Human valve tissue with immunofluorescence staining for vimentin (a valve cell marker) and glial fibrillary acidic protein, that specifically stains valve cells from the spongiosa valve layer.

A Molecular Atlas of Calcific Aortic Valve Disease

Study builds molecular networks of calcific aortic valve disease to identify key molecules and therapeutic targets for a disease that affects one in four older Americans

Calcific aortic valve disease (CAVD) – a disease that leaves the aortic valve stiff and calcified, preventing blood flow from the heart into the aorta – affects one quarter of the U.S. population aged 65 and over. There is no pharmacological treatment for CAVD. Without an invasive valve replacement surgery, most patients will die within two years of disease onset. CAVD progresses rapidly through multiple, distinct stages of disease, but is general diagnosed late, making it challenging to develop targeted treatments. A team of researchers from BWH has tackled this problem by comprehensively analyzing gene expression and protein distribution in human aortic valves obtained from valve replacement surgery. Their results are published in Circulation.

“Together, our multi-pronged omics assessment of CAVD has led us to a number of new insights into the pathobiology of this poorly understood disease,” said senior author Elena Aikawa, MD, PhD, director of the Heart Valve Translational Research Program (HVTRP) at BWH.

By examining tissue from different disease stages within valve samples of the same patient, the researchers were able to avoid donor variation in their analysis. They identified that cells from one of the three distinct layers in an aortic valve leaflet, the lamina fibrosa, had the highest propensity to calcify. The questions of why the lamina fibrosa was prone to calcification, and what the genetic drivers of calcification progression were, remained unknown. The researchers identified proteins underlying the disease states in the lamina fibrosa, and were able to build a molecular network representing the different stages of CAVD.

In addition to building molecular networks for the fibrotic and calcific stages of CAVD, the researchers also determined that CAVD has a prominent inflammatory fingerprint. Inflammatory markers were identified in tissue samples from all disease stages in the aortic valve leaflets.

“We have been able to produce a precise omics-level molecular atlas of the aortic valve and the molecular network of calcific aortic valve disease,” said first author Florian Schlotter, MD, a research fellow in the Center for Interdisciplinary Cardiovascular Sciences at BWH. “By identifying key molecular drivers within these networks, we have been able to determine potential therapeutic targets that could help us to develop the first pharmacological therapy for CAVD.”

This study was funded by a series of grants from the National Institutes of Health and a research grant from Kowa Company, Ltd. (Nagoya, Japan).

Paper cited: Florian Schlotter et al. “Spatiotemporal Multi-omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease” Circulation DOI: https://doi.org/10.1161/CIRCULATIONAHA.117.032291

Blood Test May Predict Future Risk of Cardiovascular Events

Study of 27,000 women finds that branched chain amino acid levels in the blood stream are as predictive of heart disease as LDL cholesterol, other risk factors

Despite heart disease and type 2 diabetes being among the leading causes of death in the U.S., the mechanisms leading to and linking these two diseases remain incompletely understood. A new study by investigators at Brigham and Women’s Hospital may help shed light on a molecular pathway that heart disease and diabetes share, and points to a biomarker that is elevated in women at risk of cardiovascular disease and diabetes. The team’s results were presented by Deirdre Tobias, ScD, at the AHA Epidemiology and Lifestyle meeting and simultaneously published in Circulation: Genomic and Precision Medicine.

“We examined more than 27,000 women in the Women’s Health Study and found that a one-time measurement of branched chain amino acids in the blood stream – a test that now can be easily done – predicted future risk of cardiovascular events to the same extent and independent of LDL cholesterol and other risk factors,” said corresponding author Samia Mora, MD, of the Center for Lipid Metabolomics at BWH. “This was particularly so for women who developed type 2 diabetes prior to their cardiovascular disease.”

Branched chain amino acids (BCAAs) are thought to play a causal role in the development of insulin resistance and type 2 diabetes. However, few studies have evaluated the association between BCAAs and cardiovascular disease. To investigate, the team measured BCAA levels in blood samples using NMR spectrometry. Of the more than 27,000 women studied, 2,207 experienced a cardiovascular event over the 18 year follow up period.

The team found a positive association between BCAA levels and incident of CVD events. This association was much more pronounced in women who developed diabetes before experiencing a cardiovascular event. The team adjusted for other biomarkers related to diabetes – including hbA1c – finding evidence that BCAAs may be tied to downstream biomarkers of type 2 diabetes metabolism.

“Impaired BCAA metabolism may represent a shared pathway of the metabolic pathophysiology that links the risks of T2D and CVD,” the authors conclude.

“There is little known at this time as to what leads to elevated levels of BCAAs or what can be done clinically to reduce them, and if this leads to a reduction in risk, but further research will target these important questions,” said Tobias.

The Women’s Health Study is supported by National Institutes of Health (NIH) grants (CA-047988, HL-043851, HL-080467, HL-099355, and UM1 CA182913). A full listing of funding sources, conflict of interest disclosures and more are available in the published paper.

Paper cited: Tobias DK et al. “Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women” Circulation: Genomic and Precision Medicine DOI: 10.1161/CIRCGEN.118.002157