A review of gene- and cell-based therapies for familial hypercholesterolemia

Hajighasemi, Saeideh; Gorabi, Armita Mahdavi; Bianconi, Vanessa; Pirro, Matteo; Banach, Maciej; Tafti, Hossein Ahmadi; Reiner, Željko; Sahebkar, Amirhossein

doi:10.1016/j.phrs.2019.03.016

Cited by 27 publications

(20 citation statements)

References 94 publications

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“…It gives approximately 4.5 million individuals in Europe, of whom 20–25% are children and adolescents [ 15 ]. Despite analyses proofing cost effectiveness of FH screening [ 16 ] and treatment standards, which are developed (diet, controlling risk factors, statins [ 5 ]) or developing (gene- and cell-based therapies [ 17 ]), under-diagnosing of the disease is a major problem [ 18 ]. This work provides another argument for introducing screening programs because, even in children with no significant morphological changes, arterial wall function can be already impaired.…”

Section: Discussionmentioning

confidence: 99%

“Apple does not fall far from the tree” – subclinical atherosclerosis in children with familial hypercholesterolemia

et al. 2020

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Background Familial hypercholesterolemia (FH) increases the risk of atherosclerosis in children and adults. Atherosclerotic cardiovascular disease in young patients FH is usually subclinical but recognition of children with more pronounced changes is crucial for adjusting effective management. Aim of this research was to use ultrasonography with two-dimensional speckle tracking (2DST) and tonometry to evaluate atherosclerotic changes in patients with FH (parents and their offspring). Methods Applanation tonometry and carotid arteries sonography with evaluation of the intima-media complex thickness (IMCT) and application of the 2DST were performed in 20 families with FH (20 parents and 29 children). The same size control group (age and sex matched) was included. Results were compared between peers and between generations together with the correlation analysis. Results Adults with FH, in comparison with healthy peers, presented significantly more atherosclerotic plaques (9 vs. 2, p = 0.0230), had significantly thicker IMC (0.84 ± 0.19 vs. 0.56 ± 0.06 mm, p < 0.0001) and had stiffer arterial wall (for stain: 6.25 ± 2.3 vs. 8.15 ± 2.46, p = 0.0103). In children from both groups there were no atherosclerotic plaques and IMCT did not differ significantly (0.42 ± 0.07 vs. 0.39 ± 0.04, p = 0.1722). However, children with FH had significantly stiffer arterial wall according to 2DST (for strain: 9.22 ± 3.4 vs. 11.93 ± 3.11, p = 0.0057) and tonometry (for the pulse wave velocity: 4.5 ± 0.64 vs.3.96 ± 0.62, p = 0.0047). These parameters correlated with atherosclerosis surrogates in their parents ( p < 0.001) but were not significantly affected by presence of presumed pathogenic gene variant. Conclusions Children with FH presented subclinical atherosclerosis manifested as decreased arterial wall elasticity. Degree of stiffening was associated with advancement of atherosclerosis in their parents but did not present significant association with gene variants. Sonography with application of 2DST seems to be a good candidate for comprehensive evaluation of atherosclerosis in families with FH.

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Section: Discussionmentioning

confidence: 99%

“Apple does not fall far from the tree” – subclinical atherosclerosis in children with familial hypercholesterolemia

et al. 2020

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“…It gives approximately 4.5 million individuals in Europe, of whom 20-25% are children and adolescents [15]. Despite analyses proo ng cost effectiveness of FH screening [16] and treatment standards, which are developed (diet, controlling risk factors, statins [5]) or developing (gene-and cell-based therapies [17]), under-diagnosing of the disease is a major problem [18]. This work provides another argument for introducing screening programs because, even in children with no signi cant morphological changes, arterial wall function can be already impaired.…”

Section: Discussionmentioning

confidence: 99%

“Apple does not fall far from the tree” – subclinical atherosclerosis in children with familial hypercholesterolemia.

