Lipoprotein (a) and Incident Coronary Heart Disease in the Community: Impact of Traditional Cardiovascular Risk Factors

Clin Res Cardiol (2025). DOI 10.1007/s00392-025-02625-4
N. Arnold (Hamburg)¹, A. Goßling (Hamburg)¹, B. Bay (Hamburg)¹, J. Weimann (Hamburg)¹, C. Blaum (Hamburg)¹, F. J. Brunner (Hamburg)¹, M. M. Ferrario (Varese)², P. Brambilla (Milan)³, G. Cesana (Milan)³, V. Leoni (Desio)⁴, L. Palmieri (Roma)⁵, C. Donfrancesco (Roma)⁵, T. Padró (Barcelona)⁶, J. Andersson (Skellefteå)⁷, P. Jousilahti (Helsinki)⁸, F. M. Ojeda (Hamburg)¹, T. Zeller (Hamburg)¹, A. Linneberg (Copenhagen)⁹, S. Söderberg (Umea)¹⁰, L. Iacoviello (Pozzilli)¹¹, F. Gianfagna (Varese)², S. Sans (Barcelona,)¹², G. Veronesi (Varese)², B. Thorand (Neuherberg)¹³, A. Peters (Neuherberg)¹³, H. Tunstall-Pedoe (Dundee)¹⁴, F. Kee (Belfast)¹⁵, V. Salomaa (Helsinki)⁸, R. Schnabel (Hamburg)¹, K. Kuulasmaa (Helsinki)⁸, S. Blankenberg (Hamburg)¹, C. Waldeyer (Hamburg)¹, W. Koenig (München)^16
1Universitäres Herz- und Gefäßzentrum Hamburg Klinik für Kardiologie Hamburg, Deutschland; ²Research Center in Epidemiology and Preventive Medicine - EPIMED, University of Insubria, Department of Medicine and Surgery, Varese, Italien; ³Department of Medicine and Surgery, University of Milano-Bicocca, , Italy Milan, Italien; ⁴Hospital Pio XI of Desio, ASST Brianza Laboratory of Clinical Pathology Desio, Italien; ⁵Istituto Superiore di Sanità-ISS, Rome, Italy Department of Cardiovascular, Endocrine-Metabolic Diseases and Aging, Roma, Italien; ⁶Biomarkers of Cardiovascular Disease Group, In-stitut Recerca Sant Pau., Spain Barcelona, Spanien; ⁷Skellefteå Research Unit, Umeå University, Skellefteå, Sweden; Department of Public Health and Clinical Medicine Skellefteå, Schweden; ⁸Finnish Institute for Health and Welfare (THL) Department of Public Health Helsinki, Finnland; ⁹ispebjerg and Frederiksberg Hospital Center for Clinical Research and Prevention Copenhagen, Dänemark; ¹⁰Umeå University Department of Public Health and Clinical Medicine Umea, Schweden; ¹¹IRCCS Neuromed Department of Epidemiology and Prevention Pozzilli, Italien; ¹²Catalan Department of Health Barcelona,, Spanien; ¹³Helmholtz Zentrum München, German Research Center for Environmental Health Institute of Epidemiology Neuherberg, Deutschland; ¹⁴Institute of Cardiovascular Research, University of Dundee Cardiovascular Epidemiology Unit Dundee, Großbritannien; ¹⁵Queens University of Belfast Centre for Public Health Belfast, Großbritannien; ¹⁶Deutsches Herzzentrum München Klinik für Herz- und Kreislauferkrankungen München, Deutschland

Background: In the absence of approved medication to lower high Lipoprotein (a) (Lp(a)), its deleterious effects might be mitigated by overall cardiovascular (CV) risk reduction. However, data on the relationship between increased Lp(a) and incident coronary heart disease (CHD) according to the distribution of modifiable CV risk factors (CVRF) at baseline are still scarce.

Objective: To evaluate the association between high Lp(a) and incident CHD in the general population, depending on the presence or absence of four major CVRFs (hypertension, diabetes, dyslipidemia, smoking) at baseline. 

Methods:  The present analysis includes 66,495 individuals from eight European prospective population-based cohorts, who were free of clinically diagnosed CHD at baseline (primary prevention setting).  All participants were followed-up prospectively for the occurrence of a CHD event. The cohort was stratified according to CVRF burden at baseline in two categories: "zero or one CVRF” and ”≥2 CVRFs”, reflecting very low versus increased baseline risk, respectively. Fine and Gray competing risk-adjusted models were calculated for the association between Lp(a) mass (<90^th (ref.) versus ≥90^th percentile (pctl.) of Lp(a) distribution) and future CHD events.

Results: At baseline, the majority of CHD-free subjects demonstrated very low CV risk, having zero or one CVRF (overall n= 41,770), whereas 24,725 individuals reported ≥2 CVRFs. During a median follow-up of 9.7 years, 3,467 incident CHD events occurred. Despite being at very low absolute risk based on traditional CVRF, individuals with zero or one CVRF at baseline demonstrated a strong association between increased Lp(a) mass (≥90^th pctl.) and future CHD events, which was comparable to the association observed among individuals with ≥2 CVRFs. The fully-adjusted sub-distribution Hazard Ratios [sHRs] for elevated Lp(a) were 1.38 (95% CI, 1.12-1.71) in individuals with zero or one CVRF versus 1.27 (95% CI, 1.10-1.46) in those having ≥2 CVRFs at baseline (P _interaction between two groups 0.50).          

Conclusion: Among CHD-free subjects, high Lp(a) was related to adverse outcome even in individuals with no or only one CVRF at baseline, thereby generating substantial challenges in mitigating Lp(a)-associated CHD risk in very low risk populations.