Assessing Residual Risks for Coronary Artery Disease There are many biomarkers that have been shown as residual risks for coronary artery disease (CAD). Among them, serum lipids, including ...triglycerides (triglyceride-rich lipoproteins), lipoprotein (a) Lp(a), and small dense low-density lipoprotein (LDL) cholesterol (sd-LDL-C) can be considered as "established" residual risks, as not only observational studies but also post-hoc analysis of randomized controlled trial using statins, as well as Mendelian randomization studies suggested that these lipids appear to be associated with CAD, independent of LDL-C. We need to keep in mind the simple fact that cholesterol is one of the major causes of atherosclerosis. In this sense, it is not surprising that these lipids containing cholesterol that are not cleared sufficiently from blood using statins are one of the major residual risks.
See article vol.30 : 467-480 Mysteries of Antiatherosclerotic Properties among "Supernormal" Individuals Coronary artery disease is one of the most important causes of death across the world. Several ...researchers have tried to identify factors associated with this situation to combat this disease. Through this process, affected individuals who had suffered from coronary artery disease had been the target of interest, compared with the "controls" without coronary artery disease in almost all studies. Based on these studies investigating factors associated with coronary artery disease, researchers had identified that hypertension, diabetes, smoking, and low-density lipoprotein (LDL) cholesterol were significantly associated with this phenotype.
Background:A substantial proportion of patients clinically diagnosed as having familial hypercholesterolemia (FH) do not manifest causative mutation(s) in the FH genes such asLDLR,APOB, andPCSK9. We ...aimed to evaluate the effect of rare and deleterious mutation(s) inABCG5/ABCG8on hyper-low-density lipoprotein (LDL) cholesterolemia in individuals who meet the clinical criteria for FH.Methods and Results:We compared the LDL cholesterol (LDL-C) values among 487 subjects with FH; the subjects were grouped according to the presence of mutation(s) in FH andABCG5/ABCG8genes. We identified 276 individuals with a deleterious mutation in 1 FH gene (57%, monogenic FH), but found no causative mutations in 156 individuals (32%, mutation-negative). A total of 37 individuals had deleterious mutations inABCG5orABCG8, but not in FH genes (8%,ABCG5/ABCG8mutation carriers). Among these, 3 individuals had sitosterolemia (0.6%) with double mutations. We also identified 18 individuals with deleterious mutations in an FH gene andABCG5orABCG8(4%,ABCG5/ABCG8-oligogenic FH). Subjects without mutations had significantly higher polygenic scores than those in any other groups. LDL-C levels in oligogenic FH subjects were significantly higher than in the monogenic FH subjects. Moreover, sitosterol/lathosterol levels were significantly affected by those mutations.Conclusions:The results suggested that rare and deleterious mutations inABCG5/ABCG8contribute substantially to mimicking and exacerbation of the FH phenotype.
Homozygous Familial Hypercholesterolemia Nohara, Atsushi; Tada, Hayato; Ogura, Masatsune ...
Journal of Atherosclerosis and Thrombosis,
07/2021, Letnik:
28, Številka:
7
Journal Article
Odprti dostop
Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them ...exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis.Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases.This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.
Sitosterolemia is a rare inherited disease characterized by increased levels of plant sterols, such as sitosterol. The cause of this disease is ATP-binding cassette (ABC) subfamily G member 5 or ...member 8 (ABCG5 or ABCG8, respectively) gene mutations. Recent advances in genetics have revealed that the prevalence of subjects with deleterious mutations in ABCG5 and/or ABCG8 genes could be more than 1 in ~200,000 individuals among the general population. Furthermore, accumulated evidence, including infantile cases exhibiting progression/regression of systemic xanthomas associated with LDL cholesterol levels, have shown that the elevation of LDL cholesterol seems to be the major cause of development of atherosclerosis and not the elevation of sitosterol. Regarding therapies, LDL apheresis, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, could be useful for sitosterolemia, in addition to ezetimibe and/or colestimide. In this study, we provide the current understanding and future perspectives of sitosterolemia, which is currently considered an extremely rare disorder but is expected to be much more prevalent in clinical settings.
Lipoprotein(a) Lp(a), discovered in 1963, has been associated with atherosclerotic cardiovascular disease (ASCVD) independent of other traditional risk factors, including LDL cholesterol. Lp(a) is an ...apolipoprotein B (apoB)-containing lipoprotein, which contains an LDL-like particle. Unlike LDL, which is a primary therapeutic target to decrease ASCVD, current guidelines recommend measuring Lp(a) for risk assessments because there is no clear evidence demonstrating the clinical benefit of decreasing Lp(a) using classical drugs such as niacin. However, recent Mendelian randomization studies indicate that Lp(a) causally correlates with ASCVD. In addition, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for apo(a), have exhibited efficacy in decreasing Lp(a) substantially, invigorating a discussion whether Lp(a) could be a novel therapeutic target for further ASCVD risk reduction. This review aims to provide current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings.
Developing Risk Prediction Models for High Platelet Reactivity A recent randomized trial showed that a CYP2C19 genotype-guided strategy for oral P2Y12 inhibitor therapy was noninferior to standard ...treatment at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding among patients undergoing primary percutaneous coronary intervention (PCI). In addition, recent studies showed that integrating CYP2C19 loss-offunction genotypes with clinical factors that influence P2Y12 inhibitor response may enhance the ability to identify patients at risk of high platelet reactivity (HPR), and thus, appropriate selection of P2Y12 inhibitor therapy is necessary.
Cholesterol Homeostasis via its Absorption and Synthesis In our daily clinic, we measure serum cholesterol to assess the risk for atherosclerosis. However, we do not care much about the cholesterol ...homeostasis (its balance between absorption and synthesis) in humans. It has been shown that cholesterol homeostasis is strictly regulated by absorption from the intestine and its synthesis in the liver. Generally, approximately 70% of serum cholesterol is derived from synthesis in the liver, while the remaining 30% of serum cholesterol comes from absorption from the intestine.
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