Peripheral artery disease(PAD)is a common condition characterized by atherosclerosis in the peripheral arteries,associated with concomitant coronary and cerebrovascular diseases.Proprotein convertase subtilisin/kexin ...Peripheral artery disease(PAD)is a common condition characterized by atherosclerosis in the peripheral arteries,associated with concomitant coronary and cerebrovascular diseases.Proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients.This review focuses on the efficacy,safety,and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed.Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events,offering a potential treatment option for PAD patients.Safety evaluations from trials show few adverse events,most of which are injection-site reactions,indicating the overall safety profile of PCSK9 inhibitors.Clinical outcomes show a reduction in cardiovascular events,ischemic strokes,and major adverse limb events.However,despite these positive findings,PCSK9 inhibitors are still underutilized in clinical practice,possibly due to a lack of awareness among care providers and cost concerns.Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.展开更多
Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atheroscleros...Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor （LDLR） pathway. Mutations in the LDLR cause familiar hyperch- olesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 （SREBP-2） and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 （PCSK9） and inducible degrader of the LDLR （IDOL）. In this review, we summarize the latest advances in the studies of PCSK9.展开更多
BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease(NAFLD)and its predisposing risk factors,but the conclusions from these studies have been conflicting.More challenging is th...BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease(NAFLD)and its predisposing risk factors,but the conclusions from these studies have been conflicting.More challenging is the fact that no effective treatment is currently available for NAFLD.AIM To determine the effects of proprotein convertase subtilisin/kexin type-9(PCSK9)inhibitors on fatty infiltration of the liver.METHODS This retrospective,chart review-based study was conducted on patients,18-yearold and above,who were currently on PCSK9 inhibitor drug therapy.Patients were excluded from the study according to missing pre-or post-treatment imaging or laboratory values,presence of cirrhosis or rhabdomyolysis,or development of acute liver injury during the PCSK9 inhibitor treatment period;the latter being due to false elevation of liver function markers,alanine aminotransferase(ALT)and aspartate aminotransferase(AST).Radiographic improvement was assessed by a single radiologist,who read both the pre-and post-treatment images to minimize reading bias.Fatty infiltration of the liver was also assessed by changes in ALT and AST,with pre-and post-treatment levels compared by paired t-test(alpha criterion:0.05).RESULTS Of the 29 patients included in the study,8 were male(27.6%)and 21 were female(72.4%).Essential hypertension was present in 25(86.2%)of the patients,diabetes mellitus in 18(62.1%)and obesity in 15(51.7%).In all,patients were on PCSK9 inhibitors for a mean duration of 23.69±11.18 mo until the most recent ALT and AST measures were obtained.Of the 11 patients who received the radiologic diagnosis of hepatic steatosis,8(72.73%)achieved complete radiologic resolution upon use of PCSK9 inhibitors(mean duration of 17.6 mo).On average,the ALT level(IU/L)decreased from 21.83±11.89 at pretreatment to 17.69±8.00 at posttreatment(2-tailed P=0.042)and AST level(IU/L)decreased from 22.48±9.00 pretreatment to 20.59±5.47 post-treatment(2-tailed P=0.201).CONCLUSION PCSK9 inhibitors can slow down or even completely resolve NAFLD.展开更多
Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup...Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P【0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P【0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P【0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P【0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P【0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P【0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population,both gender show different relations to different serum lipid parameters.The G allele carriers might have higher serum lipid profiles than the G allele noncarriers. ormal LDL-C(≤3.20 mmol/L) and high LDL-C subgroups (】 3.20 mmol/L,P【0.01;respectively) in Bai Ku Yao, and between normal ApoB(≤1.14 g/L) and high ApoB subgroups(】 1.14 g/L,P 【 0.01;respectively) in Han.展开更多
