Risk stacking in peripheral artery disease (PAD): Integrating genetics, cardiometabolic disease and social determinants of health to explain worsening PAD outcomes.

Peripheral artery disease (PAD) contributes disproportionately to disability, limb loss, and premature mortality, and U.S. major amputation rates have risen in the past decade among increasingly younger adults. Traditional risk tools incompletely explain these trends. We propose to examine a hypothesis generating risk-stacked model in which three interacting layers: 1) genetic susceptibility via lipoprotein(a) [Lp(a)]; 2) cardiovascular-kidney-metabolic syndrome (CKM; chronic kidney disease/diabetes mellitus/insulin resistance); and 3) social determinants of health (SDOH) jointly influence PAD incidence, phenotype at presentation (critical limb-threatening ischemia), and outcomes (major adverse limb events [MALE], including amputation). We summarize the independent and joint associations of elevated Lp(a), CKM/diabetes mellitus/insulin resistance, and adverse SDOH with PAD onset and MALE and practice-level implementation strategies (one-time Lp(a) testing, SDOH screening/routing, intensified preventive therapies). We hypothesize that high Lp(a) and diabetes/insulin resistance synergize to impair collateralization and promote thrombosis-prone plaque biology, while adverse SDOH delay diagnosis and limit access to guideline-directed care, together driving worse PAD outcomes. This conceptual framework supports universal one-time Lp(a) measurement, aggressive prevention, and embedded SDOH workflows while informing trials of equity-focused delivery models for patients with PAD. These factors may refine PAD risk stratification and align prevention resources to those at highest risk of limb loss.