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Promise of a Novel Bedside-to-Bench Paradigm: Can Percutaneous Coronary Intervention Proteomics Balloon Into Clinical Practice?

Originally publishedhttps://doi.org/10.1161/ATVBAHA.122.317802Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:865–867

See accompanying article on page 857

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).

Figure.

Figure. The percutaneous coronary intervention (PCI) procedure’s potential to integrate in situ proteomics into its growing therapeutic and diagnostic practices. Blood drawn for chemistry panels can also be used for plasma proteome profiling, in parallel with proteome profiling of lesions acquired during PCI (in situ proteomics). Protein profiles can be analyzed with imaging data, blood chemistry profiles, and medical information. Integrating these diverse diagnostic tools can form the basis for precision care and postprocedure management of patients.

Article Information

Disclosures M. Aikawa has received a research grant from Kowa Company, Ltd., Nagoya, Japan. The other authors report no conflicts.

Footnotes

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Sources of Funding and Disclosures, see page 866.

Correspondence to: Sasha A. Singh, PhD, The Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School, 3 Blackfan Street, 17th Floor, Boston, MA 02115. Email

References

  • 1. Zhu Y, Aebersold R, Mann M, Guo T. SnapShot: clinical proteomics.Cell. 2021; 184:4840–4840.e1. doi: 10.1016/j.cell.2021.08.015CrossrefMedlineGoogle Scholar
  • 2. Schlotter F, Halu A, Goto S, Blaser MC, Body SC, Lee LH, Higashi H, DeLaughter DM, Hutcheson JD, Vyas P, et al.. Spatiotemporal multi-omics mapping generates a molecular atlas of the aortic valve and reveals networks driving disease.Circulation. 2018; 138:377–393. doi: 10.1161/CIRCULATIONAHA.117.032291LinkGoogle Scholar
  • 3. Herrington DM, Mao C, Parker SJ, Fu Z, Yu G, Chen L, Venkatraman V, Fu Y, Wang Y, Howard TD, et al.. Proteomic architecture of human coronary and aortic atherosclerosis.Circulation. 2018; 137:2741–2756. doi: 10.1161/CIRCULATIONAHA.118.034365LinkGoogle Scholar
  • 4. Heberden W. Some account of a disorder of the breast.Medical Transactions The Royal College of Physicians of London. 1772; 2:59–67.Google Scholar
  • 5. Joshi PH, de Lemos JA. Diagnosis and management of stable angina: a review.JAMA. 2021; 325:1765–1778. doi: 10.1001/jama.2021.1527CrossrefMedlineGoogle Scholar
  • 6. Bhatt DL, Lopes RD, Harrington RA. Diagnosis and treatment of acute coronary syndromes: a review.JAMA. 2022; 327:662–675. doi: 10.1001/jama.2022.0358CrossrefMedlineGoogle Scholar
  • 7. Lorentzen LG, Hansen GM, Iversen KK, Bundgaard H, Davies MJ. Proteomic characterization of atherosclerotic lesions in situ using percutaneous coronary intervention angioplasty balloons—brief report.Arterioscler Thromb Vasc Biol. 2022; 42:857–864. doi: 10.1161/ATVBAHA.122.317491LinkGoogle Scholar
  • 8. Geyer PE, Kulak NA, Pichler G, Holdt LM, Teupser D, Mann M. Plasma Proteome Profiling to Assess Human Health and Disease.Cell Syst. 2016; 2:185–195. doi: 10.1016/j.cels.2016.02.015CrossrefMedlineGoogle Scholar
  • 9. Oksala N, Pärssinen J, Seppälä I, Klopp N, Illig T, Laaksonen R, Levula M, Raitoharju E, Kholova I, Sioris T, et al.. Kindlin 3 (FERMT3) is associated with unstable atherosclerotic plaques, anti-inflammatory type II macrophages and upregulation of beta-2 integrins in all major arterial beds.Atherosclerosis. 2015; 242:145–154. doi: 10.1016/j.atherosclerosis.2015.06.058CrossrefMedlineGoogle Scholar
  • 10. Decano JL, Singh SA, Gasparotto Bueno C, Ho Lee L, Halu A, Chelvanambi S, Matamalas JT, Zhang H, Mlynarchik AK, Qiao J, et al.. Systems approach to discovery of therapeutic targets for vein graft disease: pparα pivotally regulates metabolism, activation, and heterogeneity of macrophages and lesion development.Circulation. 2021; 143:2454–2470. doi: 10.1161/CIRCULATIONAHA.119.043724LinkGoogle Scholar
  • 11. Iwata H, Osborn EA, Ughi GJ, Murakami K, Goettsch C, Hutcheson JD, Mauskapf A, Mattson PC, Libby P, Singh SA, et al.. Highly selective pparα (peroxisome proliferator-activated receptor α) agonist pemafibrate inhibits stent inflammation and restenosis assessed by multimodality molecular-microstructural imaging.J Am Heart Assoc. 2021; 10:e020834. doi: 10.1161/JAHA.121.020834LinkGoogle Scholar
  • 12. Serruys PW, Ono M, Garg S, Hara H, Kawashima H, Pompilio G, Andreini D, Holmes DR, Onuma Y, King Iii SB. Percutaneous coronary revascularization: JACC historical breakthroughs in perspective.J Am Coll Cardiol. 2021; 78:384–407. doi: 10.1016/j.jacc.2021.05.024CrossrefMedlineGoogle Scholar
  • 13. Khraishah H, Jaffer FA. Intravascular molecular imaging: near-infrared fluorescence as a new frontier.Front Cardiovasc Med. 2020; 7:587100. doi: 10.3389/fcvm.2020.587100CrossrefMedlineGoogle Scholar
  • 14. Inohara T, Kohsaka S, Spertus JA, Masoudi FA, Rumsfeld JS, Kennedy KF, Wang TY, Yamaji K, Amano T, Nakamura M. Comparative trends in percutaneous coronary intervention in japan and the united states, 2013 to 2017.J Am Coll Cardiol. 2020; 76:1328–1340. doi: 10.1016/j.jacc.2020.07.037CrossrefMedlineGoogle Scholar