Jeng-Feng Lin

Growth-Differentiation Factor-15 and Major Cardiac Events

Background:Growth-differentiation factor (GDF)-15 is a strong predictor of cardiovascular events in patients with ST-elevation myocardial infarction (STEMI). However, the effects of GDF-15 on left ventricular (LV) remodeling have not been clearly elucidated. The aim of this study is to investigate whether GDF-15 will be of benefit in predicting LV remodeling, heart failure and death in patients with STEMI. Methods:The authors enrolled 216 patients with STEMI who received measurement of GDF-15 level on day 2 of hospitalization. Echocardiographic studies were performed at baseline and were repeated 6 months later. Clinical events, including all-cause death and readmission for heart failure, were followed up for a maximum of 3 years. Results:Patients with GDF-15 levels above the median had lower LV ejection fraction at baseline (43.9% versus 48.0%, P = 0.041) and at 6 months (51.5% versus 56.9%, P = 0.025). In univariable regression model, log-transformed GDF-15 level was not a predictor of increase in LV end-diastolic volume index at 6 months (P = 0.767). Kaplan-Meier survival curves showed that the combination of high GDF-15 and high N-terminal pro-B-type natriuretic peptide was a strong predictor of death and heart failure (P < 0.001). In multivariable Cox regression model, the independent predictors of death and heart failure were age, GDF-15 level and diabetes mellitus. Conclusions:High GDF-15 level is a strong predictor of death and heart failure in patients with STEMI. Although patients with higher GDF-15 levels tend to have lower LV ejection fraction, they have similar degree of the increase in LV end-diastolic volume index at 6 months.

Right Ventricular Function in Patients With Different Infarction Sites After a First Acute Myocardial Infarction

Introduction:To investigate the effect of different infarction sites on right ventricular (RV) functional changes in patients with a first acute ST-elevation myocardial infarction without concomitant RV infarction. Methods:Sixty consecutive patients underwent conventional echocardiography and pulsed-wave tissue Doppler imaging for RV function evaluation after successful primary percutaneous coronary intervention. They were divided into 2 groups according to infarct location based on the electrocardiographic findings: group I consisted of 35 patients with anterior (including anteroseptal) wall infarction and group II included 25 patients with inferior (including inferoposterior) wall infarction. Ten healthy individuals served as the control group. Results:The tricuspid annular plane systolic excursion was significantly lower in group I compared with that in the controls (20.3 ± 3.8 versus 23.9 ± 2.4 mm, P < 0.05). The ratio of transtricuspid peak early filling velocity to tricuspid annular early diastolic velocity (E/Em) was comparable between group I and group II, whereas it was higher in group II than in the controls (6.10 ± 1.37 versus 4.33 ± 1.17, P < 0.05). The RV myocardial performance index determined by tissue Doppler imaging was significantly higher in group I than in group II (0.48 ± 0.25 versus 0.32 ± 0.10, P < 0.05) and the healthy controls (0.48 ± 0.25 versus 0.27 ± 0.08, P < 0.05). Conclusions:In patients with a first, acute reperfused ST-elevation myocardial infarction without associated RV infarction, RV function may be affected discrepantly depending on the different infarction sites. In patients with inferior infarction without concomitant RV infarction, only regional RV diastolic dysfunction is observed, whereas the alteration of global RV function is more pronounced in patients with anterior wall infarction.

Growth Differentiation Factor 15 May Predict Mortality of Peripheral and Coronary Artery Diseases and Correlate with Their Risk Factors

Plasma GDF15 concentrations were measured in 612 Taiwanese individuals without overt systemic disease. Clinical parameters, GDF15 genetic variants, and 22 biomarker levels were analyzed. We further enrolled 86 patients with PAD and 481 patients with CAD, who received endovascular intervention and coronary angiography, respectively, to examine the role of GDF15 level in predicting all-cause mortality. Significant associations were found between GDF15 genotypes/haplotypes and GDF15 levels. The circulating GDF15 level was positively associated with age, smoking, hypertension, and diabetes mellitus as well as circulating levels of lipocalin 2 and various biomarkers of inflammation and oxidative stress. Kaplan-Meier survival analysis showed that baseline GDF15 levels of above 3096 pg/mL and 1123 pg/mL were strong predictors of death for patients with PAD and CAD, respectively (P = 0.011 and P < 0.001). GDF15 more accurately reclassified 17.3% and 29.2% of patients with PAD and CAD, respectively (P = 0.0046 and P = 0.0197), compared to C-reactive protein. Both genetic and nongenetic factors, including cardiometabolic and inflammatory markers and adipokines, were significantly associated with GDF15 level. A high level of GDF15 was significantly associated with an increase of all-cause mortality in patients with high-risk PAD and in patients with angiographically documented CAD.

