Prognostic Biomarkers For Stroke And Combined Effects Of Hypertension And Heart Rate,Lipid Accumulation Product On The Risk Of Stroke

BackgroundStroke has become the second cause of death worldwide,and the leading cause of long-term disability and mortality in China.Stroke not only brings physical and psychological pain to the patients,but also brings serious financial burden to the family,society and the country.Stroke is a complex disease caused by multiple risk factors.It has been documented that several risk factors may interact or act synergistically with each other on stroke incidence.Previous studies showed that traditional risk factors have a low attribute risk to poor prognosis of ischemic stroke.Early identification novel risk factors of prognosis are extremely important for treatment and recovery of stroke patients.The main pathological basis of ischemic stroke includes atherosclerosis,plaque formation,rupture and abscission,while inflammatory process plays a crucial role in this series of processes.Epidemiological and clinical studies have found that inflammation related biomarkers are associated with cardiovascular disease,including ischemic stroke,but the association between inflammation related biomarkers and clinical outcomes after ischemic stroke is uncertain.In this study,we aim to investigate the prognostic value of several inflammatory biomarkers,and the combined effects of traditional risk factors on the risk of stroke.Part I: To study the incremental performance of serum matrix metalloproteinase-9(MMP-9),high sensitivity C-reactive protein(hs CRP),lipoprotein-associated phospholipase A2(Lp-PLA2),and plasma homocysteine(Hcy)in ischemic stroke patients,using data derived from the China Antihypertensive Trial in Acute Ischemic Stroke(CATIS).Part II: To prospectively evaluate the combined effects of hypertension and heart rate,lipid accumulation product(LAP)on the development of stroke on the basis of an ~ 10-year follow-up study in an Inner Mongolian population of China.Part IObjectiveTo study the association between serum MMP-9,hs CRP,Lp-PLA2,and plasma Hcy and poor clinical outcomes after acute ischemic stroke.Subjects and MethodsThis study was conducted among patients from the CATIS trial.Baseline data on demographic characteristics,lifestyle risk factors,clinical characteristics,medical history,and use of medications were collected with a standard questionnaire by trained neurologists or research nurses at admission.A total of 3474 patients with blood samples were included in the present analysis.Serum MMP-9,hs CRP and Lp-PLA2 concentrations were measured with a commercially available ELISA kit,and plasma Hcy was determined by enzymatic cycling assay on the Cobas c 501 analyzer.Participants were followed up in person at 3 months after hospitalization by trained neurologists.The primary outcome was a combination of death and major disability(m RS score 3-6)within 3 months.Secondary outcomes were separately those of death and major disability(Mrs score of 6 and 3-5,respectively)and vascular events.Categorical logistic regression analyses were performed to evaluate the associations between MMP-9,hs CRP,Lp-PLA2 and Hcy and 3-month prognosis among acute ischemic stroke patients.Odds ratios(ORs)and 95 % confidence intervals(95 % CIs)across quartiles were calculated(the lowest quartile as a reference).We used restricted cubic splines to examine the shape of the association between MMP-9,hs CRP,Lp-PLA2 and Hcy and death or major disability.In addition,net reclassification index(NRI)and integrated discrimination improvement(IDI)were used to evaluate the incremental prognostic value of MMP-9,hs CRP,Lp-PLA2 and Hcy beyond conventional risk factors.ResultsDuring 3 months of follow-up,866 participants(24.6%)experienced major disability or died(99 deaths),61 had a recurrent stroke,91 experienced vascular events.And 65 participants were lost to follow-up.The multivariable adjusted ORs for the highest quartile vs lowest one of MMP-9 was 1.36(95% CI 1.05-1.78)for the primary outcome,and 2.01(95% CI 1.02-3.99)for death.There were dose-dependent relationships between serum MMP-9 levels and the combined outcome(P for trend=0.003),major disability(P for trend=0.03)and death(P for trend=0.046).Adding serum MMP-9 to a model containing conventional risk factors significantly improve risk reclassification for the combined outcome(NRI 12.8,P=0.002;IDI 0.37,P=0.002).A high hs CRP level was associated with an increased risk of 2.20-fold for the combined outcome(OR 2.20;95% CI 1.68-2.87),1.84-fold for major disability(OR 1.84;95% CI 1.40-2.42),and 2.56-fold for death(OR 2.56;95% CI 1.33-4.91)when highest and lowest categories were compared.Also,there were dose-dependent relationships between serum hs CRP levels and the combined outcome(P for trend<0.001),major disability(P for trend=0.002)and death(P for trend<0.001).Furthermore,adding hs CRP level to the basic model improved risk prediction for the combined outcome(NRI 18.9,P<0.001;IDI 1.51,P<0.001),major disability(NRI 12.1,P=0.003;IDI 0.70,P<0.001),and death(NRI 44.3,P<0.001;IDI 2.50,P<0.001).We did not find any