Detection of subclinical atherosclerosis in familial hypercholesterolemia using non-invasive imaging modalities
Highlights
► Despite treatment FH patients have higher atherosclerotic burden than controls. ► Aortic MRI allows to characterize atherosclerotic plaques in FH patients. ► In FH patients there is a correlation between aortic wall volume and cIMT. ► Lipid plaques in FH were associated with coronary artery disease in relatives.
Introduction
Familial hypercholesterolemia (FH) is the most common genetic disease associated with premature coronary artery disease (CAD). The molecular disorder is caused by mutations in the low-density lipoprotein receptor (LDL-r) gene resulting in high LDL-cholesterol (LDL-c) levels since birth [1]. As consequence, life expectancy is shortened with sudden death and myocardial infarction as the principal causes of mortality [2]. Although, coronary and total mortality in FH patients have markedly decreased since 1990s, in part due to the use of statins [3], [4], most of these patients still have a high risk for premature CAD. Therefore, FH patients require an intense L-LT in order to reduce LDL-cholesterol levels at least 50%, a goal that in most cases is not appropriately achieved [2], [5].
Detection of subclinical atherosclerosis using non-invasive images techniques could improve risk stratification and clinical management in FH patients [6]. Carotid intima media thickness (cIMT) is increasingly used as a surrogate marker for atherosclerosis and future vascular events [7]. Also, aortic MRI has been used in the last decade to evaluate atherosclerosis burden in high risk patients including FH patients [8], [9], [10]; however, there are no consistent MRI studies for the characterization of atherosclerotic plaques in this population.
The main objectives of this study were to evaluate atherosclerosis burden and plaque composition using quantitative aortic MRI and the presence of plaques and cIMT by B-mode carotid ultrasound in asymptomatic FH patients who had been receiving long-term stable lipid-lowering treatment (L-LT) compared to controls.
Section snippets
Patients and methods
In this observational study, 38 patients with FH (19 men, 19 women; age range, 25–65 years) were randomly selected from the SAFEHEART database [5]. All FH subjects had DNA-based diagnosis, and were receiving stable L-LT at least one year before the inclusion. Cases with diabetes mellitus or clinical cardiovascular disease were excluded. Two patients (1 man and 1 woman) were excluded because of claustrophobia and therefore, the total study population included 36 cases.
Patients were classified
Results
Baseline characteristics of FH cases and controls are shown in Table 1. There were no differences in mean age, gender, tobacco status, prevalence of hypertension and BMI between FH patients and control group. Almost half of FH cases (47.2%) were receiving maximum tolerated combined L-LT and the rest were receiving maximum tolerated statin dose. The mean duration of L-LT was 10 years (SD: 6.6, range 1–20 years). Cases with FH had higher LDL-c levels, TC/HDL-cholesterol ratio, and lower HDL-c
Discussion
This study shows that middle-aged asymptomatic FH patients despite long-term L-LT have higher aortic and carotid atherosclerotic burden measured by MRI and B-mode ultrasound respectively, when compared with controls. Although a good correlation between aortic wall volume and cIMT has been observed, MRI detected more atherosclerotic plaques in aorta than ultrasound in carotid arteries. In our study, MRI has shown that lipidic plaques were observed only in FH patients whereas fibrotic plaques
Conclusion
Middle-aged asymptomatic FH patients have an increased aortic and carotid atherosclerotic burden, despite long-term L-LT, when compared with a non-FH control group. cIMT has shown to have a significant correlation with aortic wall volume and aortic MRI allowed the detection and characterization of atherosclerotic plaques in FH subjects. Lipid-rich plaques in aorta were only observed in FH subjects and were associated with family history of premature coronary artery disease.
Funding
This study has been supported by Fundación Hipercolesterolemia Familiar and grant 08-2008 from Centro Nacional de Investigaciones Cardiovasculares (to PM and LB), Spain.
Disclosure
No conflict of interest.
Contributors
RA, NM, LB, JJB, PM provided support in the study design. PC, PR, LFF have performed the imaging techniques and interpreted the images in a blinded way. RA, PM, PC, JJB coordinated the execution of the project. NM and RA analysed the data and performed the statistical analysis. PC, RA and PM wrote the manuscript. All authors's revised critically the manuscript and participated in the final version.
Acknowledgements
We thank the Spanish Familial Hypercholesterolemia Foundation for assistance in the recruitment of participants and controls, and to the FH patients for their valuable contribution and willingness to participate.
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Intima-media thickness in treated and untreated patients with and without familial hypercholesterolemia: A systematic review and meta-analysis
2022, Journal of Clinical LipidologyCitation Excerpt :Analysis of the pooled data showed a significant difference in mean carotid IMT between FH patients and controls of 0.16 mm (95% CI 0.03 to 0.30; P=0.02). Six studies also assessed carotid plaques, and 5 of these showed a significantly more often occurrence of plaques in patients with FH as compared to unaffected controls.34,40,43,44,53 One study showed more often plaques in FH patient, but this was not significant.49
Why patients with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels
2021, Trends in Cardiovascular MedicineAtherosclerosis in cholesterol-fed rabbits and in homozygous and heterozygous LDL receptor-deficient humans
2018, AtherosclerosisCitation Excerpt :It is tempting to link the two and speculate that the increased risk of CHD reflects not just the severity and location of atheromatous lesions in FH subjects but also that they may be lipid-rich and unstable. Evidence showing the occurrence of lipid-rich plaques in the aortas of FH subjects has come from magnetic resonance imaging [37] and therapeutic reduction of the amount of lipid in such plaques would be anticipated to increase their stability and reduce the risk of acute ischaemic events [38]. Although data on plaque stabilisation in FH patients are lacking Watanabe Heritable Hyperlipidaemic (WHHL) rabbits, an animal model of FH, have lipid-rich plaques and it has been shown that administration of statins reduces their lipid content and increases their collagen content, rendering them less liable to rupture [39].
Lipoprotein-associated phospholipase A₂ activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia
2018, Nutrition, Metabolism and Cardiovascular DiseasesCarotid artery plaques – Are risk factors the same in men and women with familial hypercholesterolemia?
2017, International Journal of CardiologyCitation Excerpt :One can hypothesize that some specific risk factors of cardiovascular outcomes are different for men and women with FH and that they may depend on ethnic origin. Carotid plaques are associated with atherosclerosis of coronary arteries and, as an increasing number of data indicates, they might be a useful prognostic tool of coronary events [9,10]. We previously reported risk factors associated with the presence of early atherosclerosis in a cohort of FH patients [11].
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These authors contributed equally to this work.