Check out “What’s New in Research” to find out about discoveries and advancements from Brigham researchers. This month, we feature new research from Brigham researchers on a therapeutic target for diabetic atheroslcerosis, biomarkers of aging, machine learning to help predict drug delivery, the effectiveness of direct oral anticoagulants (DOACs),biomarkers of cardiovascular health and more.

Mark Feinberg

Researchers Uncover Key Therapeutic Target Involved in Diabetic Atherosclerosis

Diabetes accelerates the development of atherosclerosis, increasing the incidence of cardiovascular events. In atherosclerosis, immune cells called macrophages release molecules such as chemokines and cytokines, causing inflammation and leading to arterial plaque formation. However, significant gaps persist in understanding the exact molecular mechanisms controlling this increased inflammatory response in individuals with diabetes. In a new, preclinical study, researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, identified a long non-coding RNA (lncRNA) sequence that could help them unravel the complex processes underlying diabetic atherosclerosis, potentially paving the way for future therapeutic interventions in humans.

Through genetic analysis of a mouse model of diabetic atherosclerosis, the research team identified a specific sequence of long-noncoding RNA, they named MERRICAL, which is involved in recruiting macrophages to the arterial wall. As atherosclerosis progressed in these mice, the researchers found a notable increase in the expression of MERRICAL at arterial lesions—areas where atherosclerosis plaque built up and damaged the arteries. Furthermore, when the research team therapeutically delivered inhibitors to reduce MERRICAL expression levels, they observed an impressive reduction in macrophage recruitment and in atherosclerosis and aortic lesion formation (74 percent in the aortic sinus and 86 percent in the descending aorta).

“Our work provides new insights for targets that underlie the impaired responses in the vessel walls in diabetes and identifies a key therapeutic target for reversing the accelerated atherosclerosis in diabetes,” said Mark W. Feinberg, MD, a cardiologist and Associate Professor of Medicine of the Brigham’s Heart and Vascular Center and Harvard Medical School, Boston.

Read more in Cell Reports.

Study Proposes Framework to Standardize Biomarkers of Aging and Accelerate Clinical Use

Jesse Poganik

Biomarkers are measurable characteristics that can be used to evaluate normal biological processes, diseases, or responses to treatment in patients. Using biomarkers to assess biological aging, or the increase in molecular and cellular damage over time, has recently gained popularity for its potential to predict longevity and quality of life. However, there are currently no guidelines for standardizing the development and validation of biomarkers of aging — a necessary process to ensure accurate and reliable outcomes in the clinic.

A new study led by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, proposed a framework for future validation of aging biomarkers that could help translate them into clinically actionable tools.

To do this, the team examined population-based cohort studies of blood-based biomarkers of aging built using omic data. Using this information, they identified challenges in comparing the predictive strength of biomarkers, such as variations in study design and data collection methods, as well as inherent differences in population-specific traits.

The authors then provided recommendations to address these difficulties. They suggest that “multi-omic approaches” involving different technologies like metabolomics, proteomics and epigenetics, and transcriptomics will provide greater insights into biomarker predictive performance. Instead of relying only on mortality as an aging-related outcome, the researchers advocate for the consideration of biomarker associations with other health factors like functional decline, frailty, chronic disease and disability. In addition, they recommend standardizing omic data to enhance validation efforts. “Omics and biomarkers harmonization efforts, such as the Bio-learn project, are instrumental in validation of biomarkers of aging,” said co-first author Mahdi Moqri, PhD, of the Division of Genetics.

The framework also encourages increased collaboration between research groups on large-scale, longitudinal studies that can track long-term physiological changes and responses to therapeutics in diverse populations. Further work is required to understand how implementation of biomarker evaluation in clinical trials might improve patient quality of life and survival.

“If we hope to have clinical trials for interventions that extend healthy lifespan in humans, we need reliable, validated biomarkers of aging,” said co-first author Jesse Poganik, PhD, of the Division of Genetics. “We hope that our framework will help prioritize the most promising biomarkers and provide health care providers with clinically valuable and actionable tools.”

Read more in Nature Medicine.

