Paradoxical prognostic role of alpha-klotho protein: a marker of increased mortality risk in the post-myocardial infarction setting

Background: Alpha-Klotho (α-Klotho) an anti-ageing protein, expressed also in human cardiomyocytes, exerts crucial cardioprotective effects. Its overexpression extends lifespan, and higher circulating levels are linked to lower cardiovascular risk. Intriguingly, one study, limited to in-hospital recovery, suggested that higher α-Klotho levels after acute myocardial infarction (AMI) correlate with increased in-hospital mortality. A comprehensive understanding of factors that can influence α-Klotho concentration during the AMI and its long-term prognostic role is critical. Purpose: In the present study, we aimed to 1) identify potential predictors of α-Klotho levels in AMI patients and 2) evaluate the role of α-Klotho levels during MI as a biomarker of long-term mortality. Methods: We included 516 consecutive patients with AMI (399 with STEMI and 117 with NSTEMI presentation). Blood samples for α-Klotho determination were collected of all patients at admission. Analyses were conducted using the log-transformed values of α-Klotho due to its skewed distribution. Results: The mean age was 67±12 years, and 71% of patients were male. All patients underwent coronary revascularization, with optimal TIMI flow score 3. The median glomerular filtration rate (GFR) was 79[61–97]mL/min/1.73m², while the median C-reactive protein (CRP) level was 5.2 [1.9–16] mg/L. Median α-Klotho was 230 [153-884] pg/ml. α-Klotho levels were higher in females (p=0.02), NSTEMI (p<0.01), diabetics (p=0.01), and patients with≥3 risk factors (p=0.02). No significant differences were observed according to age (p=0.26). After log-transformation, α-Klotho showed a bimodal distribution, with a log value of 6 (403.4 pg/mL on the original scale) identified as the threshold sep- arating the two subgroups (Fig.1A). Independent predictors of α-Klotho above this threshold were younger age, NSTEMI presentation, and HbA1c≥48 mmol/mol, after adjustment for gender, CRP, IL-1β, GFR, and LDL cholesterol. During a mean 75-month follow-up, 145 patients (28.5%) died. Kaplan–Meier curves showed higher mortality among patients with α-Klotho above the threshold (p<0.01, Fig.1B). Increasing log-transformed α-Klotho levels were linearly associated with reduced mortality (Fig.1C, with the dashed line in- dicating the median value). In multivariate Cox analysis, elevated α-Klotho remained independently associated with all-cause mortality (HR1.26, p=0.04 for log-transformed values), together with older age, NSTEMI diagnosis, reduced LVEF, and smoking, after adjustment for CRP, IL-1β, LDL cholesterol, and GFR (Fig.1D). Conclusions: For the first time, high plasma α-Klotho was independently linked to increased long-term mortality post-AMI. Predictors of high α-Klotho included younger age, NSTEMI presentation, and HbA1c≥48 mmol/mol. These findings validate α-Klotho as a novel biomarker crucial for identifying pa- tients who require escalated monitoring and immediate therapeutic intensification.