BACKGROUND Familial hypercholesterolemia(FH)is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein(LDL)cholesterol levels.At the same time,elevated LDL levels accelerated...BACKGROUND Familial hypercholesterolemia(FH)is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein(LDL)cholesterol levels.At the same time,elevated LDL levels accelerated the development of coronary heart disease.Several classes of drugs are currently in use to treat FH.Proprotein convertase subtilisin/kexin type 9 inhibitor(PCSK9i)is novel one of these.CASE SUMMARY This manuscript reports a case of FH that responded modestly after treatment with PCSK9i and statin drugs.Of even more concern is that the patient frequently admitted to the hospital during a 12-year follow-up period.Subsequently,we identified a heterozygous mutation,1448G>A(W483X)of the LDL receptor(LDLR)in this patient.The serum levels of PCSK9(proprotein convertase subtilisin/kexin type 9)in the patient was 71.30±26.66 ng/mL,which is close the average level reported in the literature.This LDLR mutation affects LDLR metabolism or structure,which may make it unsuitable for use of PCSK9i.CONCLUSION Our outcome demonstrates that LDLR-W483X represents a partial loss-of-function LDLR and may contribute to PCSK9i ineffective. In the meanwhile, additional measures aretherefore required (particularly with gene sequencing or change the treatment plan) must beinitiated as early as possible. Genetic testing for clinically challenging cases who do not respond toPCSK9i therapy is very helpful.展开更多
Oxidized low density lipoprotein is a risk factor for cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 （PCSK9） can increase the level of low density lipoprotein. Therefore, this study assumed t...Oxidized low density lipoprotein is a risk factor for cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 （PCSK9） can increase the level of low density lipoprotein. Therefore, this study assumed that PCSK9 plays important roles in ischemic cerebrovascular disease. The present study established transient focal cerebral ischemia models after 100 minutes of middle cerebral artery occlusion. In situ hybridization demonstrated that PCSK9 mRNA expression increased gradually with prolonged reperfusion time in ischemic cortices. This indicated that transient focal cerebral ischemia upregulated PCSK9 mRNA expression in ischemic cortices.展开更多
Objective::The purpose of this study was to determine the relationship between remnant-like particle cholesterol(RLP-C)and major adverse cardiovascular events(MACEs)in patients with different levels of proprotein conv...Objective::The purpose of this study was to determine the relationship between remnant-like particle cholesterol(RLP-C)and major adverse cardiovascular events(MACEs)in patients with different levels of proprotein convertase subtilisin/kexin 9(PCSK9).Methods::From September 2007 to January 2009,1,859 subjects in Pingguoyuan communities in Beijing were initially screened.After excluding those with bedridden status,mental illness,severe systemic diseases,and missing data,1,680 subjects were recruited for follow up.All recruited subjects were followed up from February 2013 to September 2013(181 subjects were lost to follow-up)and from June 2017 to September 2018(174 subjects were lost to follow up).Finally,1,325 subjects were included in the study.General demographic characteristics,lifestyle and behaviors,disease history and use of medication was collected.Levels of total cholesterol,triglycerides,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,fast blood glucose,RLP-C,low-density lipoprotein triglycerides and PCSK9 were measured.The levels of RLP-C(low:RLP-C≤157 mg/L;high:RLP-C>157 mg/L)and PCSK9(low:PCSK9≤135.87μg/L;high:PCSK9>135.87μg/L)were represented using quartiles.Subjects were categorized into 4 groups according to their RLP-C and PCSK9 levels:Q4,high levels of RLP-C with high levels of PCSK9;Q3,high levels of RLP-C with low levels of PCSK9;Q2,low levels of RLP-C with high levels of PCSK9;and Q1,low levels of RLP-C with low levels of PCSK9.The association of RLP-C with MACEs in subjects with different PCSK9 levels was evaluated.Results::After a median follow-up of 9.5 years,1,325 subjects were included in the study and a total of 191 MACEs had occurred.The incidence of MACEs was higher in the RLP-C>157 mg/L group than the RLP-C≤157 mg/L group(18.40%vs.10.42%).Cox proportional hazards regression model analysis showed that increased RLP-C levels were associated with an increased risk of MACEs(hazard ratio:1.405;95%confidence interval:1.005-1.964;P<0.005).The incidence of MACEs was higher in the high RLP-C/PCSK9 group vs.the low RLP-C/PCSK9 group(20.68%vs.8.76%).Cox proportional hazards regression model analysis showed that RLP-C was associated with an increased risk of MACEs in subjects with high PCSK9 levels independent of traditional risk factors(hazard ratio:1.791;95%confidence interval:1.168-2.825;P=0.001),but not in those with low PCSK9 levels.Conclusions::RLP-C was identified as a risk factor for MACEs,particularly in subjects with high PCSK9 levels.Lowering PCSK9 levels may reduce residual risk in subjects with elevated plasma RLP-C levels.展开更多
文摘Peripheral artery disease(PAD)is a common condition characterized by atherosclerosis in the peripheral arteries,associated with concomitant coronary and cerebrovascular diseases.Proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients.This review focuses on the efficacy,safety,and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed.Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events,offering a potential treatment option for PAD patients.Safety evaluations from trials show few adverse events,most of which are injection-site reactions,indicating the overall safety profile of PCSK9 inhibitors.Clinical outcomes show a reduction in cardiovascular events,ischemic strokes,and major adverse limb events.However,despite these positive findings,PCSK9 inhibitors are still underutilized in clinical practice,possibly due to a lack of awareness among care providers and cost concerns.Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.