Researchers Use Machine Learning to Predict How Ingested Drugs Will Interact with Transport Proteins

Giovanni Traverso

Before orally administered drugs can make their way throughout the body, they must first bind to membrane proteins called drug transporters, which carry compounds across the intestinal tract and help them reach their intended targets. But because one drug can bind to several different drug transporters, they may struggle to get past this gut barrier, potentially leading to decreased drug absorption and efficacy. If another drug is added to the mix, interactions between the two compounds and their transporters can cause dangerous side effects.

Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, and MIT have designed a model that analyzes the flow of drugs through tissues and uses machine learning to predict how specific compounds will interact with different transporters. When they used pig tissue to test their machine learning model on 50 approved and investigational drugs, they identified 58 previously unknown drug-transporter interactions and 1,810,270 unknown potential interactions between different drugs.

“Our model has the potential to help accelerate drug discovery and allow drugmakers to better understand safety concerns associated with mixing different medicines,” said senior author Giovanni Traverso, MD, PhD, MBBCH a gastroenterologist in the Brigham’s Division of Gastroenterology, Hepatology, and Endoscopy.

Read more in Nature Biomedical Engineering.

Do’s and Don’ts With Direct Oral Anticoagulants

Behnood Bikdeli

Direct oral anticoagulants (DOACs) are a common treatment for patients with a wide variety of cardiovascular conditions. DOACs are the preferred treatment over vitamin K antagonists (VKAs) for many patients with atrial fibrillation or venous thromboembolism, since the latter would have a higher risk of intracranial bleeding and more complex dosing routine. However, new research suggests that DOACs should not be the first line of treatment for every patient who need to treat or prevent blood clots. A systematic overview from researchers at Brigham and Women’s Hospital, a founding member of Mass General Brigham, discusses the efficacy of DOACs compared to other treatment methods. This review utilized data from randomized controlled trials to compare DOACs with other treatment methods for various cardiovascular conditions. Although there is merit to using DOACs in many common conditions, the manuscript provides a robust summary of clinical trials indicating that DOACs fare worse in patients with mechanical heart valves, thrombotic antiphospholipid syndrome, atrial fibrillation associated with rheumatic heart disease, and patients with embolic stroke of unclear source. The authors also highlight clinical scenarios in which there is uncertainty, with a look toward future for better evidence generation.

“The results we reviewed here have significant implications for optimizing anticoagulation therapy and improving patient outcomes in clinical practice,” said Behnood Bikdeli, MD, MS, of the Brigham’s Heart and Vascular Center. “There is a critical need for further research regarding why DOACs are less efficacious or safe than the standard of care in certain scenarios.”

Read more in the Journal of the American College of Cardiology.

New Study Shows Glycan Sugar Coatings of IgG immunoglobulin Can Predict Cardiovascular Health

Samia Mora

When people hear about predicting heart disease, most will think of cholesterol levels. While cholesterol is a major contributor to heart disease, a recent study from Brigham and Women’s Hospital, a founding member of Mass General Brigham, found that a glycan biomarker of IgG is also an important predictor for cardiovascular diseases (CVD). The researchers studied the sugar coatings on an antibody known as immunoglobulin G (IgG), which is implicated in the immune responses associated with chronic inflammation among participants in two case-control studies. The results of this investigation provide another biomarker for identifying risk of CVD, which could lead to earlier diagnosis of heart disease or stroke. Since CVD worsens with time, early diagnosis is crucial to having a better outcome for the patient. The research team found that the sugar coatings on the IgG were directly related to the risk of a CVD event, most likely through inflammatory effects, and that an IgG glycan score predicted future cardiovascular events independent of other risk factors.

“IgG N-glycans which are the sugar coatings that modify the IgG immunoglobulins might be not only novel biomarkers for cardiometabolic health, but also potential new drug targets,” said Samia Mora, MD, MHS, of the Brigham’s Divisions of Preventive and Cardiovascular Medicine. “Our results represent a promising and underappreciated novel biomarker that has great potential for risk stratification, CVD prevention, diagnostics and treatment purposes.”

Read more about the study and pertinent disclosures in Circulation Research.

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