CHIP-related Gene Mutations:predictors For Cardiovascular Risks In AML Patients During Chemotherapy

Study backgroundAging is an inevitable process for everyone.In the aging process of individuals,their bodily functions gradually deteriorate over time.Human aging is associated with the loss of physiological function and anatomical stability,leading to bad physical state and increased mortality.It has been found that aging is related to the accumulation of somatic mutations in tissues.Individual HSPCs develop mutations during replication with age,and such modifications accumulates with time.Mutations in some of these genes promote competitive advantage and expansion of specific leukocyte clones when they have the VAF of>2%and are not associated with severe cytopenia or other hematological diseases,which can be defined as clonal hematopoiesis of indefinite potential(CHIP).CHIP-related genes,such as DNMT3a,TET2,and ASXL-1,encode enzymes that regulate DNA methylation and play an essential role in cell division.Thus,mutations in CHIP-related genes can disrupt bodily function by interfering with the process of DNA methylation and protein synthesis.Most patients with the DNMT3a mutation have higher recurrence rate and lower survival rate than patients without the CHIPrelated mutations.Therefore,these mutations may suggest poor prognosis and lower survival rate in AML patients.CHIP reflects the accumulation of mutations in somatic cells during aging.Although CHIP is associated with mutations and has the potential risk of malignant transformation,the transformation of CHIP into a malignant disease requires a more protracted process because malignant lesions are a long process.Therefore,in most patients with CHIP,the main effect of it on the body is the complications.Recent studies have shown that the mutant profiles detected by NGS confirm that DNMT3a,ASXL-1,JAK2,TP53,and TET2 are the most common mutated genes in CHIP.Most of these genes paly a role in DNA methylation and somatic cell proliferation.AML is a hematological malignancy caused by abnormal clonal expansion of hematopoietic stem and progenitor cells.Its clinical manifestations and prognosis are highly heterogeneous.Gene mutation is a fundamental cause of its heterogeneity.Some of CHIP-related genes also mutates frequently in AML,such as DNMT3a,ASXL-1 and JAK2,which are associated with poor prognosis.More than 70%of AML patients carry gene mutations encoding proteins involved in epigenetic regulation.These mutations could affect the self-renewal and differentiation of hematopoietic cells,playing an essential role in the occurrence and development of AML.AML patients have a poor prognosis,with 5-year survival rates of less than 40%for AML patients under 60.Currently,the commonly used therapies for AML patients include chemotherapy,hematopoietic stem cell transplantation,immunological and targeted therapy.Chemotherapy is the most widely used treatment.Many chemotherapy drugs,especially anthracyclines,could cause severe cardiotoxicity,including myocardial damage and decreased LVEF.Myocardial damage is also the common cardiovascular complication of antitumor therapy.CHIP carrier status was also strongly associated with cardiovascular disease.CHIP can significantly increase the degree of coronary artery calcification and aggravate the progress of atherosclerosis.Furthermore,CHIP is also closely related to heart failure,aortic stenosis and other diseases,seriously affecting the prognosis of patients.CHIP-related gene mutations are associated with both AML and the progression of cardiovascular disease.The common complication during chemotherapy in AML is cardiovascular injury.Therefore,we hypothesize that AML patients with CHIP-related gene mutations are more prone to increase cardiovascular risks during chemotherapy.Objectives(1)To investigate the predictive effect of CHIP-related gene mutations on cardiovascular risks in AML patients during chemotherapy;(2)To identify the manifestations of cardiovascular risks in AML patients with CHIP-related gene mutations during chemotherapy.Study methodsNinety-eight AML patients who received regular chemotherapy in department of hematopathology of Qilu Hospital of Shandong University from January 1st,2020 to December 31st,2020 were selected and divided into two groups,namely CHIP group and control group,according to whether CHIP-related genes were mutated.There were 49 patients in each group.According to patients’ regular chemotherapy time,patients’first chemotherapy time was taken as the enrollment time,three months and six months after the first chemotherapy was taken as the two follow-up time points respectively.And the relevant examination results of patients were collected at the three-time points respectively,as follows:Gender,age,SBP,DBP,HR,BMI,smoking