Plasma Biomarkers to Predict Cardiovascular Outcome in Patients With Peripheral Artery Disease: A Systematic Review and Meta-Analysis

Abstract

Objective: Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events. Numerous plasma biomarkers have been investigated in lower extremity PAD, but none are used for clinical risk assessment. We aimed to provide a comprehensive overview of biomarker testing in PAD as a first step to improve risk stratification. Approach and Results: A systematic literature review in MEDLINE/PubMed, Cochrane, and Embase was performed, identifying all studies investigating plasma biomarkers in association with cardiovascular events and mortality in lower extremity PAD. Forty-seven studies comprising 21 473 PAD patients met our criteria and were included. Effect estimates were provided by the studies based on a minimum follow-up of 1 year. Meta-analyses were performed by pooling studies per biomarker for each end point. Patients with increased high-sensitivity CRP (C-reactive protein) levels had a relative risk of 1.86 (1.48-2.33) for major adverse cardiovascular events and a relative risk of 3.49 (2.35-5.19) for mortality. Increased fibrinogen and d-dimer levels were associated with an increased relative risk of mortality of 2.08 (1.46-2.97) and 2.22 (1.24-3.98), respectively. Additionally, patients with increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cTnT (cardiac troponin T) levels were at an even higher risk of mortality with relative risks of 4.50 (2.98-6.81) and 3.33 (2.70-4.10), respectively.

Conclusions: This systematic review identifies promising biomarkers representing different pathophysiological processes implicated in lower extremity PAD, including high-sensitivity CRP, neutrophil-lymphocyte ratio, fibrinogen, d-dimer, NT-proBNP, and high-sensitivity cTnT. Clinical implementation should be preceded by a management study to test the utility of a combination of these markers for individual risk stratification. Ultimately, this may contribute to tailored treatment and increased effectiveness of current treatment strategies in PAD.

Keywords: lower extremity; meta-analysis; peptide fragments; peripheral artery disease; risk assessment.

Figure 1.

Search and study selection. PAD indicates peripheral artery disease.

Figure 2.

Forest plots for inflammatory and coagulation markers. A, High-sensitivity CRP (C-reactive protein; hs-CRP) levels and the risk of mortality. B, hs-CRP levels and the risk of major adverse cardiovascular events (MACE). C, Fibrinogen levels and the risk of mortality. D, d-dimer levels and the risk of mortality (all-cause and cardiovascular [CV] mortality). The diamond and its width indicate the pooled risk ratio and the corresponding 95% CI. M-H indicates Mantel-Haenszel.

Figure 3.

Forest plots for cardiac markers and markers for arterial vessel wall damage. A, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels and the risk of mortality. B, Sensitivity analysis of A. C, hs-cTnT (high-sensitivity cardiac troponin T) levels and the risk of mortality. D, Sensitivity analysis of C. E, Adiponectin and the risk of mortality. The diamond and its width indicate the pooled risk ratio and the corresponding 95% CI. M-H indicates Mantel-Haenszel.

Figure 4.

Plasma biomarkers included in this review. High-sensitivity CRP (C-reactive protein; hs-CRP) indicates a state of chronic inflammation with increased numbers of neutrophils (neutrophil-lymphocyte ratio [NLR]) expressing proatherogenic markers such as MPO (myeloperoxidase). Fibrinogen plays an important role in early atherogenesis, apart from its role in coagulation, whereas d-dimer marks a hypercoagulable state. Cytokines such as GDF-15 (growth differentiation factor-15) and acute-phase proteins like SAA (serum amyloid A) are implicated in further progression of atherosclerotic lesions. Within these lesions, adiponectin, asymmetrical dimethylarginine (ADMA), and homocysteine cause further damage and disruption of the arterial vessel wall. Progression of atherosclerosis leads to ischemia in organs, including the heart. Cardiac markers NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-cTnT (high-sensitivity cardiac troponin T) reflect myocardial ischemia, which can be primarily due to coronary artery disease but can also be a sign of systemic microvascular disease and inflammation.