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et al. 2020

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Background: Familial hypercholesterolemia (FH) increases the risk of atherosclerosis in children and adults. Atherosclerotic cardiovascular disease in young patients FH is usually subclinical but recognition of children with more pronounced changes is crucial for adjusting effective management. Aim of this research was to use ultrasonography with two-dimensional speckle tracking (2DST) and tonometry to evaluate atherosclerotic changes in patients with FH (parents and their offspring).Methods: Applanation tonometry and carotid arteries sonography with evaluation of the intima-media complex thickness (IMCT) and application of the 2DST were performed in 20 families with FH (20 parents and 29 children). The same size control group (age and sex matched) was included. Results were compared between peers and between generations together with the correlation analysis.Results: Adults with FH, in comparison with healthy peers, presented significantly more atherosclerotic plaques (9 vs. 2, p=0.0230), had significantly thicker IMC (0.84±0.19 vs. 0.56±0.06 mm, p<0.0001) and had stiffer arterial wall (for stain: 6.25±2.3 vs. 8.15±2.46, p=0.0103). In children from both groups there were no atherosclerotic plaques and IMCT did not differ significantly (0.42±0.07 vs. 0.39±0.04, p=0.1722). However, children with FH had significantly stiffer arterial wall according to 2DST (for strain: 9.22±3.4 vs. 11.93±3.11, p=0.0057) and tonometry (for the pulse wave velocity: 4.5±0.64 vs.3.96±0.62, p=0.0047). These parameters correlated with atherosclerosis surrogates in their parents (p<0.001) but were not significantly affected by presence of presumed pathogenic gene variant.Conclusions: Children with FH presented subclinical atherosclerosis manifested as decreased arterial wall elasticity. Degree of stiffening was associated with advancement of atherosclerosis in their parents but did not present significant association with gene variants. Sonography with application of 2DST seems to be a good candidate for comprehensive evaluation of atherosclerosis in families with FH.

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“…2 Despite less frequently, the Apolipoprotein B100 (APOB)-encoding gene, the proprotein convertase subtilisin/kexin type9 ([PCSK9], which is a protein that binds to LDLR and promotes its degradation) gene, and rare mutations in the LDLRAP1 gene, APOE p.Leu167del or lysosomal acid lipase (LIPA) genes, 3 SREBP2, 4 STAP1 5 or ATP-binding cassette sub-family G member 5 (ABCG5), and ATP-binding cassette sub-family G member 8 (ABCG8) genes can be also involved in FH. 6,7 Since untreated FH significantly accelerates cardiovascular diseases (CVD), such as myocardial infarction, carotid atherosclerosis and coronary artery disease (CAD), it is considered as a major public health burden. [8][9][10] Homozygous and heterozygous FH patients are characterized by extremely high, declining to moderate cholesterol levels.…”

Section: Introductionmentioning

confidence: 99%

“…FH occurs mainly due to more than 1,600 loss‐of‐function mutations identified in the genes of low‐density lipoprotein receptor (LDLR), which can lead to defective clearance of LDL‐C from the blood and sequentially can elevate the plasma LDL‐C level . Despite less frequently, the Apolipoprotein B100 (APOB)‐encoding gene, the proprotein convertase subtilisin/kexin type9 ([PCSK9], which is a protein that binds to LDLR and promotes its degradation) gene, and rare mutations in the LDLRAP1 gene, APOE p.Leu167del or lysosomal acid lipase ( LIPA ) genes, SREBP2, STAP1 or ATP‐binding cassette sub‐family G member 5 ( ABCG5 ), and ATP‐binding cassette sub‐family G member 8 ( ABCG8 ) genes can be also involved in FH . Since untreated FH significantly accelerates cardiovascular diseases (CVD), such as myocardial infarction, carotid atherosclerosis and coronary artery disease (CAD), it is considered as a major public health burden .…”

Section: Introductionmentioning

confidence: 99%

The atherogenic role of immune cells in familial hypercholesterolemia

et al. 2019

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Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism that mainly occurs due to mutations in the low‐density lipoprotein receptor gene and is characterized by increased levels of low‐density lipoprotein cholesterol, leading to accelerated atherogenesis and premature coronary heart disease. Both innate and adaptive immune responses, which mainly include monocytes, macrophages, neutrophils, T lymphocytes, and B lymphocytes, have been shown to play a key role for the initiation and progression of atherogenesis in the general population. In FH patients, these immune cells have been suggested to play specific pro‐atherosclerotic activities, from the initial leukocyte recruitment to plaque rupture. In fact, the accumulation of cholesterol crystals and oxLDL in the vessels in FH patients is particularly high, with consequent abnormal mobilization of immune cells and secretion of various pro‐inflammatory and chemokines. In addition, cholesterol accumulation in immune cells is exaggerated with chronic exposure to relevant pro‐atherosclerotic triggers. The topics considered in this review may provide a more specific focus on the immune system alterations in FH and open new insights toward immune cells as potential therapeutic targets in FH.

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A review of gene- and cell-based therapies for familial hypercholesterolemia

Cited by 27 publications

References 94 publications

“Apple does not fall far from the tree” – subclinical atherosclerosis in children with familial hypercholesterolemia

“Apple does not fall far from the tree” – subclinical atherosclerosis in children with familial hypercholesterolemia

“Apple does not fall far from the tree” – subclinical atherosclerosis in children with familial hypercholesterolemia.

The atherogenic role of immune cells in familial hypercholesterolemia

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