, diabetes, high blood pressure and high cholesterol were taken into account.

Armed with these findings, the researchers will next look to both replicate the results in bigger sample sets and to figure out whether cardiovascular disease and cancer might have some biological underpinnings in common.

“Our next steps include validating these findings in additional large, diverse cohort studies. Ultimately, prospective clinical cohorts specifically designed to examine the relationship between baseline cardiac biomarkers and cancer outcomes would provide stronger evidence,” Dr. Cai said. “In parallel, mechanistic studies are needed to better understand the biological pathways underlying this association—particularly the roles of inflammation, oxidative stress, and other shared pathophysiological mechanisms between cardiovascular disease and cancer.” 

Dr. Cai believes the study’s success is a result of the intellectual environment, resources and collaborative opportunities provided by the DoM as well as the strength of its interdisciplinary research team, which included scientists from the Lundquist Institute at Harbor-UCLA Medical Center, the University of Washington, Johns Hopkins School of Medicine, Inova Heart and Vascular Institute in addition to UCLA.

“I benefit from outstanding mentorship and strong infrastructure for both basic and translational research in the DoM,” Dr. Cai said. “Importantly, the DoM demonstrates a deep commitment to supporting the career development of early-career physician-scientists like myself.” 

Kudos to Dr. Cai, Dr. Watson, Dr. Yang and the rest of the team on a fascinating study! 

DoM Quality Cardiology Incentive Program Improves Patient Adherence To Life Saving Medical Therapy Outcomes

Outstanding patient care is our top priority, and the UCLA Department of Medicine Quality team is at the forefront of helping us succeed in our mission. One of the initiatives the team is most excited about is our specialty quality incentive programs, the first of which rolled out to the cardiology division in July 2021. Since then the UCLA Cardiology Quality Improvement Program (CQIP) has grown to include more than 60 cardiologists across 16 clinics — and, as a new study shows, is demonstrably improving patient outcomes. A publication on the program’s impact was published June 20 in JACC: Advances, becoming one of the first-peer reviewed evaluations of a specialty-specific quality incentive program that demonstrated statistically significant and sustained improvement in guideline-directed medical therapy (GDMT) for cardiovascular disease.

“The study provides evidence that combining financial incentives with accurate data infrastructure and embedded clinical decision support tools can lead to durable improvements in care delivery,” David H. Cho, MD, co-director of the UCLA Cardiology Quality Program, said. “The findings establish CQIP as a potential scalable model across other health care systems and specialties. Our program also shows that quality improvement doesn’t have to feel punitive or burdensome, but can be designed as a practical, constructive tool that helps physicians deliver better care over time” 

The program is a pay-for-performance initiative that makes it easier for physicians and patients to adhere to GDMT for cardiovascular disease. Physicians each get their own quality dashboards with monthly scorecards that benchmark them against the entire division. They receive incentives based on achievement of key quality metrics in heart failure, blood pressure control and lipid management, and have access to tools to help them close care gaps in real time without additional administrative work.

The analysis documented in the paper showed that the incentive has led to statistically significant improvements in adherence to therapies for heart failure with reduced ejection fraction and sustained improvements in blood pressure control and the use of statin/PCSK9i use for atherosclerotic cardiovascular disease prevention. It also demonstrated the importance of gaining clinician trust, providing real-time feedback and actionable data in driving change.

“We hope other institutions see this as a potential blueprint for launching their own specialty QI initiatives. Our experience demonstrates that high-impact change is possible when physicians are empowered with accurate data, clear benchmarks, and aligned incentives,” Pooya I. Bookhoor, MD, co-director of the UCLA Cardiology Quality Program, said. “Rewarding physicians for providing high quality care that meaningfully improves patient health without overburdening their workflows can also potentially improve resilience and reduce burnout.” 

Similar programs are already underway in the DoM in the divisions of nephrology, hospital medicine and primary care, and the quality team is in the process of expanding them to palliative care, endocrinology, rheumatology and infectious disease. 

“This work wouldn’t have been possible without the strong support of our department of medicine and cardiology division leadership, as well as the dedication of our programmers, analysts, and project managers who helped bring the program to life,” Dr. Cho said. “We are very thankful to be a part of a team that brings together clinical expertise, operational support, and technical collaboration to improve our patients’ health.” 

Fantastic work, DoM Quality! Thank you for helping us serve our patients better.

Dale

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