Peripheral artery disease [PAD] is associated with conventional and novel risk factors. Conventional risk factors are well established, but the specific prognostic impact of readily available clinical markers – such as resting heart rate – in patients with PAD remains elusive. Among novel risk factors, specific markers of lipid metabolism (e.g., subtypes of high-density lipoprotein [HDL] and low-density lipoprotein [LDL] cholesterol), oxidative stress (e.g., total antioxidant status [TAS]), and global hemostatic assays (i.e., overall hemostatic, coagulation and fibrinolytic potentials [OHP/OCP/OFP]) are promising determinants of PAD pathophysiology, but fairly under-studied.
In the doctoral thesis, we sought to appraise the association of clinical and novel lipid and hemostatic markers with the extent and prognosis of PAD. Specifically, we aimed to i) assess the association of selected novel lipid parameters (namely HDL3, sLDL and TAS) and hemostatic potentials (namely OHP, OCP and OFP) with the extent and severity of PAD, and ii) establish the prognostic impact of resting heart rate (adjusted for conventional clinical characteristics) in patients with PAD.
We conducted two cohort studies in patients: a cross-sectional and a longitudinal cohort study. In the cross-sectional study, we included 212 consecutive patients hospitalized for invasive management of PAD (median age 68 years, 36% women). We determined the association of HDL3, sLDL, TAS, and hemostatic potentials with patients’ clinical characteristics — namely PAD severity (Rutherford grade 䁥II), anatomic extent (iliac-femoral vs. popliteal-distal), atherosclerotic vascular disease extent (isolated PAD vs. concomitant coronary and/or cerebrovascular disease, and presence of diabetes mellitus. After multivariate logistic regression adjustment, HDL3 was independently associated with Rutherford grade 䁥II (1% decrease in odds for 1 mg/L increase in HDL3 level, adjusted p = 0.020) and OHP was independently associated with diabetes mellitus (12% increase in odds for 1 Abs-sum unit increase in OHP, adjusted p = 0.039). Conversely, none of the selected biomarkers was associated with either anatomic extent or extent of atherosclerotic vascular disease.
In the longitudinal cohort study, we included 1720 consecutive patients hospitalized for invasive management of PAD (median age 71 years, 38% women, 39% with critical limb ischemia). With a non-concurrent prospective design, we assessed the long-term independent prognostic impact of resting heart rate along with clinical determinants and traditional risk factors on all-cause mortality in patients with PAD. During a median follow-up of 729 days, 364 (21.2%) patients died. After multivariate Cox proportional hazards regression adjustment, resting heart rate — along with age, critical limb ischemia, diabetes mellitus, dyslipidemia, chronic kidney disease, atrial fibrillation, and lack of statin therapy — emerged as independent predictors of all-cause mortality. Each 1 bpm increase in resting heart rate was independently associated with a 1% increase in all-cause mortality (adjusted p = 0.006).
The thesis provides novel insight into clinical determinants, lipid metabolism and hemostatic activity in patients with PAD. Novel lipid and hemostatic biomarkers do not predict PAD severity or extent beyond traditional risk factors, with one notable exception — HDL3. Our results suggest an inverse association between small, dense HDL particles and PAD severity, therefore expanding our insight into the complex interrelationship between HDL and atherosclerotic vascular disease. Conversely, clinical determinants and traditional risk factors strongly predict all-cause mortality. In particular, we have shown that resting heart rate is an independent prognostic factor in patients with PAD.
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