Promise of a Novel Bedside-to-Bench Paradigm: Can Percutaneous Coronary Intervention Proteomics Balloon Into Clinical Practice?
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Clinical proteomic studies, including cardiovascular disease biomarker discovery, often target plasma1 since blood collection is minimally invasive and routine in the clinic. However, the plasma proteome represents multiple tissues, challenging efforts to identify major sources of circulating proteins and their disease-relevant changes. Clinical proteomics thus also entails profiling the diseased tissue itself, increasing the specificity of candidate biomarkers and therapeutic targets. Unfortunately, acquisition of these tissues relies on the patient reaching a stage of extreme morbidity2 or worse, mortality3; consequently, driving drug target and biomarker discovery towards minimally invasive early disease stage practices, without added risk to the patients.
William Heberden first characterized angina pectoris4 as an intense exertional type of chest pain. Now recognized as myocardial ischemia-related pain, it can be due to either stable angina pectoris (SAP) or acute coronary syndromes such as ST-segment–elevation myocardial infarction (STEMI). Stable angina occurs when myocardial oxygen demand outpaces supply leading to ischemia and carries a <5% annual risk for a heart attack. Although relieved by rest and medications, a percutaneous coronary intervention (PCI) provides significant relief to moderate and severe SAP.5 In contrast, STEMI, precipitated by sudden blood oxygen supply reduction, is not relieved by rest. Hence, rapid reperfusion PCI is the standard of care that reduces mortality when performed within 2 hours of symptoms.6
In this issue of ATVB, Lorentzen et al7 demonstrate that angioplasty balloons, inflated during PCIs, retain sufficient protein from the lesions for mass spectrometry-enabled proteomics. Patients diagnosed with STEMI or SAP underwent a PCI procedure. Over 1300 proteins were quantified, exceeding the number of proteins observed in plasma proteomic studies.8 If each proteome could in fact reflect its predicted disease progression, it would support the further development and implementation of this in situ molecular profiling approach as a diagnostic tool in the clinic.
Lorentzen et al7 demonstrated that proteins associated with atherothrombotic pathways such as blood coagulation, myeloid cell-driven inflammation, and lipid-processing were enriched in STEMI versus SAP balloons. For instance, FERMT3 (Fermitin family homolog 3), an integrin binding and leukocyte and platelet adhesion molecule, was enriched in STEMI-balloons. A previous study demonstrated that increased FERMT3 transcript levels associated with plaque vulnerability; but also, its expression correlated with macrophages exhibiting an anti-inflammatory signature,9 reflecting myeloid-derived heterogeneity in atherosclerotic plaques. The vascular inflammation-myeloid cell links also point to suppression of PPARα (peroxisome proliferator-activated receptor alpha)-regulated metabolism reported in 2 other studies.3,10 Suppression of PPARα pathways in macrophages drive disease progression in murine models of vein graft disease and arteriovenous fistula lesions.10 Pharmalogical activation of PPARα reduced lesion size and inflammation in these mice,10 underscoring the connection between metabolism and inflammation in vascular disease progression.3 Moreover, PPARα activation also reduced inflammation and restenosis in pigs that underwent coronary arterial stent implantation.11
Equally relevant are the technical considerations in the Lorentzen et al study.7 A low pressure-inflated balloon, with limited vessel wall contact, accounted for proteins that adhered nonspecifically. Pre-, stent-, and post-dilation balloons provided sample replicates that facilitate differentiating between technical and biological sources of variability. Angioplasty balloons yielded proteins with lower estimated plasma concentrations compared with the controls, underscoring that the procedure enriches lesion-specific signatures. Protein yield and identifications increased with lesion severity, reflecting the increased tissue deposition in STEMI vessels compared to either SAP vessels or control samples. Finally, protein recovery was conducted using standard workflows making the procedure feasible for others to replicate. Since PCI remains a staple in anginal and acute coronary syndromes management, this budding in situ proteomics strategy has potential to mature into a theranostic modality.
Several technological breakthroughs have already combined therapeutic and diagnostic modalities with PCI.12 Newer generation drug-eluting stents and drug-coated balloons offer localized delivery of immunomodulating treatment.12 The rapidly evolving diagnostic field of intravascular ultrasound allows better stent optimization.12 Additionally, intravascular ultrasound with photoacoustic imaging or optical coherence tomography provides molecular characterization of the coronary plaque phenotype.11,13 With ever-increasing volume of PCI procedures14 and intravascular multimodality imaging,13 optimized PCI-sourced proteomics may influence daily clinical practice, providing a modern toolkit for diagnosis, patient phenotyping, disease course-therapeutic response surveillance, and planning precision medicine-based management strategies (Figure).
Sources of Funding
Disclosures M. Aikawa has received a research grant from Kowa Company, Ltd., Nagoya, Japan. The other authors report no conflicts.
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