Peripheral artery disease: Evaluation of novel biomarkers and adverse events in unexplored subtypes

Abstract

Our research indicates that patients with non-revascularizable (NR) chronic limb-threatening ischemia (CLTI) have an amputation-free survival rate of 43% after five years, driven by an equal rate of all-cause mortality and amputation. Amputation after one year from inclusion is rare. Although the five-year prognosis for these patients is poor, their prospects are not (much) worse than those of patients with revascularizable CLTI. Using the same cohort of NR-CLTI patients, we validated a novel survival model. Our analysis demonstrates a C-statistic of 0.86, indicating that the combined hazards of twelve covariates provide excellent discrimination in our cohort. This model can thus be used to identify no-option CLTI patients with elevated risk of death. Another cardiovascular minority with a high risk of PAD (complications) is patients with pseudoxanthoma elasticum (PXE). Our research indicates that half of these patients meet the criteria for PAD, which is seven times the expected prevalence compared to the general population. Although PAD is common in PXE, progression to higher ischemic stages is much rarer, and peripheral interventions are generally not performed very often (2.25 per 1,000 patient-years). However, the reintervention rate is quite unfavorable in most patients undergoing interventions, with multiple reinterventions occurring within one year after the primary intervention (21 out of 35). Differences between biomarker sources are investigated, and we conclude that the correlation between plasma and EVs is moderate, on average, but with a broad range. Hypothetically, some well-correlating proteins might reflect the same processes in an equal origin in plasma and EVs, whereas poorly-correlating proteins indicate that origins or pathophysiological mechanisms differ in these sources. Plaque proteins correlate quantitatively better with EV-proteins than with their plasma protein counterparts. More plaque-derived proteins are differentially expressed when stratifying for a recent (presurgical) stroke compared to the circulating markers. In contrast, proteins from plasma and EVs are more often differentially expressed when stratifying for future major adverse cardiovascular events (MACE) compared to proteins from plaque. EVs contain the most significantly higher proteins in patients with MACE and could therefore be of more use when it comes to risk stratification. Although plasma is an excellent source for prognostic biomarkers of (systemic) events, EVs should be investigated, preferably in combination with plasma markers. We thus explored the prognostic features of four EV-proteins, cystatin C (CysC), CD14, serpinC1 (SC1), and serpinG1 (SG1), in patients undergoing femoral endarterectomy. Our results indicate that CD14 is independently associated with MACE, and SG1 is independently associated with both MACE and major adverse limb events (MALE). Using these risk factors within (existing) risk models leads to a modest improvement in these models’ efficacy. An equivalent investigation is performed with plasma lipoprotein(a) (Lp[a]). Our study shows that in patients undergoing femoral endarterectomy, high Lp(a) levels are consistently associated with first MALE and recurrent MALE. This could, in the future, help establish a risk model that could stratify patients according to clinically important adverse events. As part of the CLTI framework, stratification enables the patient-tailored management of preventive treatments, future revascularizations and limb salvage.