Plasma Proteomics Unveils VEGFR1 as a High-Precision Prognostic Biomarker in Cardiogenic Shock

Highlights

• High-throughput plasma proteomic screening identified Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) as a significantly elevated protein in patients with acute myocardial infarction-related cardiogenic shock (AMICS).
• Validation in the CULPRIT-SHOCK cohort (n=421) confirmed that nonsurvivors had significantly higher VEGFR1 levels compared to survivors (6.8 vs. 3.8 ng/L).
• VEGFR1 remained an independent predictor of 180-day mortality even after adjustment for the Simplified Acute Physiology Score II (SAPS II) and serum lactate levels.
• Longitudinal analysis demonstrated that VEGFR1 levels remain persistently elevated in nonsurvivors throughout the first five days of treatment.

Background: The Unmet Need in Cardiogenic Shock

Cardiogenic shock (CS) remains the leading cause of in-hospital mortality in patients presenting with acute myocardial infarction (AMI). Despite the widespread implementation of early revascularization and advancements in mechanical circulatory support (MCS), mortality rates continue to hover around 40% to 50%. One of the primary challenges in managing AMICS is the heterogeneity of the patient population and the lack of highly specific biomarkers for risk stratification and therapeutic monitoring.

While traditional markers like serum lactate and the Simplified Acute Physiology Score II (SAPS II) are widely used, they often reflect end-organ damage that has already occurred rather than the underlying pathophysiology of the shock state. There is an urgent clinical need for novel biomarkers that can identify high-risk patients earlier, potentially guiding more aggressive interventions or the selection of specific mechanical support strategies. In this context, the study by Jung et al. leverages modern proximity extension assay (PEA) technology to map the plasma proteome and identify novel prognostic signals.

Study Design: From Discovery to Validation

The researchers employed a robust three-stage methodological approach to identify and validate prognostic biomarkers in AMICS.

The Discovery Phase

The exploration cohort consisted of 17 patients: 9 patients with AMI without shock and 8 patients with AMICS. Using the Olink Explore platform, which utilizes PEA technology, the team analyzed 2942 proteins. This high-throughput screening successfully profiled 2925 proteins, identifying VEGFR1 (also known as Flt1) as the most significantly elevated protein in the shock group compared to the non-shock group.

The Validation Phase

To confirm the prognostic relevance of VEGFR1, the researchers utilized the validation cohort from the CULPRIT-SHOCK trial (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock). This cohort included 421 patients with AMICS. The primary endpoint for validation was 180-day survival. This large, well-defined clinical trial population provided the statistical power necessary to assess the independent prognostic value of the biomarker.

The Longitudinal Phase

A third, independent cohort of 50 patients (29 survivors and 21 nonsurvivors at 30 days) was analyzed at different time points (Day 0, Day 1, and Day 5). This allowed the researchers to observe the temporal dynamics of VEGFR1 levels and how they correlate with clinical outcomes over the first week of intensive care.

Key Findings: VEGFR1 as a Robust Predictor of Mortality

The results of the validation study were striking. In the CULPRIT-SHOCK cohort, plasma levels of VEGFR1 were markedly higher in patients who did not survive to 180 days (median 6.8 ng/L) compared to those who did (median 3.8 ng/L; P < 0.001).

Independent Prognostic Power

Using Cox regression analysis, VEGFR1 was shown to be independently associated with a higher risk of 180-day mortality. Even after adjusting for the SAPS II score, which accounts for various clinical and physiological variables, the adjusted hazard ratio (aHR) was 1.06 per ng/L increase (95% CI, 1.03–1.09; P < 0.001). Furthermore, the study demonstrated that VEGFR1 provided incremental prognostic information beyond serum lactate levels, which is currently the gold-standard biochemical marker for shock severity.

Temporal Dynamics

The longitudinal data revealed that in nonsurvivors, VEGFR1 levels were not only high at admission but remained consistently elevated throughout the first five days of the shock state. In contrast, survivors showed a gradual decline in VEGFR1 levels. This suggests that VEGFR1 may be a marker of persistent pathological processes rather than just a transient response to the initial cardiac insult.

Mechanistic Insights: Why VEGFR1?

Vascular Endothelial Growth Factor Receptor 1 (VEGFR1/Flt1) is a tyrosine kinase receptor that binds to VEGF-A, VEGF-B, and placental growth factor (PlGF). In the context of cardiogenic shock, the elevation of VEGFR1 is likely linked to several pathophysiological pathways:

Endothelial Dysfunction and Capillary Leak

VEGFR1 can exist in a soluble form (sFlt-1), which acts as a decoy receptor, sequestering VEGF and preventing it from binding to its signaling receptors. This disruption of VEGF signaling can lead to endothelial dysfunction, increased vascular permeability, and capillary leak, all of which are hallmarks of the systemic inflammatory response syndrome (SIRS) often seen in advanced cardiogenic shock.

Hypoxia and Myocardial Stress

The expression of VEGFR1 is upregulated by hypoxia-inducible factor 1-alpha (HIF-1α). In AMICS, the combination of low cardiac output and systemic hypoxia likely drives the massive release of VEGFR1 into the circulation. Its persistence in nonsurvivors may reflect an inability to resolve this state of systemic tissue hypoxia and endothelial stress.

Expert Commentary and Clinical Implications

The identification of VEGFR1 via an unbiased proteomic approach adds a significant piece to the puzzle of CS management. Clinicians have long struggled with the fact that lactate, while useful, is a late marker of metabolic failure. VEGFR1 appears to offer a more nuanced view of the vascular and endothelial status of the patient.

Risk Stratification and MCS Selection

If VEGFR1 can be measured rapidly in a clinical setting (e.g., via point-of-care testing), it could assist in earlier decision-making regarding the escalation of care. For instance, patients with extremely high VEGFR1 levels at admission might be candidates for earlier mechanical circulatory support or more intensive hemodynamic monitoring.

Study Limitations

Despite the strong data, certain limitations must be considered. First, while the association with mortality is robust, the study is observational and does not prove a causal link between VEGFR1 levels and death. Second, the current analysis focused on AMI-related shock; whether these findings extend to other forms of cardiogenic shock (e.g., acute-on-chronic heart failure) remains to be determined. Finally, the practical application of this biomarker requires the development of standardized, rapid assays that can be integrated into emergency department and cath-lab workflows.

Conclusion

The study by Jung et al. represents a significant step forward in the precision medicine approach to cardiogenic shock. By identifying VEGFR1 as a potent, independent prognostic biomarker through unbiased proteomic screening and validating it in the large-scale CULPRIT-SHOCK cohort, the researchers have provided a new tool for understanding and predicting outcomes in this high-mortality population. Future research should focus on whether targeting the VEGF/VEGFR1 pathway could offer therapeutic benefits and how this biomarker can be best integrated into clinical decision-support systems.

Funding and Clinical Trials

The CULPRIT-SHOCK trial was supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) and the German Heart Research Foundation. The study is registered at ClinicalTrials.gov (NCT01927549).

References

1. Jung C, Lang A, Duse DA, et al. Plasma Proteome Analysis Identifies Vascular Endothelial Growth Factor Receptor 1 as a Prognostic Biomarker in Cardiogenic Shock. Circ Heart Fail. 2025;18(12):e012890.
2. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367(14):1287-1296.
3. Thiele H, Akin I, Sandri M, et al. PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock. N Engl J Med. 2017;377(25):2419-2432.
4. Olink Explore 3000 Technical Documentation. Proximity Extension Assay (PEA) Technology for High-Throughput Proteomics.