significant relationship of serum Lp-PLA2 leval with clinical outcomes among our study participants.There was a significant interaction between plasma Hcy and sex,in relation to risk of the primary outcome(P-interaction=0.03).Adjusted OR comparing two extreme Hcy quartiles were 1.59(95% CI 1.02-2.48)in women,while no significant statistical relation was observed in men.A larger number of elevated biomarkers were significantly associated with increased risk of the combined outcome(P for trend<0.001)and major disability(P for trend<0.001).Simultaneously adding significant biomarkers to conventional model led to substantial reclassification for the combined outcome of death and major disability,major disability,and death.ConclusionsWe found higher serum MMP-9 and hs CRP levels were significantly associated with increased risk of 3-month death or major disability,the addition of MMP-9 or hs CRP to conventional risk factors improves risk prediction for clinical outcomes.Elevated Hcy is positively associated with poor prognosis of acute ischemic stroke in women,but not in men.And clear gradient relationships between the number of elevated inflammatory biomarkers and risk of mortality or major disability were observed in both men and women.Incorporation of a combination of significant biomarkers observed substantially improved the risk stratification for adverse outcomes in patients with ischemic stroke.Part IIObjectiveTo prospectively assess the joint effects of hypertension and heart rate,LAP on the risk of stroke.Subjects and MethodsBaseline survey was conducted between 2002 and 2003 in 32 villages of Kezuohou Banner and Naiman Banner in Tongliao City of Inner Mongolia.Baseline data about demographic characteristics,medical history and lifestyle risk factors followed a standard questionnaire were collected by the trained staff.Blood pressure,heart rate,and waist circumference(WC)were measured.Heart rate was grouped comparing the upper tertile(?80 bpm)to the bottom 2 tertiles(<80 bpm).Fasting plasma glucose(FPG),total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),and triglycerides(TG)were tested,low-density lipoprotein cholesterol(LDL-C)levels were calculated.LAP was calculated by WC and TG concentration,LAP for men = [WC(cm)-65]×[TG concentration(mmol/L)],LAP for women = [WC(cm)-58]×[TG concentration(mmol/L)].High LAP was defined as LAP ?16.83(median).According to the hypertensive status and heart rate or LAP,the participants were divided into following groups: normotensives/heart rate<80 bpm,normotensives/heart rate?80 bpm,hypertensives/heart rate<80 bpm,and hypertensives/heart rate?80 bpm;normotensives/low LAP,normotensives/high LAP,hypertensives/low LAP,and hypertensives/high LAP.Hazard ratios(HRs)and 95% confidence intervals(CIs)for future stroke were calculated by Cox proportional hazard models.In addition,we assessed the discriminatory value of hypertension/heart rate,or hypertension/LAP status on stroke by computing the area under receiver operating characteristic(AUC)curves and comparing a model including hypertension/heart rate,or hypertension/LAP status and other conventional risk factors with a model including only other conventional factors.ResultsDuring the 9.2 years of follow-up,a total of 124 stroke patients occurred,the cumulative incidence rate was 4.79%.After multivariable adjustment,hypertension was significantly associated with stroke but heart rate was not,no matter as a continuous variable or categorical variable.Compared with the normotensives with a heart rate <80 bpm,the multivariable adjusted HRs of stroke for hypertensives with a heart rate <80 bpm(HR 3.19;95% CI 1.80-5.66;P<0.001)and hypertensives with a heart rate ?80 bpm(HR 3.38;95% CI 1.83-6.24;P<0.001)were statistically significant.The hypertensives with a heart rate ?80 bpm had the highest risk of stroke.The AUC for the model including hypertension and heart rate ?80 bpm,and other conventional risk factors was larger than for the model including only other conventional risk factors(0.854 vs 0.836,P=0.023).Participants with higher LAP were associated with increased risk of stroke(HR,1.26;95% CI,1.02-2.39)compared with lower LAP group.After adjusting for other cardiovascular risk factors,compared to normotensives with low LAP,adjusted HRs(95% CIs)for hypertensives with low LAP and hypertensives with high LAP were 2.96(1.52-5.78)and 4.10(2.08-8.08),respectively.The hypertensives with high LAP had the highest risk of stroke.The AUC for the model including hypertension and high LAP,and other conventional risk factors was larger than for the model including only other conventional risk factors(0.854 vs 0.837,P=0.036).ConclusionsThis study showed that hypertension and high LAP were associated with incidence of future stroke,independently of other traditional risk factors.Hypertensives with high heart rate,or high LAP had the highest risk of stroke among inner Mongolians.High heart rate or LAP could enlarge the risk of stroke among population with hypertension.Our findings suggested that the coexistence of hypertension and high heart rate or LAP may be a valuable predictor of stroke incidence.