Genetic variants associated with circulating MMP1 levels near matrix metalloproteinase genes on chromosome 11q21-22 in Taiwanese: interaction with obesity

BackgroundMMP1 is implicated in the pathogenesis of atherothrombotic cardiovascular disease. We aimed to elucidate genetic determinants of inflammatory marker levels, including circulating MMP1, in Taiwanese, and their association with obesity.MethodsFive genetic polymorphisms around matrix metalloproteinase genes on chromosome 11q21-22 region were genotyped in 519 subjects.ResultsAfter adjusting for clinical covariates, two polymorphisms were significantly associated with MMP1 levels, rs1799750 and rs495366, using an additive inheritance model (P = 1.5x10-4 and P = 2.57x10-5, respectively). Using dominant model, minor alleles of rs1799750 and rs495366 were associated with higher MMP1 levels (P = 1.3x10-4 and P = 1.95x10-5, respectively). In haplotype analysis, two haplotypes inferred from five SNPs (A2GATA and A1GATG) were associated with MMP1 levels (P = 5x10-4 and P = 8.47x10-5, respectively). Subgroup and interaction analysis revealed an association of rs1799750 and rs495366 with MMP1 levels only in non-obese subjects (P = 6.66x10-6 and P = 4.38x10-5, respectively, and interaction P = 0.008 for rs1799750). Haplotype interaction analysis also showed significant interaction for haplotype A1GATG (interaction P = 0.003).ConclusionsGenotypes/haplotypes around MMP1 locus are associated with MMP1 levels in Taiwanese. Further, since genotypes/haplotypes near MMP1 locus interact with obesity to set MMP1 levels, genetic determinants for MMP1 level may be different between obese and non-obese individuals.

Association of SELE genotypes/haplotypes with sE-selectin levels in Taiwanese individuals: interactive effect of MMP9 level

BackgroundE-selectin is implicated in various inflammatory processes and related disorders. We aimed to investigate the role of SELE-gene genotypes/haplotypes on plasma levels of MMP9 and sE-selectin in Taiwanese individuals.MethodsFive hundred twenty individuals were enrolled. Seven tagging SELE single nucleotide polymorphisms were analyzed.ResultsSELE genotypes were found associated with MMP9 and sE-selectin levels. Multivariate analysis identified that the most significant genetic polymorphism (rs5368 genotype) was independently associated with MMP9 levels (P < 0.001). One haplotype (GGAGAGT) was marginally associated with MMP9 levels (P = 0.0490). One SELE SNP, (rs3917406, P = 0.031) was associated with sE-selectin levels after adjusting for MMP9 and sICAM1 levels. Subgroup and interaction analysis revealed association of SELE SNP rs10800469 with sE-selectin levels only in the highest quartile of MMP9 level (P = 0.002, interaction P = 0.023). Haplotype analysis showed one haplotype (AAAAAGC) borderline associated with sE-selectin level (P = 0.0511).ConclusionSELE genotypes/haplotypes are independently associated with MMP9 and E-selectin levels in Taiwanese individuals. The associations of SELE genotypes/haplotypes with sE-selectin levels are affected by MMP9 levels.

Activin A Predicts Left Ventricular Remodeling and Mortality in Patients with ST-Elevation Myocardial Infarction.

BACKGROUND Activin A levels increase in a variety of heart diseases including ST-elevation myocardial infarction (STEMI). The aim of this study is to investigate whether the level of activin A can be beneficial in predicting left ventricular remodeling, heart failure, and death in patients with ST-elevation myocardial infarction (STEMI). METHODS We enrolled 278 patients with STEMI who had their activin A levels measured on day 2 of hospitalization. Echocardiographic studies were performed at baseline and were repeated 6 months later. Thereafter, the clinical events of these patients were followed for a maximum of 3 years, including all-cause death and readmission for heart failure. RESULTS During hospitalization, higher activin A level was associated with higher triglyceride level, lower left ventricular ejection fraction (LVEF), and lower left ventricular end diastolic ventricular volume index (LVEDVI) in multivariable linear regression model. During follow-up, patients with activin A levels > 129 pg/ml had significantly lower LVEF, and higher LVEDVI at 6 months. Kaplan-Meier survival curves showed that activin A level > 129 pg/ml was a predictor of all-cause death (p = 0.022), but not a predictor of heart failure (p = 0.767). CONCLUSIONS Activin A level > 129 pg/ml predicts worse left ventricular remodeling and all-cause death in STEMI.

Resveratrol Protects Left Ventricle by Increasing Adenylate Kinase 1 and Isocitrate Dehydrogenase Activities in Rats with Myocardial Infarction

Our prior study had shown that resveratrol was a potent cardioprotective agent in rats with myocardial infarction (MI). In this study, we further evaluated the mechanism of cardioprotection of resveratrol by proteomic analysis. After permanent ligation of the left anterior descending artery under isoflurane anesthesia, surviving rats were randomly allocated to three groups and treated with resveratrol at 1 mg/kg/day (MI/R group), or vehicles (sham group and MI group) once daily for four weeks. In proteomic analysis, the MI group showed decreased expression of adenylate kinase 1 (AK1) and mitochondrial NADP⁺-dependent isocitrate dehydrogenase (IDPm) after MI compared with the sham group. These variations were reversed by resveratrol in the MI/R group. Validation with Western blot and immunohistochemical analyses showed similar trends in protein expression profiling. Our studies suggest that the beneficial effects of resveratrol on ventricular modeling may be due to increased expression of AK1 and IDPm, which have been known to increase myocardial energetic efficiency and reduce reactive oxygen species-mediated damage, respectively.

