Analysis Of Risk Factors Related To Cardio-oncology And Exploratory Research On Early Warning Models

Cancer and cardiovascular disease are two common chronic diseases that threaten human health and have high morbidity and mortality.The survival of cancer patients is longer than before due to the development of cancer diagnosis and treatment.While more and more studies showed that a large number of cancer survivors died from non-tumor causes,and cardiovascular disease is considered as one of the common causes of death.This is closely related to the cardiovascular toxicity caused by cancer treatment.Moreover,elderly people are likely to suffer from cancer and cardiovascular disease simultaneously as these two diseases often share some common risk factors.In this study,we mainly focused on analysis of the risk factors related to cadio-oncology and exploratory research on early warning model.The former mainly aimed at screening the risk factors associated with atherosclerotic cardiovascular disease(ASCVD)and cancer based on the epidemiological statistical analysis in Kailuan cohort.In addition,we discussed the association of total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C)and non-high-density lipoprotein cholesterol(non-HDL-C)with ASCVD and cancer.The latter was to evaluate the cardiovascular toxicity induced by chemotherapeutic drugs in vitro by using human induced pluripotent stem cell derived cardiomyocyte(i PSC-CM).1.Analysis of risk factors related to cancer and atherosclerotic cardiovascular disease(ASCVD)Hypertension,hyperglycemia,hyperlipidemia,smoking,drinking,lack of physical exercise,etc.have important impacts on the occurrence of cardiovascular diseases and cancer.First,our study used the big data from Tangshan Kailuan cohort to screen the risk factors of cancer and ASCVD.We found that age,smoking and high level of C-reactive protein(CRP)were common risk factors for ASCVD and cancer.Men were more likely to develop ASCVD and women were more likely to develop cancer.Moderate drinking was beneficial for ASCVD and cancer.Hypertension and diabetes mellitus were risk factors for ASCVD but not for cancer,while hypertension was closely related to the occurrence of kidney cancer.TC was positively associated with ASCVD occurrence and negatively associated with total cancer.Body mass index(BMI)was positively associated with ASCVD occurrence but had no effects on cancer.Dyslipidemia such as high levels of TC,LDL-C and non-HDL-C are considered as risk factors of ASCVD,but their association with cancer remains unclear.This study used a prospective cohort study method and included 81,110 males who had first physical examination at baseline between 2006 and 2007.After excluding the subjects who had a history of cardiovascular disease or cancer,used of lipid-lowing agents or missing information of lipid profiles in the first examination,68,769 male subjects were registered in the present study.They were followed up for approximately 8 years until occurrence of ASCVD,cancer or death or until December31,2014.Cox regression models were used to estimate hazard ratios(HRs)and their95% confidence intervals(CIs)and investigate the association between TC,LDL-C and non-HDL-C with ASCVD and cancer.Multivariable analysis was adjusted for age,cigarette smoking,alcohol consumption,physical activity,hypertension,diabetes mellitus and BMI at baseline.During 8 years follow-up,2,916 males(2.4%)developed ASCVD and 1,884 males(2.7%)developed cancer.Compared with the lowest quartile,the upper-most quartiles of TC,LDL-C and non-HDL-C were all positively associated with ASCVD occurrence(HR 1.53,95% CI 1.37-1.70;HR 1.16,95% CI 1.05-1.28;HR 1.55,95% CI 1.39-1.72).However,the upper-most quartiles of TC,LDL-C and non-HDL-C were all negatively associated with cancer(HR 0.84,95% CI 0.74-0.95;HR 0.82,95% CI 0.72-0.93;HR 0.80,95%CI 0.70-0.90).To explore the preclinical effect of cancer on lipid profiles,we further excluded the participations who were diagnosed with cancer in the first 4 years of follow-up.TC,LDL-C and non-HDL-C were still inversely associated with cancer occurrence(HR0.79;HR 0.81;HR 0.77).Moreover,TC and non-HDL-C mainly had a strong inverse association with liver cancer(HR,0.26;HR,0.27)and stomach cancer(HR,0.63;HR,0.53).After we excluded the participations who were diagnosed with cancer in the first 4 years of follow-up,TC remained negatively associated with liver cancer(HR,0.39)but not with stomach cancer,and non-HDL-C was still negatively associated with liver cancer and stomach cancer(HR,0.37;HR,0.41).Taken together,we conclude that the higher levels of TC,LDL-C and non-HDL-C increased risk of ASCVD but they were inversely associated with total cancer and several individual cancers.2.Human induced pluripotent stem cell-derived cardiomyocyte(i PSC-CM):an ideal platform for in vitro evaluation of chemotherapy-induced cardiotoxicityAnthracycline drugs such as doxorubicin is widely used for anti-tumor therapy and has a significant anti-tumor effect.However,the use of doxorubicin is often restricted due to it has cardiotoxicity and other adverse reactions.Cardiotoxicity caused by anthracyclines can be classified into acute stage,early stage and late stage.Acute phase cardiotoxicity usually occurs after drugs infusion quickly,and may manifest as electrocardiograph changes such as several kinds of arrhythmias and transient left ventricular dysfunction,but these changes are often reversible.Early cardiotoxicity may occur within several months to one year after drugs infusion.Delayed cardiotoxicity may occur several years after chemotherapy and is characterized by left ventricular function declines progressively and leads to heart failure.Cardiotoxicity induced by anthracyclines can seriously affect the prognosis of cancer patients and even is the leading cause of death.Therefore,it is important to understand the potential mechanism and screen cardiovascular protective drugs for prevention of cardiac injure.In this study,we used four healthy people's i PSC-CMs to establish doxorubicin induced cardiac injure models and screened for cardiac-protective drugs which can reduced doxorubicin-induced myocardial injury.We used immunofluorescent imaging to evaluate sarcomeric disarray and DNA damage caused by doxorubicin.Immunofluorescent imaging demonstrated the severity of damage on sarcomeric organization in hi PSC-CM is a concentration dependent.The lowest concentration(0.1u M)of doxorubicin had no significant effect on sarcomeric disarray,but caused DNA damage obviously in hi PSC-CMs.Used cardio Excyte 96 to evaluate the effects of differential concentration of doxorubicin on cell index,beating frequency and contraction amplitude of i PSC-CMs from four healthy people,we found both medium(1u M)and high(10u M)concentration reduced cell index and contraction amplitude of i PSC-CMs.The effects of doxorubicin on the beating frequenc varied in different individuals.Patch clamp indicated doxorubicin could prolong the action potential duration(APD)of several kinds of i PSC-CM,which may explain why some patients use doxorubicin can easily have QT interval prolongation in clinic.Annexin V binding and propidium iodide(PI)uptake followed by flow cytometry could estimate apoptosis and necrosis of i PSC-CMs.Both medium(1u M)and high(10u M)concentration of doxorubicin induced cell apoptosis and necrosis obviously.Lactate dehydrogenase(LDH)detection was used to evaluate cardiac injure and LDH cytotoxicity assay demonstrated a dose-dependent effect of doxorubicin on cardiotoxicity.Meanwhile,we screened cardiovascular protective drugs for reducing cardiac injure included trimetazidine,carvedilol,atenolol,angiotensin converting enzyme inhibitor(ACEI)and angiotensin receptor blocker(ARB)by LDH cytotoxicity assay.Carvedilol and atenolol reduced cytotoxicity caused by doxorubicin.Moreover,dexrazoxane reduced the decline of cell activity and contraction amplitude induced by doxorubicin,but had no effect on the frequency change.Therefore,i PSC-CM may be an ideal tool to early warning the myocardial toxicity induced by anti-tumor drugs,as well as an ideal drug screening model.