Abstract
Chronic limb-threatening ischemia (CLTI) results in devastating complications such as lower-limb amputations. In this study, a genome-wide plasma microRNAs (miRNA) sequencing was performed to identify miRNA(s) associated with CLTI. Blood samples were collected from early stage CLTI patients (ABI < 0.9) and non-PAD controls (ABI ≥ 0.9) for 3 experiments: discovery phase (n = 23), confirmatory phase (n = 52) and validation phase (n = 20). In the discovery phase, next generation sequencing (NGS) was used to identify miRNA circulating in the plasma CLTI (n = 13) patients, compared to non-PAD controls (n = 10). Two down-regulated miRNAs (miRNA-6843-3p and miRNA-6766-5p) and three upregulated miRNAs (miRNA-1827, miRNA-320 and miRNA-98-3p) were identified (≥2-fold change). In the confirmatory phase, these 5 deregulated miRNAs were further investigated in non-PAD (n = 21) and CTLI (n = 31) patients using qRT-PCR. Only miRNA-1827 was found to be significantly upregulated (≥3-fold, p-value < 0. 001) in the CLTI group. Lastly, to minimize the influence of confounding factors, miRNA-1827 plasma levels were validated in a third cohort of CLTI patients (n = 10) matched to non-PAD controls (n = 10). Our analysis demonstrated that miRNA-1827 expression was increased in the CLTI cohort (≥2-folds, p-value < 0.001). In summary, circulating miRNA-1827 is significantly elevated in patients with CLTI.
Highlights
Peripheral arterial disease (PAD) is a devastating disease in which atherosclerotic plaque buildup leads to a narrowing of peripheral arteries in the lower limb, manifesting as ischemic pain [1,2]
In the chronic limb threatening ischemia (CLTI) group of each phase, patients were mainly comprised of males who had a higher prevalence of cardiovascular risk factors as compared to the non-PAD subjects, with the exception of the validation phase due to matching (Table 1)
Using two independent parameters, we identified five miRNAs which were significantly deregulated when comparing non-PAD controls and CLTI patients
Summary
Peripheral arterial disease (PAD) is a devastating disease in which atherosclerotic plaque buildup leads to a narrowing of peripheral arteries in the lower limb, manifesting as ischemic pain [1,2]. PAD affects more than 200 million patients worldwide, with 12 million people suffering from the disease in. North America alone [3]. Common PAD symptoms include pain induced by walking which resolves at rest (claudication). PAD can progress in disease state and severity to chronic limb threatening ischemia (CLTI) [4]. CLTI manifests as rest and/or night pain (early stages), or non-healing ulceration with tissue loss and gangrene (late stages). Patients with early CLTI often require arterial reconstructive surgeries
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