基金D.W.Z.is a Scholar of the Alberta Heritage Foundation for Medical Research and is supported in part by a Canadian Institutes of Health Research New Investigator AwardZhang laboratory is supported by Canadian Foundation for Innovation,grants from a Grant-in-Aidfor Heart and Stroke Foundation of CanadaPfizer Canada, the Canadian Institutes of Health Research(MOP 93794), and Mazankowski Alberta Heart Institute
文摘Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor （LDLR） pathway. Mutations in the LDLR cause familiar hyperch- olesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 （SREBP-2） and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 （PCSK9） and inducible degrader of the LDLR （IDOL）. In this review, we summarize the latest advances in the studies of PCSK9.
基金Data for this research project was obtained from Health System of the University of Kansas Medical Center,Kansas City,KS 66160,United States.The authors are grateful to the Department of Clinical Informatics at the University of Kansas Medical Center for their help in accessing the patient medical record database.Data extraction was conducted by the HERON automated data extraction tool.
文摘BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease(NAFLD)and its predisposing risk factors,but the conclusions from these studies have been conflicting.More challenging is the fact that no effective treatment is currently available for NAFLD.AIM To determine the effects of proprotein convertase subtilisin/kexin type-9(PCSK9)inhibitors on fatty infiltration of the liver.METHODS This retrospective,chart review-based study was conducted on patients,18-yearold and above,who were currently on PCSK9 inhibitor drug therapy.Patients were excluded from the study according to missing pre-or post-treatment imaging or laboratory values,presence of cirrhosis or rhabdomyolysis,or development of acute liver injury during the PCSK9 inhibitor treatment period;the latter being due to false elevation of liver function markers,alanine aminotransferase(ALT)and aspartate aminotransferase(AST).Radiographic improvement was assessed by a single radiologist,who read both the pre-and post-treatment images to minimize reading bias.Fatty infiltration of the liver was also assessed by changes in ALT and AST,with pre-and post-treatment levels compared by paired t-test(alpha criterion:0.05).RESULTS Of the 29 patients included in the study,8 were male(27.6%)and 21 were female(72.4%).Essential hypertension was present in 25(86.2%)of the patients,diabetes mellitus in 18(62.1%)and obesity in 15(51.7%).In all,patients were on PCSK9 inhibitors for a mean duration of 23.69±11.18 mo until the most recent ALT and AST measures were obtained.Of the 11 patients who received the radiologic diagnosis of hepatic steatosis,8(72.73%)achieved complete radiologic resolution upon use of PCSK9 inhibitors(mean duration of 17.6 mo).On average,the ALT level(IU/L)decreased from 21.83±11.89 at pretreatment to 17.69±8.00 at posttreatment(2-tailed P=0.042)and AST level(IU/L)decreased from 22.48±9.00 pretreatment to 20.59±5.47 post-treatment(2-tailed P=0.201).CONCLUSION PCSK9 inhibitors can slow down or even completely resolve NAFLD.
文摘Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P【0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P【0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P【0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P【0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P【0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P【0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population,both gender show different relations to different serum lipid parameters.The G allele carriers might have higher serum lipid profiles than the G allele noncarriers. ormal LDL-C(≤3.20 mmol/L) and high LDL-C subgroups (】 3.20 mmol/L,P【0.01;respectively) in Bai Ku Yao, and between normal ApoB(≤1.14 g/L) and high ApoB subgroups(】 1.14 g/L,P 【 0.01;respectively) in Han.
基金the Doctor Start-up fund of Jiangxi provincial People's Hospital,The First Affiliated Hospital of Nanchang Medical College,No.19-236.
