The Value Of Thyroid Hormone And Its Potential Biomarker MDK In The Diagnosis And Treatment Of Myocardial Infarction And Heart Failure

Background:Acute myocardial infarction(AMI)patients always underwent thyroid disfunction and increased serum N-terminal pro-B-type natriuretic peptide(NT-proBNP).The aim of this study is investigating relationship between free triiodothyronine(FT3)and NT-proBNP and whether FT3 and NT-proBNP are prognostic factors for patients with AMI.Methods:813 AMI patients were enrolled and divided into two groups according to FT3 levels:low FT3(FT3<2.5 pg/mL,n=252)and normal FT3(2.5?FT3<4.09 pg/mL,n=561).Primary outcome of this study was major adverse cardiovascular events(MACE).Association of these 2 paraments were analysis.After 2 years follow-up,Kaplan-Meier surviving curve,Cox regression analysis was used to assess the prognosis value of FT3 and NT-proBNP.Results:Serum FT3 was inversely correlated with 1g NT-proBNP(r=-0.311,P<0.001).After over 2 years follow-up,low FT3 group patients had higher rates of MACEs than those with normal FT3(27.0%vs.7.8%,P<0.001).Univariable Cox proportional hazards regression analyses showed that NT-proBNP>802.7 pg/mL[hazard ratio(HR)=5.063,95%CI=3.176-8.071,P<0.001]and FT3<2.5 pg/mL(HR=3.867,95%CI=2.646-5.651,P<0.001)were the strongest predictors of MACEs.After adjustment for traditional risk predictors,FT3<2.5 pg/mL(HR=2.570,95%CI=1.653-3.993,P<0.001)was one of the most important independent predictors of MACEs.Patients with NT-proBNP?802.7 pg/mL and FT3?2.5 pg/mL had the best prognosis,while patients with NT-proBNP>802.7 pg/mL and FT3<2.5 pg/mL had the worst outcomes(P<0.001).Conclusions:Low FT3 is a strong predictor of poor prognosis after AMI.Serum FT3 have negative correlation with NT-proBNP.Combining FT3 with NT-proBNP can better predict MACE of AMI.Background:Hypothyroidism used to occur in patients after myocardial infarction(MI).However,whether to supple thyroid hormone such as triiodothyronine(T3)for patients with MI is still controversial.Hyperthyroidism caused by over treatment of thyroid hormone hinders clinical use of thyroid hormone.As the standard therapy for MI,?-receptor blockers are widely used in hyperthyroidism.There is an interaction between thyroid hormone and adrenergic system.No study investigates influences of combining T3 and ?-receptor blockers metoprolol(Met)in treating MI.Methods:Myocardial infarction or sham surgeries were performed on 12-week-old female Sprague-Dawley rats followed by T3 or Met treatment for 8 weeks.T3 and Met were dissolved in the water at doses of 5 ?g/kg/d and 100 mg/kg/d respectively.Rats were thus divided into 5 following group(n=9/group):Sham group,MI+Veh group,MI+T3 group,MI+Met group and MI+T3+Met group.Ultrasound and hemodynamic tests of each rat were measured,and arrhythmia induction experiment was performed on each rat.Pathological changes of heart were detected using Masson,Sirius Red staining.qRT-PCR were employed to detect molecular changes after MI.Results:T3,Met or T3+Met treatment all significantly enhanced left ventricular contractility and reduced the collagen fiber deposition in the non-infarct area after MI,while T3+Met showed highest level of enhancement.T3 therapy can cause increased myocardial mass and increased ventricular rate,but these changes disappeared in MI+T3+Met group.Both T3 and Met can significantly reduce incidence of tachyarrhythmia and its duration.But there is a significant difference in arrhythmia duration between MI+Veh group and MI+T3+Met group(0.87±0.59s in MI+Veh group vs.0.14±0.27s in MI+T3+Met group,P<0.05),while T3 or Met treatment did not show statistically significant.The results of qRT-PCR showed that T3,Met or T3+Met treatment can reduce inflammation and fibrosis-related genes expression after MI,and restore expression of ion channels and cardiac contractile proteins.Conclusions:T3,Met or T3+Met treatment all can increase myocardial contractility,reduce myocardial fibrosis,prevent arrhythmia,and improve the expression of ion channel protein and contractile protein genes after MI.However,T3 alone treatment still increased the risk of myocardial hypertrophy and increased heart rate.Combining T3 and Met not only preserved the therapeutic effects of T3 and Met,but also further enhanced contractility,reduced arrhythmia while greatly reduced potential risks.This provided a new therapeutic strategy for clinical use of thyroid hormone.Background:Previous studies have shown hypothyroidism correlated with cardiovascular diseases prognosis,patients with low serum thyroid hormone levels have poor prognosis and a significant increase in mortality.However,serum thyroid hormone level is not consistent with the local thyroid level in myocardial tissue.New biomarkers are needed to detect low cardiac thyroid hormone function.The function of Midkine(MDK)in cardiovascular system is getting attention.MDK may be a potential serum biomarker for reflecting level of thyroid hormone in heart tissue.Methods:12-week-old female Sprague-Dawley rats were taken orally with Propylthiouracil(PTU)drinking water for 8 weeks or underwent left anterior descending coronary artery ligation to make hypothyroid model and myocardial infarction-heart failure model respectively.In hypothyroid model,hypothyroid rats were treated with oral triiodothyronine(T3)for 3 days,6 days and 14 days.In myocardial infarction-heart failure model,survival rats also treated with T3 for 8 weeks.Ultrasound and hemodynamic tests were performed on each group of rats.The serum thyroid hormone levels and expression of MDK in myocardial tissues were detected in each group of rats.Detect myocardial tissue T3 levels and serum MDK levels in each group of rats in two models to evaluate the correlation between serum MDK and cardiac tissue T3.Ventricular cardiomyocytes of adult female Sprague-Dawley rats were isolated and cultured to detect MDK expression in the cardiomyocytes with or without T3.Results:In hypothyroid model,most of cardiac function parameters through echocardiography and in vivo hemodynamic measurements have returned to normal after 14 days T3 treatment.Compared to euthyroid rats,serum MDK of hypothyroid rats doubled.T3 treatment decreased serum MDK and increased cardiac tissue T3.Serum MDK was negatively correlated with cardiac tissue T3 in hypothyroid model(R2=0.5551,P<0.001).Rats' serum and cardiac tissue MDK significantly increased after MI.8 weeks T3 treatment after MI dramatically decreased serum MDK and increased cardiac tissue T3.The serum MDK in MI rats showed an inverse relationship with cardiac tissue T3(R2=0.5680,P<0.001).MDK protein and mRNA expression of adult rat cardiomyocytes without T3 gradually increased over time,while MDK protein and mRNA remain unchanged in cardiomyocytes with T3 in culture medium.Conclusions:Results from 2 rat models confirmed an inverse relationship between serum MDK and cardiac tissue T3.Reduction of serum MDK and increase of T3 level in heart tissue after T3 treatment reflected MDK can be used as a reliable potential biomarker of thyroid hormone levels in heart.