Study Uncovers Hundreds of Blood Proteins Linked to Different Cardiac Diseases

Mass General Brigham researchers identified protein predictors of conditions such as heart failure and atrial fibrillation

By analyzing proteins circulating in the blood of tens of thousands of middle-aged adults, a team led by investigators from Mass General Brigham has revealed numerous candidates linked to the development of various types of heart disease. Monitoring the blood levels of these proteins may help clinicians identify individuals at risk of developing conditions such as heart failure and atrial fibrillation, and targeting the proteins may represent promising new treatment strategies for those who already have such diseases. Results are published in Nature Cardiovascular Research.

“The pathobiology underlying cardiovascular diseases remains incompletely understood. The proteins circulating throughout our body are influenced by genetics, the environment, and our lifestyle, and there is an incredible amount of information that could be leveraged for both risk prediction and disease risk modification,” said co-senior author Pradeep Natarajan, MD, MMSC, the director of Preventive Cardiology and the Paul and Phyllis Fireman Endowed Chair in Vascular Medicine at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system.

The research team, led by co-first authors Art Schuermans, of the Cardiovascular Research Center and Center for Genomic Medicine at MGH, and Ashley B. Pournamdari, MD, measured the levels of 1,459 proteins in blood samples taken from 44,313 unrelated adults in the UK. Among these participants, 10.4% experienced at least one cardiac event over a median follow-up of 11 years after they provided blood samples. Analyses flagged 820 proteins as having close associations that potentially mediated or indicated a high risk for the development of coronary artery disease, heart failure, atrial fibrillation, or aortic stenosis—conditions that account for more than 90% of cardiac deaths.

Many of these proteins are natriuretic peptides (hormones that regulate blood pressure and blood volume), proteins that promote inflammation, and factors that control cell death. “Some of our most interesting and novel associations were for atrial fibrillation, with spondin-1 and adrenomedullin being identified as causal atrial fibrillation biomarkers that could represent therapeutic targets,” said co–senior author Michael Honigberg, MD, MPP, a cardiologist and researcher in the Cardiovascular Research Center at MGH.

Although in many cases high levels of particular proteins were linked to higher risks of cardiac disease, in other cases, elevated levels were associated with lower risks.

With this information in hand, the scientists constructed protein-based risk scores that could be applied to blood samples from individual patients to estimate their likelihood of later experiencing different cardiac diseases. Adding these risk scores significantly improved the prediction of cardiac diseases compared with using traditional risk factors alone.

“Our study lays a foundation for future investigations to better understand the mechanisms behind different cardiac diseases and to develop diagnostic tools, prevention strategies, and novel therapies based on the proteins we identified,” said Honigberg.

Authorship: In addition to Natarajan, Schuermans, and Honigberg, Mass General Brigham authors include Jiwoo Lee, Rohan Bhukar, Shriienidhie Ganesh, Nicholas Darosa, Aeron M. Small, Zhi Yu, Whitney Hornsby, Satoshi Koyama, and James L. Januzzi Jr. Additional authors include Charles Kooperberg and Alexander P. Reiner.

Disclosures: Januzzi reports board membership of Imbria Pharmaceuticals; grant support from Abbott Diagnostics, AstraZeneca, BMS, HeartFlow and Novartis; previous consulting income from Abbott Diagnostics, AstraZeneca, Bayer, Beckman Coulter, Jana Care, Janssen, Novartis, Quidel, Roche Diagnostics and Siemens; and clinical end point committee/data safety monitoring board membership for Abbott, Bayer, AbbVie, CVRx, Pfizer, Roche Diagnostics and Takeda. Honigberg reports consulting fees from CRISPR Therapeutics and Comanche Biopharma; advisory board service for Miga Health; and grant support from Genentech. Natarajan reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, TenSixteen Bio and Tourmaline Bio; equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work.

Funding: This work was supported by funding from the Belgian American Educational Foundation, the US National Heart, Lung and Blood Institute (K08HL166687, R01HL127564,), the US National Human Genome Research Institute (R00HG012956), the American Heart Association (940166 and 979465), the Adolph M. Hutter MD Professorship, and the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine from the Massachusetts General Hospital.

Paper cited: Schuermans, A., Pournamdari, A.B., Lee, J. et al. Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction. Nat Cardiovasc Res (2024). https://doi.org/10.1038/s44161-024-00567-0