文摘BACKGROUND Familial hypercholesterolemia(FH)is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein(LDL)cholesterol levels.At the same time,elevated LDL levels accelerated the development of coronary heart disease.Several classes of drugs are currently in use to treat FH.Proprotein convertase subtilisin/kexin type 9 inhibitor(PCSK9i)is novel one of these.CASE SUMMARY This manuscript reports a case of FH that responded modestly after treatment with PCSK9i and statin drugs.Of even more concern is that the patient frequently admitted to the hospital during a 12-year follow-up period.Subsequently,we identified a heterozygous mutation,1448G>A(W483X)of the LDL receptor(LDLR)in this patient.The serum levels of PCSK9(proprotein convertase subtilisin/kexin type 9)in the patient was 71.30±26.66 ng/mL,which is close the average level reported in the literature.This LDLR mutation affects LDLR metabolism or structure,which may make it unsuitable for use of PCSK9i.CONCLUSION Our outcome demonstrates that LDLR-W483X represents a partial loss-of-function LDLR and may contribute to PCSK9i ineffective. In the meanwhile, additional measures aretherefore required (particularly with gene sequencing or change the treatment plan) must beinitiated as early as possible. Genetic testing for clinically challenging cases who do not respond toPCSK9i therapy is very helpful.
基金the National Natural Science Foundation of China,No.81070999the National Institutes of Health (America),No.NS046560the American Heart Association,No.0450142Z
文摘Oxidized low density lipoprotein is a risk factor for cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 （PCSK9） can increase the level of low density lipoprotein. Therefore, this study assumed that PCSK9 plays important roles in ischemic cerebrovascular disease. The present study established transient focal cerebral ischemia models after 100 minutes of middle cerebral artery occlusion. In situ hybridization demonstrated that PCSK9 mRNA expression increased gradually with prolonged reperfusion time in ischemic cortices. This indicated that transient focal cerebral ischemia upregulated PCSK9 mRNA expression in ischemic cortices.
基金supported by the National Key Research and Development Program of China (2021YFC2500604)to Li Sheng.
文摘Objective::The purpose of this study was to determine the relationship between remnant-like particle cholesterol(RLP-C)and major adverse cardiovascular events(MACEs)in patients with different levels of proprotein convertase subtilisin/kexin 9(PCSK9).Methods::From September 2007 to January 2009,1,859 subjects in Pingguoyuan communities in Beijing were initially screened.After excluding those with bedridden status,mental illness,severe systemic diseases,and missing data,1,680 subjects were recruited for follow up.All recruited subjects were followed up from February 2013 to September 2013(181 subjects were lost to follow-up)and from June 2017 to September 2018(174 subjects were lost to follow up).Finally,1,325 subjects were included in the study.General demographic characteristics,lifestyle and behaviors,disease history and use of medication was collected.Levels of total cholesterol,triglycerides,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,fast blood glucose,RLP-C,low-density lipoprotein triglycerides and PCSK9 were measured.The levels of RLP-C(low:RLP-C≤157 mg/L;high:RLP-C>157 mg/L)and PCSK9(low:PCSK9≤135.87μg/L;high:PCSK9>135.87μg/L)were represented using quartiles.Subjects were categorized into 4 groups according to their RLP-C and PCSK9 levels:Q4,high levels of RLP-C with high levels of PCSK9;Q3,high levels of RLP-C with low levels of PCSK9;Q2,low levels of RLP-C with high levels of PCSK9;and Q1,low levels of RLP-C with low levels of PCSK9.The association of RLP-C with MACEs in subjects with different PCSK9 levels was evaluated.Results::After a median follow-up of 9.5 years,1,325 subjects were included in the study and a total of 191 MACEs had occurred.The incidence of MACEs was higher in the RLP-C>157 mg/L group than the RLP-C≤157 mg/L group(18.40%vs.10.42%).Cox proportional hazards regression model analysis showed that increased RLP-C levels were associated with an increased risk of MACEs(hazard ratio:1.405;95%confidence interval:1.005-1.964;P<0.005).The incidence of MACEs was higher in the high RLP-C/PCSK9 group vs.the low RLP-C/PCSK9 group(20.68%vs.8.76%).Cox proportional hazards regression model analysis showed that RLP-C was associated with an increased risk of MACEs in subjects with high PCSK9 levels independent of traditional risk factors(hazard ratio:1.791;95%confidence interval:1.168-2.825;P=0.001),but not in those with low PCSK9 levels.Conclusions::RLP-C was identified as a risk factor for MACEs,particularly in subjects with high PCSK9 levels.Lowering PCSK9 levels may reduce residual risk in subjects with elevated plasma RLP-C levels.
