LC-MS Reveals 5-OP as Heart Failure Risk Marker

As heart failure gets worse, it is closely tied to a process called oxidative stress, which is basically wear-and-tear damage happening inside cells at a chemical level. One substance connected to this process is 5-oxoproline (5-OP), a leftover byproduct created when the body breaks down glutathione, an important antioxidant. Normally, an enzyme called 5-oxoprolinase (OPLAH) clears this byproduct out of the system. But when the body's antioxidant recycling process gets disrupted, 5-OP can build up instead of being cleared away. Researchers recently examined what happens with 5-OP levels in the blood of heart failure patients, including who tends to have higher levels, what other biological markers it is connected to, and whether it is linked to how well or poorly patients do over time. To measure 5-OP accurately, they used validated liquid chromatography-mass spectrometry (LC-MS) to separate and identify molecules in a blood sample, then checked whether the results lined up with patient outcomes. A paper based on their work was published in the journal Redox Biology.¹

What Role Does Oxidative Stress Play in the Progression of Heart and Kidney Failure?

Oxidative stress plays a major role in how both heart failure and kidney failure get worse over time.^2-4 Normally, the body keeps a healthy balance between producing potentially damaging molecules (called reactive oxygen species) and neutralizing them with antioxidants. This balance is essential for keeping cells in the heart and kidneys functioning properly. But when that balance tips too far toward damage, it can set off a chain reaction that speeds up the decline of the heart, the kidneys, or both at once.^2,3,5-6

What is 5-OP Linked To in Heart Failure, and Where Does It Come From?

The researchers looked at blood samples from 823 heart failure patients (adults with new-onset or worsening heart failure enrolled in a major European systems biology project to optimize medical treatment called BIOSTAT-CHF⁷) and used a statistical technique to sift through 355 different proteins, pinpointing which ones were most closely tied to 5-OP levels. To better understand what might be driving these changes in the body, they also studied a large-animal model (pigs) that had multiple related health conditions affecting the heart, kidneys, and metabolism together, and specifically checked how much of the enzyme that breaks down 5-OP (OPLAH) was present in different organs.¹

The results showed that patients with higher 5-OP levels tended to have worse kidney function; as 5-OP levels rose, average kidney function dropped in a clear, stepwise pattern. Higher 5-OP levels were also linked to a higher risk of dying from any cause, and to a higher risk of experiencing a serious health setback (like hospitalization or death) within two years. Notably, this pattern held up regardless of how healthy or damaged a patient's kidneys were to begin with, suggesting kidney disease status didn't change the relationship. Among all the proteins studied, one called TGF-α showed the strongest and most reliable connection to 5-OP levels.¹

In the animal studies, the pigs with multiple combined heart-kidney-metabolic conditions also had elevated 5-OP in their blood. Interestingly, the enzyme responsible for clearing 5-OP was reduced specifically in the kidneys, but not in the heart, suggesting that the kidneys play a key role in why 5-OP builds up in the body.¹

“Circulating 5-OP,” write the authors of the paper,¹ “identifies HF patients at higher risk and is robustly associated with TGF-α. In a translational swine model, selective loss of renal cortical OPLAH provides tissue context supporting a renal contribution to systemic 5-OP elevation in cardiorenal syndrome.”

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References

1. Esquivel-Gaytan, A.; Al-Mubarak, A. A.; Sorop, O. et al. Elevated 5-oxoproline Levels and Adverse Outcomes in Heart Failure: Association with Renal Cortical OPLAH Loss in a Multi-Comorbidity Model. Redox Biol. 2026, 96, 104354. DOI: 10.1016/j.redox.2026.104354
2. Tsutsui, H.; S. Kinugawa, S.; Matsushima, S. Oxidative Stress and Heart Failure. Am. J. Physiol. Heart Circ. Physiol.2011, 301, 2181-2190. DOI: 10.1152/AJPHEART.00554.2011/ASSET/IMAGES/LARGE/ZH40121101550006.JPEG
3. A. Duni, A.; V. Liakopoulos, V.; S. Roumeliotis, S. et al. Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne's Thread. Int. J. Mol. Sci.2019, 20, 3711. DOI: 10.3390/IJMS20153711
4. Irazabal, M. V.; Torres. V. E. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells2020, 9, 1342. DOI: 10.3390/CELLS9061342
5. Rubattu, S.; Mennuni, S.; Testa, M. et al. Pathogenesis of Chronic Cardiorenal Syndrome: Is There a Role for Oxidative Stress? Int. J. Mol. Sci.2013, 14, 23011. DOI: 10.3390/IJMS141123011
6. Shah, B. N.; Greaves, K.; Rosner, M. H. The Cardiorenal Syndrome: A Review. Int. J. Nephrol. 2010, 2011, 920195. DOI: 10.4061/2011/920195
7. Markousis-Mavrogenis, G.; Tromp, J.; Ouwerkerk, W. et al. Multimarker Profiling Identifies Protective and Harmful Immune Processes in Heart Failure: Findings from BIOSTAT-CHF. Cardiovasc Res. 2022, 118 (8), 1964-1977. DOI: DOI: 10.1093/cvr/cvab23