Elevated Lp(a) and family history of CHD have independent and additive joint associations with CV events

Lipoprotein(a) and Family History Predict Cardiovascular Disease Risk

Literature - Mehta A, Virani SS, Ayers CR et al., - J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.06.040.

Introduction and methods

Several studies have shown that Lp(a) is an independent risk factor for atherosclerotic CVD (ASCVD) [1-5]. A family history (FHx) of coronary heart disease (CHD) is another established independent risk factor for ASCVD among asymptomatic subjects [6]. While the association of Lp(a) and FHx with ASCVD risk has been well established, little is known about their independent and joint associations with long-term risk. The current study assessed the independent and joint associations of elevated Lp(a) level and FHx with incident ASCVD and CHD events among asymptomatic subjects of 2 cohorts: The ARIC (Athersclerosis Risk in Communities) study and DHS (Dallas Heart Study) [7,8].

A total of 12,149 ARIC participants (mean age was 53.9±5.7 years, 56.1% were women, 76.8% were white, 22.9% were black, 44.4% had FHx. 9.8% had premature FHx) and 2,756 DHS participants (mean age was 43.6±9.9 years, 56.8% were women, 32.1% were white, 49.6% were black, 16.1% were Hispanic, 31.1% had FHx, 10.1% had premature FHx) were included in the analysis. Included participants were free of prevalent CVD and had information available regarding Lp(a) level, FHx of CHD, CV risk factors, and adjudicated ASCVD events during follow-up. In ARIC, premature FHx was defined as paternal age<55 years or maternal age <60 years at time of MI diagnosis. In DHS, premature FHx was defined as occurrence of MI in a first-degree male relative <50 years of age or in a first degree female relative <55 years of age.

CV outcomes were time to first ASCVD event (defined as coronary death, nonfatal MI, or stroke) and time to first CHD event (defined as first occurrence of coronary death or nonfatal MI). Mean follow-up for incident ASCVD was 21.1±8.5 years in ARIC and 10.9±1.9 years in DHS.

Main results

  • Among ARIC participants, FHx and elevated Lp(a) level (race-specific quintile 5) were independently associated with increased ASCVD risk (HR 1.17, 95%CI 1.09-1.26, P<0.001; and HR 1.25, 95%CI 1.12-1.40, P<0.001, respectively) and increased CHD risk (HR 1.31, 95%CI 1.20-1.42, P<0.001; and HR 1.27, 95%CI 1.12-1.45, P<0.001, respectively). Premature FHx was also independently associated with increased ASCVD and CHD risk (HR 1.25, 95%CI 1.11-1.41, P<0.001; and HR 1.43, 95CI 1.26-1.63, P<0.001, respectively).
  • Among DHS participants, FHx was independently associated with ASCVD events (HR 1.65, 95%CI 1.19-2.28, P=0.002). In constrast, elevated Lp(a) and premature FHx had a nominal association with ASCVD events (HR 1.64, 95%CI 0.96-2.80, P=0.069; and HR 1.49, 95%CI 0.97-2.29, P=0.069, respectively). FHx and elevated Lp(a) were independently associated with increased CHD risk (HR 2.18, 95%CI 1.35-3.53, P=0.001; and HR 3.37, 95%CI 1.41-8.06, P=0.006, respectively). Premature FHx was also independently associated with CHD events (HR 2.12, 95%CI 1.19-3.78, P=0.011).
  • To study joint associations of elevated Lp(a) and FHx, participants were stratified into groups based on elevated or nonelevated Lp(a) and presence or absence of FHx. ARIC participants with elevated Lp(a) and positive FHx had an increased risk for ASCVD and CHD events (HR 1.43, 95%CI 1.27-1.62; and HR 1.68, 95%CI 1.47-1.93, respectively), compared with participants with nonelevated Lp(a) and negative FHx . The association of elevated Lp(a) with ASCVD and CHD was not modified by FHx (P for interaction = 0.753 and 0.848, respectively).
  • ARIC participants with elevated Lp(a) and positive premature FHx also had an increased risk for ASCVD and CHD events (HR 1.74, 95%CI 1.41-2.16; and HR 2.14, 95%CI 1.71-2.67, respectively), compared with participants with nonelevated Lp(a) and negative premature FHx.
  • DHS participants with elevated Lp(a) and positive FHx had an increased risk for ASCVD and CHD events (HR 2.57, 95%CI 1.52-4.34; and HR 5.49, 95%CI 2.85-10.60, respectively), compared with participants with nonelevated Lp(a) and negative FHx. Furthermore, participants with elevated Lp(a) and positive premature FHx had an increased risk for ASCVD and CHD events (HR 3.35, 95%CI 1.66-6.74; and HR 7.96, 95%CI 3.60-17.59, respectively), compared with participants with nonelevated Lp(a) and negative premature FHx. Significant multiplicative interactions between elevated Lp(a) and FHx and between elevated Lp(a) and premature FHx were observed for ASCVD (P for interaction=0.043 and P=0.016, respectively) and CHD (P for interaction =0.006 and P=0.004, respectively).
  • Addition of elevated Lp(a) and FHx (or premature FHx) to a traditional risk factor model led to an increase in net reclassification improvement and integrated discrimination index for ASCVD and CHD events. Improvements in both metrics were greater when both elevated Lp(a) and FHx were included, compared with adding each marker alone.

Conclusion

Elevated Lp(a) and FHx of CHD have independent associations with long-term ASCVD and CHD risk among asymptomatic subjects. Moreover, subjects with elevated Lp(a) and positive FHx had an increased risk for ASCVD and CHD events, compared to those having neither risk factor. Addition of both elevated Lp(a) and FHx led to greater improvement in ASCVD and CHD risk classification and discrimination indexes than addition of either marker alone.

References

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5. Waldeyer C, Makarova N, Zeller T, et al. Lipoprotein(a) and the risk of cardiovascular disease in the European population: results from the BiomarCaRE consortium. Eur Heart J 2017;38: 2490–8.

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7. The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) study: design and objectives. Am J Epidemiol 1989;129:687–702.

8. Victor RG, Haley RW, Willett DL, et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am J Cardiol 2004;93:1473–80.

Find this article online at J Am Coll Cardiol.

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