Diseases · 6 authors, 3 centres
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This study of 250 patients found that elevated lipoprotein(a) (Lp(a) ≥30 mg/dL) and low IgM autoantibodies to oxidized Lp(a) are independently associated with calcific aortic valve stenosis (CAVS). The combination of high Lp(a) and low IgM autoantibodies dramatically increased CAVS risk (OR 17.3 with coronary heart disease, OR 6.4 without). These findings suggest that both Lp(a) levels and immune responses to oxidized Lp(a) may be important in CAVS pathogenesis and risk stratification.
**Background:** Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease in the Western world and is becoming a serious health burden due to population aging. Lipoprotein(a) (Lp(a)) is an established independent risk factor for both coronary heart disease (CHD) and CAVS. Oxidation-specific epitopes on lipoproteins are recognized by natural IgM antibodies, which may play a protective role in atherosclerosis. This study aimed to assess the association of Lp(a) and IgM autoantibodies to native and oxidized Lp(a) with CAVS in patients with and without CHD.
**Methods:** This cross-sectional, single-center study included 250 patients aged over 45 years. Patients were divided into three groups: Group 1 (n=102) had CAVS and angiographically confirmed CHD (≥50% stenosis in at least one coronary artery); Group 2 (n=62) had CAVS without CHD; and the control group (n=86) had intact or minimally affected coronary arteries and unaffected aortic valves. Exclusion criteria included congenital bicuspid aortic valve, rheumatic heart disease, infective endocarditis, oncology, and systemic connective tissue diseases. CAVS was diagnosed by transthoracic echocardiography (maximum blood flow velocity >2.0 m/s, mean pressure gradient >20 mm Hg). Lp(a) concentration was measured by ELISA using sheep monospecific polyclonal antibodies. IgM autoantibodies against Lp(a) and oxidized Lp(a) were measured by ELISA with highly purified Lp(a) coupled to plates. Statistical analysis included ROC analysis, logistic regression, and calculation of odds ratios with 95% confidence intervals.
**Key Results:** Patients with CAVS were significantly older than controls (p<0.01). Lp(a) concentration was highest in patients with CAVS and CHD (median 22.6 mg/dL [IQR 6.5-51.1]) compared to CAVS without CHD (14.0 [5.9-48.3]) and controls (12.1 [4.9-25.1]), p<0.05 for both comparisons. ROC analysis identified Lp(a) ≥30 mg/dL as predictive of CAVS with 39% sensitivity and 84% specificity (AUC 0.63, p<0.001). Elevated Lp(a) (≥30 mg/dL) was associated with CAVS overall (OR 3.7, 95% CI 1.8-7.3, p<0.001), with CAVS and CHD (OR 4.7, 95% CI 2.1-10.2), and with CAVS without CHD (OR 3.4, 95% CI 1.4-8.0). After adjustment for age, gender, smoking, and LDL-C, Lp(a) ≥30 mg/dL remained independently associated with CAVS (OR 3.63, 95% CI 1.47-8.98, p=0.005). IgM autoantibodies to oxidized Lp(a) were significantly lower in CAVS patients regardless of CHD presence. The cut-off value for IgM autoantibodies to oxLp(a) was 9.9 lab. units (sensitivity 68%, specificity 71%, AUC 0.74, p<0.001). Logistic regression showed that age (OR 1.15, 95% CI 1.08-1.22) and Lp(a) (OR 1.02, 95% CI 1.01-1.04) were independently associated with CAVS, while IgM autoantibodies to oxLp(a) reduced the likelihood of CAVS (OR 0.81, 95% CI 0.71-0.92, p<0.05). The combination of Lp(a) ≥30 mg/dL and IgM autoantibodies <9.9 lab. units was associated with CAVS and CHD (OR 17.3, 95% CI 4.2-90.1, p<0.001) and CAVS without CHD (OR 6.4, 95% CI 1.8-43.1, p<0.01). No association was found between Lp(a) concentration or IgM autoantibody levels and severity of aortic valve stenosis.
**Clinical Implications:** This study confirms that elevated Lp(a) (≥30 mg/dL) is an independent risk factor for CAVS regardless of concomitant CHD. The novel finding is that low IgM autoantibodies to oxidized Lp(a) are independently associated with CAVS, and the combination of high Lp(a) and low IgM autoantibodies confers a markedly elevated risk (OR 17.3 for CAVS with CHD). These results suggest that natural IgM antibodies may have a protective role by binding to oxidized Lp(a) and facilitating its clearance, thereby reducing the likelihood of developing CAVS. The findings support the potential for Lp(a)-lowering therapies (e.g., PCSK9 inhibitors) in CAVS prevention and raise the possibility of immunomodulatory approaches such as vaccination to enhance protective IgM responses. However, the cross-sectional design and small sample size limit causal inference, and larger prospective studies are needed to confirm these associations and determine whether autoantibody levels predict CAVS progression or response to therapy.