and drinking,HBP,DBP and DM history were collected.Collecting laboratory test indicators,including:Alb,PA,TC,LDL-c,Apo-B,Lp(a),FPG,NT-proBNP,cTnI,CK-MB,potassium ion(K+),magnesium ion(Mg2+)and other indicators.The results of echocardiography were collected,including LVEDD,IVS,LVPW,LVEF and E/e’.SPSS 26.0 software was used for statistical analysis.Results(1)The median age of patients in the two groups was 54,and the mean age of the CHIP group was older than that of the control group(53.94±14.47 vs.54.55± 14.8,p>0.05),but the age difference was not statistically significant.At the time of T0,compared with the control group,CHIP group had a lower BMI(25.77±4.53 vs.24.12±3.48,p<0.05),but a higher prevalence of CHD(2.04%vs.12.24%,p<0.05)and DM(2.04%vs 16.33%,p<0.05).There were no significant differences among average age,AML classification,height,weight,the prevalence of HBP,type of chemotherapy drugs,concentration per unit body surface area of chemotherapy drugs,SBP,DBP,HR,LVEF,LVEDD,IVS,LVPW,E/e’,NT-proBNP,cTnI,CK-MB,FPG,albumin,prealbumin,TC,LDL-c,Apo-B,Lp(a),K+,Mg2+ and cardiovascular drugs in CHIP group and control group.(2)At 3 and 6 months of follow-up,Alb and TC were significantly increased in both groups,but there was no statistical significance between the two groups(p>0.05).Compared with control group,Mg2+ in CHIP group(p<0.05)was lower.There was no significant difference in SBP,DBP,HR,LVEF,LVEDD,IVS,LVPW,E/e’,cTnI,CKMB,FPG,LDL-c,Apo-B,Lp(a),prealbumin and K+between the two groups at 3 time points.(3)Subtract the index collected at T1 from the index collected at T0 to obtain the△ value of the corresponding index.After the correction of CHD,HBP,DM and BMI,△CK-MB in CHIP patients was significantly higher than that in control group(p<0.05),and the difference was statistically significant.The change of K+in CHIP group was lower than that in control group(p<0.05).Compared with control group,CK-MB(0.11 ±0.52 vs.0.13±0.90,p<0.01)in CHIP group was statistically increased,and was correlated with HBP history(p<0.01),DM history(p<0.01),CHD history(p<0.01)and BMI(p<0.01).Compared with control group,K+(0.13±0.60vs.-0.28±0.53,p<0.01)in CHIP group was statistically decreased,and was associated with HBP history(p<0.01),DM history(p<0.01),CHD history(p<0.01)and BMI(p<0.001).(4)Multiple linear regression analysis was carried out with the △ index as the dependent variable and the index at T0 as the independent variable.The multiple linear regression equation of △LVEDD is as follows:△LVEDD=0.322*JAK2+0.250*LVEDD.The multiple linear regression equation of △IVS is as follows:△IVS=0.219*JAK2+0.436*E/e’+0.215*IVS-0.192*Apo-B.The multiple linear regression equation of △LVPW is as follows:△LVPW=0.296*JAK2+0.279*LVPW+0.502*E/e’+0.213*LVEF-0.226*Apo-B.The multiple linear regression equation of △LVEF is as follows:△LVEF=0.294*E/e’+0.223*LVPW+0.213*LVEF+0.203*Apo-B-0.297*JAK2-0.218*(NT-proBNP)-0.014*anthracycline.The multiple linear regression equation of △NT-proBNP is as follows:△NTproBNP=0.227*DNMT3a+0.536*NT-proBNP.The multiple linear regression equation of △cTnI is as follows:△cTnI=0.187*(ASXL-1)+0.357*CHD.The multiple linear regression equation of △CK-MB is as follows:△CK-MB=0.162*LVEDD+0.840*CK-MB+0.415*Lp(a)+0.641*cTnI-0.211*E/e’。The multiple linear regression equation of △Alb is as follows:△Alb=0.166*HR-0.151*E/e’-0.681*Alb-0.197*FPG;The multiple linear regression equation of△TC is as follows:△TC=0.185*JAK2-0.181*BMI-0.238*Alb-0.344*Apo-B;The multiple linear regression equation of △Apo-B is as follows:△ApoB=0.175*smoking-0.339*CHD-0.329*Apo-B-0.245*Mg2+;The multiple linear regression equation of △Lp(a)is as follows:△Lp(a)=0.231*TET2+0.337*CHD0.243*Apo-B;The multiple linear regression equation of △FPG is as follows:△FPG=0.186*DM+0.898×FPG-0.121*LVEF-0.148*anthracycline;The multiple linear regression equation of △K+is as follows:△K+=0.169*CHD-0.195*JAK20.174*E/e’-0.157*FPG-0.642*K+;The multiple linear regression equation of△Mg2+is as follows:△Mg2+=0.187*K+-0.215*NT-proBNP-0.671*Mg2+.Conclusions(1)CHIP-related gene mutations were closely related to the cardiovascular risk of the chemotherapy process in AML patients,and patients with CHIP mutations have increased susceptibility of the cardiovascular injury.CHIP mutations can be used as an early predictor of cardiovascular risk during chemotherapy for AML patients.(2)AML patients with CHIP mutations had a lower BMI,but were more susceptible to suffer CHD and DM,which may be a risk factor for myocardial injury during chemotherapy.(3)CHIP mutations were more likely to lead to myocardial hypertrophic and the decrease of LVEF during chemotherapy.(4)AML patients with CHIP mutations were more likely to suffer lower albumin and Mg2+,but higher TC and increased cardiovascular risk.