QT interval Independently Predicts Mortality and Heart Failure in Patients with ST-Elevation Myocardial Infarction.

Objectives: Heart-rate corrected QT (QTc) interval predicts cardiovascular mortality or all-cause mortality in the general population. Little is known about the best cut-off value of QTc interval for predicting clinical events in patients with ST-elevation myocardial infarction (STEMI). Methods: We enrolled 264 patients with STEMI who received measurement of QTc intervals at ER (QTc-ER), on day 2 (QTc-D2), and on day 3 (QTc-D3) of hospitalization. Clinical events, including all-cause death and readmission for heart failure, were followed for 2 years. Results: Prolonged QTc-ER, but not QTc-D2 or QTc-D3, well predicted clinical events with the best cut-off value of 445 ms. Patient with QTc-ER > 445 ms had lower left ventricular ejection fraction at baseline and at 6 months. Kaplan-Meier survival curves showed that the combination of QTc-ER > 445 ms and N-terminal pro-brain natriuretic peptide (NT-pro BNP) > 936 pg/mL was a strong predictor of clinical events (p<0.001). In multivariable Cox regression analysis, the independent predictors of death and heart failure were QTc-ER (p<0.001), log NT-proBNP (p<0.001), diabetes mellitus (p<0.001), history of stroke (p=0.001), and left ventricular end diastolic volume index (p<0.001). Conclusion: QTc-ER > 445 ms independently predicts clinical events in STEMI, providing incremental prognostic value to established clinical predictors and NT-proBNP.

Interactive effects of C-reactive protein levels on the association between APOE variants and triglyceride levels in a Taiwanese population

BackgroundApolipoprotein E (APOE) plays a major role in lipid metabolism and inflammation. However, the association between APOE gene polymorphisms and serum triglyceride levels remains controversial. We tested the effects of APOE variants on triglyceride levels and their interactions with the inflammatory marker C-reactive protein (CRP) in a Taiwanese population.MethodsTwo APOE single nucleotide polymorphisms (SNPs) rs429358 and rs7412 were genotyped by TaqMan Assay using real time PCR in 595 healthy subjects attending the clinic for routine visits.ResultsAfter adjustment for clinical covariates, subjects carrying the rs429358-TT genotype and non-ε4 alleles were found to have higher CRP levels, whereas those with rs7412-CC genotype and non-ε2 alleles had significantly higher total and low-density lipoprotein cholesterol levels (all P < 0.01). Using subgroup and interaction analyses, we observed significantly lower triglyceride levels in subjects carrying the rs429358-TT genotype and non-ε4 alleles in the low CRP group (P = 2.71× 10−4 and P = 4.32 × 10−4, respectively), but not in those in the high CRP group (interaction P = 0.013 and 0.045, respectively). In addition, multivariate stepwise linear regression analysis showed that subjects carrying the rs429358-TT genotype and non-ε4 alleles with low CRP levels had significantly lower triglyceride levels (P < 0.001 and P < 0.001, respectively). In addition, when combined with the risk alleles of GCKR, APOA5 and LPL gene variants, we observed that triglyceride levels increased significantly with the number of risk alleles (P = 2.9 × 10−12).ConclusionsThe combination of SNPs and ε alleles at the APOE locus is involved in managing lipid and CRP levels in the Taiwanese population. APOE polymorphisms interact with CRP to regulate triglyceride levels, thus triglyceride concentration is influenced by both the genetic background of the APOE locus and the inflammatory status of a subject.

Doses of renin-angiotensin system inhibitors but not beta-blockers predict outcome after ST-elevation myocardial infarction

ABSTRACT Objectives: In patients with ST-elevation myocardial infarction (STEMI), it is not clear whether low-dose renin-angiotensin system inhibitors and beta-blockers can result in the same benefits achievable with higher target doses. This observational study aims to investigate whether higher doses of angiotensin converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB) and beta-blockers can improve outcomes in patients with STEMI. Methods: We recorded daily doses of ACEI, ARB, and beta-blockers in 331 patients with STEMI. Echocardiographic studies were performed at baseline and were repeated 6 months later. Clinical events, including all-cause death and heart failure, were followed for 2 years. Results: Patients receiving high-dose ACEI/ARB had less increase in left ventricular end-diastolic volume index (LVEDVI) at 6 months. In multivariable linear regression model, ACEI/ARB dose or beta-blocker dose was not an independent predictor of increase in LVEDVI at 6 months. Kaplan-Meier survival curves showed that doses of ACEI/ARB (p = 0.003) and beta-blockers (p = 0.027) were significant predictors of death and heart failure. In multivariable Cox regression analysis, independent predictors of all-cause death and heart failure were diabetes mellitus (p = 0.001), left ventricular ejection fraction (p = 0.026), and ACEI/ARB dose (p = 0.025). Beta-blockers dose was not a predictor of clinical events in multivariable analysis (p = 0.413). Conclusion: High-dose ACEI/ARB, but not beta-blocker, was associated with lower rate of all-cause death and heart failure in patients with STEMI.