Hereditary hypercholesterolemia and cardiovascular disease : functional and epidemiological aspects
Background. Individuals with familial hypercholesterolemia (FH) and/or high levels of lipoprotein(a) [Lp(a)] are genetically predisposed to develop early cardiovascular disease (CVD). We aimed to study the subclinical and early vascular effects of FH and high Lp(a) through clinical and mechanistic studies as well as CVD complications of Lp(a) through epidemiological aspects.
Methods and Results. Study I: Transthoracic doppler echocardiography was used to determine coronary flow reserve (CFR) and arterial tonometry for peripheral endothelial function. Asymptomatic individuals aged 30-59 years, without manifest CVD were recruited to four groups (n=30 per group): controls with Lp(a)<30 nmol/L, mutation confirmed FH with Lp(a)<30 nmol/L or >125 nmol/L, isolated Lp(a)>125 nmol/L. Each of the three groups with lipoprotein disorder had a higher proportion (30%) of individuals with impaired CFR, compared to controls (7%; p=0.014). Longer lipid lowering time was associated with normal CFR in the group with FH and high Lp(a) levels. However, no significant differences were found between groups in median CFR or peripheral endothelial function.
Study II: To study if red blood cells (RBCs) from FH patients induce endothelial dysfunction, two groups of FH patients without previous CVD or other comorbidities were recruited. One group with low-density lipoprotein cholesterol (LDL-c) >5.0 mM and the other with <2.5 mM were compared to healthy subjects with LDL-c <2.5. RBCs were isolated from venous blood samples and were co-incubated with aortic rings from rats in the presence and absence of inhibitors of arginase and reactive oxygen species (ROS) for 18 hours. Endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired in vessels incubated with RBCs from FH individuals with LDL-c >5.0 mM compared to those incubated with RBCs from the FH with low LDL-c and healthy. This endothelial dysfunction was attenuated following inhibition of arginase or scavenging ROS in the vessel.
Study III: A registry based observational study on a cohort of 23,298 individuals who had Lp(a) measured in the routine clinical care 2003–2017 in Stockholm County. The aim was to study association of Lp(a) to incident calcified aortic valve stenosis (CAVS). Other data were obtained from national patient registries. During the study period 489 were diagnosed with CAVS. Individuals diagnosed with CAVS had significantly greater comorbidity and higher levels of Lp(a) at the 90th percentile (117 mg/dL or 249 nmol/L) compared to those without CAVS (89 mg/dL or 179 nmol/L).
Study IV: Observational cross-sectional study, where 1,860 individuals with type 1 diabetes who were receiving routine medical care were enrolled. The aim was to study CVD in relation to Lp(a) levels. Median Lp(a) level was 19 nmol/L, interquartile range 10-71 nmol/L. Patients with type-1 diabetes and concomitant high level of Lp(a) >120 nmol/L (~50 mg/dL) were associated with two-fold and one and half-fold increased relative risk ratio of CAVS and CVD respectively where the major driver of CVD is coronary events.
Conclusion. Subclinical coronary microvascular dysfunction is more prevalent in individuals with FH and/or high Lp(a) levels without evident CVD, compared to healthy controls. RBCs from FH patients with high LDL-c levels induce endothelial dysfunction through increased arginase 1 and ROS. Individuals with plasma Lp(a) levels above 117 mg/dL or 249 nmol/L, as measured in routine clinical care, are at 1.5 times higher risk of developing CAVS. Type 1 diabetes patients with Lp(a) levels >120 nmol/L have a higher prevalence of macrovascular complications and CAVS when compared to those with lower Lp(a) levels <10nmol/L.
List of scientific papers
I. Wodaje T, Mahdi A, Venkateshvaran A, Häbel H, Zenlander R, Gaylard B, Angelin B, Pernow J and Brinck J. Higher prevalence of coronary microvascular dysfunction in asymptomatic individuals with high levels of lipoprotein(a) with and without heterozygous familial hypercholesterolaemia. [Manuscript]
II. Mahdi A, Wodaje T, Kövamees O, Tengbom T, Zhao A, Jiao T, Henricsson M, Yang J, Zhou Z, Nieminen A I, Levin M, Collado A, Brinck J and Pernow J. The red blood cell as a mediator of endothelial dysfunction in patients with familial hypercholesterolemia and dyslipidemia. J Intern Med. 2023 Feb;293(2):228-245.
https://doi.org/10.1111/joim.13580
III. Wodaje T, Littmann K, Häbel H, Bottai M, Bäck M, Parini P and Brinck J. Plasma Lipoprotein(a) measured in routine clinical care and the association with incident calcified aortic valve stenosis during a 14-year observational period. Atherosclerosis. 2022 May: 349:175-182.
https://doi.org/10.1016/j.atherosclerosis.2022.02.016
IV. Littmann K, Wodaje T, Alvarsson M, Bottai M, Eriksson M, Parini P and Brinck J. The association of lipoprotein(a) plasma levels with prevalence of cardiovascular disease and metabolic control status in patients with type 1 diabetes. Diabetes Care. 2020 Aug;43(8):1851-1858.
https://doi.org/10.2337/dc19-1398
History
Defence date
2023-12-14Department
- Department of Medicine, Huddinge
Publisher/Institution
Karolinska InstitutetMain supervisor
Brinck, JonasCo-supervisors
Pernow, John; Angelin, BoPublication year
2023Thesis type
- Doctoral thesis
ISBN
978-91-8017-186-1Number of supporting papers
4Language
- eng