Familial Hypercholesterolemia and Elevated Lipoprotein(a): Cascade Testing and Other Implications for Contextual Models of Care

Wann Jia Loh, Dick C Chan, Pedro Mata, Gerald F Watts, Wann Jia Loh, Dick C Chan, Pedro Mata, Gerald F Watts

Abstract

Elevated lipoprotein(a) [Lp(a)], a predominantly genetic disorder, is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valvular disease, particularly in patients with familial hypercholesterolemia (FH), a Tier I genomic condition. The combination from birth of the cumulative exposure to elevated plasma concentrations of both Lp(a) and low-density lipoprotein is particularly detrimental and explains the enhanced morbidity and mortality risk observed in patients with both conditions. An excellent opportunity to identify at-risk patients with hyper-Lp(a) at increased risk of ASCVD is to test for hyper-Lp(a) during cascade testing for FH. With probands having FH and hyper-Lp(a), the yield of detection of hyper-Lp(a) is 1 individual for every 2.1-2.4 relatives tested, whereas the yield of detection of both conditions is 1 individual for every 3-3.4 relatives tested. In this article, we discuss the incorporation of assessment of Lp(a) in the cascade testing in FH as a feasible and crucial part of models of care for FH. We also propose a simple management tool to help physicians identify and manage elevated Lp(a) in FH, with implications for the care of Lp(a) beyond FH, noting that the clinical use of RNA therapeutics for specifically targeting the overproduction of Lp(a) in at risk patients is still under investigation.

Keywords: FH model of care; Lp(a); cascade testing; familial hypercholesterolemia; hyper-Lp(a); inherited hypercholesterolemia; lipoprotein (a).

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor AJV declared a past co-authorship with the author GFW.

Copyright © 2022 Loh, Chan, Mata and Watts.

Figures

FIGURE 1
FIGURE 1
Kaplan-Meier survival analysis showing a significant association between the FH and Lp(a) diagnoses of relatives and ASCVD events. Cox proportional hazard ratio (HR) of patients with dual FH and Lp(a) diagnoses, elevated Lp(a) alone, FH alone compared with individuals with neither disorder are shown in the figure. Modified from Ellis KL et al. Value of Measuring Lipoprotein (a) During Cascade Testing for Familial Hypercholesterolemia. J Am Coll Cardiol. 2019; 73:1029–1039, with permission.
FIGURE 2
FIGURE 2
Graphical use of SAFEHEART-RE for predicting 5 and 10-year risks of developing incident atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH) in primary prevention or secondary prevention settings; an example shown refers to a 66-year-old man with FH and low-density lipoprotein-cholesterol (LDL-C) 50 mg/dl. From Perez de Isla L et al. Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation. 2017; 135:2133–2144, with permission.
FIGURE 3
FIGURE 3
Schematic diagram of the concept of compound LDL- and Lp(a)--cholesterol burden (y-axis) that increases with age, in patients with and without FH, with assumption that in untreated heterozygous FH patients (HeFH) and in non-FH individuals. From Vuorio A, Watts GF, Schneider WJ, Tsimikas S, Kovanen PT. Familial hypercholesterolemia and elevated lipoprotein (a): double heritable risk and new therapeutic opportunities. J. Intern. Med. 2020; 287:2–18, with permission.
FIGURE 4
FIGURE 4
Pedigrees of families (A–C) with familial hypercholesterolemia (FH) and elevated lipoprotein (a) [Lp(a)] ≥ 50 mg/dL, with their LDL cholesterol concentrations (mmol/L) and Lp(a) concentrations (mg/dl). In families (A,C), two new cases of FH and elevated Lp(a) were identified among five relatives tested. In family (B), all six relatives tested were found to have elevated Lp(a) (i.e., one new case of elevated Lp(a) for every relative tested) and three identified with FH. However, there were families where fewer, or no relatives were detected than those shown in these three families. Asterisk * indicates coronary artery disease. From Chakraborty A et al. Cascade testing for elevated lipoprotein (a) in relatives of probands with familial hypercholesterolemia and elevated lipoprotein(a). Atherosclerosis 2021, with permission.
FIGURE 5
FIGURE 5
Yield of detection of diagnoses of elevated lipoprotein (a) [Lp(a)] and familial hypercholesterolemia (FH) during cascade screening of relatives from HeFH probands with or without hyper-Lp(a). One individual of hyper-Lp(a) without FH was detected for every 2.1–2.4 relatives screened if the proband had HeFH and hyper-Lp(a), whereas the yield of detection was one individual for every 5.8 relatives screened if the proband had HeFH but not hyper-Lp(a). HyperLp(a) refers to Lp(a)≥ 50 mg/dL. The SAFEHEART Study by Ellis et al., (2019); The FHWA Program by Chakraborty et al., (2021).
FIGURE 6
FIGURE 6
Proposed mnemonic (LILAC) for the management of elevated lipoprotein (a) in familial hypercholesterolemia.
FIGURE 7
FIGURE 7
Proposed algorithm for the management of relatives after cascade testing for hyper-lipoprotein (a) from probands with familial hypercholesterolemia.

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