Lower Isn't Better: Baseline LDL-C Identifies Endothelial Vulnerability and Outcomes after HSCT

LDL-C lowering reduces cardiovascular risk, but very low levels may paradoxically increase all-cause mortality and impair endothelial function. The role of LDL-C in HSCT has not been defined. PCSK9 regulates LDL receptor turnover and is implicated in vascular injury. We evaluated the prognostic impact of baseline LDL-C and the dynamics of PCSK9 and oxidized LDL (oxLDL) in allogeneic HSCT recipients. Lipid profiles (HDL-C, LDL-C, total cholesterol, triglycerides), oxLDL, and PCSK9 were measured in 86 pediatric and young adult allogeneic HSCT recipients. Cumulative incidence (CI) of transplant-associated thrombotic microangiopathy (TA-TMA) and 1-year overall survival (OS) were analyzed by stratifying baseline and day +14 lipoproteins above or below cohort medians. Profound shifts in lipid metabolism were observed between baseline and day +14 (Fig. 1). Median LDL-C increased from 72 mg/dL (range 15–206) to 125 mg/dL (22–289, p<0.0001). HDL-C fell sharply from 42 mg/dL (5–91) to 13 mg/dL (5–65, p<0.0001), and triglycerides decreased from 114 mg/dL (36–700) to 87 mg/dL (5–979, p=0.03). Baseline LDL-C was the most powerful predictor of outcomes: patients with LDL-C <72 mg/dL had a 1-year TA-TMA CI of 50% compared with 24% in those ≥72 mg/dL (p=0.01, Fig. 2A). Low baseline LDL-C was also associated with significantly inferior OS (88% vs 98% at 1 year, p=0.05, Fig. 2C). Neither HDL-C nor triglycerides stratified risk of TA-TMA or OS. OxLDL rose from 1,992 pg/mL (500–5,960) to 2,267 pg/mL (500–9,868, p=0.02), and PCSK9 increased from 503,751 pg/mL (175,433–1,390,133) to 663,125 pg/mL (383,725–2,243,403, p<0.0001) (Fig. 3A–D). Change–change analyses demonstrated ΔLDL-C correlated with ΔoxLDL (r=0.29, p=0.01), whereas ΔPCSK9 showed a modest inverse correlation with ΔoxLDL (r=−0.22, p=0.04) (Fig. 3E–F), supporting coordinated but distinct regulatory pathways. Baseline PCSK9 did not stratify 1-year TA-TMA risk (≥510,155 pg/mL vs <510,155: CI 0.42 vs 0.37; p=0.71), and baseline oxLDL likewise showed no discrimination (≥1,992 pg/mL vs <1,992: CI 0.36 vs 0.43; p=0.54) (Fig. 3G–H). Low baseline LDL-C is a simple, clinically available biomarker that identifies patients at risk for TA-TMA and inferior survival following HSCT. In contrast, PCSK9 and oxLDL—despite rising post-transplant—did not predict TA-TMA when dichotomized, indicating their role as dynamic correlates of injury rather than baseline risk. Integrating LDL-C into pre-HSCT risk assessment may enable earlier identification of vulnerable patients and guide preventive strategies. Modeling continuous and time-varying PCSK9 and oxLDL will refine mechanistic understanding and inform selection of patients for lipid-targeted interventions.