BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outc...BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.展开更多
Cardiovascular disease(CVD)remains a major cause of morbidity and mortality worldwide.Currently,it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis a...Cardiovascular disease(CVD)remains a major cause of morbidity and mortality worldwide.Currently,it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis and CVD.Statins remain the standard-of-care in the treatment of hypercholesterolemia and their use has significantly reduced cardiovascular morbidity and mortality.In addition,recent advances in lipid-modifying therapies,such as the development of proprotein convertase subtilisin/kexin type 9 inhibitors,have further improved cardiovascular outcomes in patients with hypercholesterolemia.However,despite significant progress in the treatment of dyslipidemia,there is still considerable residual risk of recurring cardiovascular events.Furthermore,in some cases,an effective therapy for the identified primary cause of a specific dyslipidemia has not been found up to date.Thus,a number of novel pharmacological interventions are under early human trials,targeting different molecular pathways of lipid formation,regulation and metabolism.This editorial aims to discuss the current clinical and scientific data on new promising lipidmodifying therapies addressing unmet needs in CVD,which may prove beneficial in the near future.展开更多
文摘BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.
文摘Cardiovascular disease(CVD)remains a major cause of morbidity and mortality worldwide.Currently,it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis and CVD.Statins remain the standard-of-care in the treatment of hypercholesterolemia and their use has significantly reduced cardiovascular morbidity and mortality.In addition,recent advances in lipid-modifying therapies,such as the development of proprotein convertase subtilisin/kexin type 9 inhibitors,have further improved cardiovascular outcomes in patients with hypercholesterolemia.However,despite significant progress in the treatment of dyslipidemia,there is still considerable residual risk of recurring cardiovascular events.Furthermore,in some cases,an effective therapy for the identified primary cause of a specific dyslipidemia has not been found up to date.Thus,a number of novel pharmacological interventions are under early human trials,targeting different molecular pathways of lipid formation,regulation and metabolism.This editorial aims to discuss the current clinical and scientific data on new promising lipidmodifying therapies addressing unmet needs in CVD,which may prove beneficial in the near future.
