Seok-Jae Hwang

Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia

AIMS Inflammation, and the subsequent proliferative activity of vascular smooth muscle cells (VSMCs), is one of the major pathophysiological mechanisms associated with neointimal hyperplasia following vascular injury. Although sulfasalazine (SSZ) has been used as an anti-inflammatory and immune-modulatory agent in various inflammatory diseases, its primary targets and therapeutic effects on vascular disease have not yet been determined. We investigated whether SSZ could suppress VSMC growth and prevent neointimal hyperplasia. METHODS AND RESULTS SSZ was found to have pro-apoptotic and anti-proliferative activity in cultured VSMCs. Unexpectedly, these effects were not mediated by nuclear factor kappa B (NF-kappaB) inhibition, which has been suggested to be the anti-inflammatory mechanism associated with the effects of SSZ. Instead, cell-cycle arrest of the VSMCs was observed, which was mediated by induction of haem oxygenase-1 (HO-1) followed by an increased expression of p21(waf1/Cip1). The underlying mechanism for SSZ-induced HO-1 expression was by reactive oxygen species (ROS)-dependent nuclear translocation and activation of nuclear factor erythroid-2-related factor 2 (Nrf2). In a rat carotid artery balloon injury model, administration of SSZ significantly suppressed neointimal growth. In a series of reverse experiments, inhibition of HO-1 by shRNA, ROS by N-acetylcysteine (NAC) or Nrf2 by dominant-negative Nrf2 abrogated the beneficial effects of SSZ. CONCLUSION Our data demonstrate that SSZ inhibits VSMC proliferation in vitro and in vivo through a novel signalling pathway and may be a promising therapeutic option for the treatment of proliferative vascular disease.

Enhanced Pulmonary Vasodilator Reserve and Abnormal Right VentricularCLINICAL PERSPECTIVE

Background— Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results— In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV d P /d t max/IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P <0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions— Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration— URL: . Unique identifier: [NCT01418248][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01418248&atom=%2Fcirchf%2F8%2F3%2F542.atomBackground—Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during &bgr;-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results—In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV dP/dtmax/IP and s′) and diastolic function (higher RV &tgr;) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P<0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions—Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to &bgr;-adrenergic stimulation in HFpEF than controls, suggesting a potential role for &bgr;-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01418248.

Prognostic value of total triiodothyronine and free thyroxine levels for the heart failure in patients with acute myocardial infarction

Background/Aims Although a low triiodothyronine (T3) state is closely associated with heart failure (HF), it is uncertain whether total T3 levels on admission is correlated with the clinical outcomes of acute myocardial infarction (AMI). The aim of this study is to investigate the prognostic value of total T3 levels for major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with AMI undergone percutaneous coronary intervention (PCI). Methods A total of 765 PCI-treated AMI patients (65.4 ± 12.6 years old, 215 women) between January 2012 and July 2014 were included and 1-year MACCEs were analyzed. We assessed the correlation of total T3 and free thyroxine (fT4) with prevalence of 1-year MACCEs and the predictive values of total T3, fT4, and the ratio of total T3 to fT4 (T3/fT4), especially for HF requiring re-hospitalization. Results Thirty patients (3.9%) were re-hospitalized within 12 months to control HF symptoms. Total T3 levels were lower in the HF group than in the non-HF group (84.32 ± 21.04 ng/dL vs. 101.20 ± 20.30 ng/dL, p < 0.001). Receiver operating characteristic curve analysis showed the cut-offs of total T3 levels (≤ 85 ng/dL) and T3/fT4 (≤ 60) for HF (area under curve [AUC] = 0.734, p < 0.001; AUC = 0.774, p < 0.001, respectively). In multivariate analysis, lower T3/fT4 was an independent predictor for 1-year HF in PCI-treated AMI patients (odds ratio, 1.035; 95% confidential interval, 1.007 to 1.064; p = 0.015). Conclusions Lower levels of total T3 were well correlated with 1-year HF in PCI-treated AMI patients. The T3/fT4 levels can be an additional marker to predict HF.

Prognostic value of brachial-ankle pulse wave velocity in patients with non-st-elevation myocardial infarction

Objective Brachial-ankle pulse wave velocity (baPWV) measurement is a well-established modality for assessing arterial stiffness and predicting cardiovascular events. However, to our knowledge, its usefulness has not been clarified among patients with non-ST-elevation myocardial infarction (NSTEMI). This study assessed the prognostic value of baPWV in patients with NSTEMI. Patients and methods Patients (n=411, mean age, 63.8±13.5 years, 75.2% men) with NSTEMI who underwent a percutaneous coronary intervention and baPWV measurement were recruited between January 2013 and December 2015. Cardiac mortality and major adverse cardiovascular events (MACE) including cardiac death, re-acute myocardial infarction, revascularization, heart failure, and stroke after discharge were analyzed. The mean follow-up duration was 350 days. Results MACE and cardiac mortality occurred in 26 (6.3%) patients and 13 (3.1%) patients. Kaplan–Meier survival curves showed that MACE and cardiac mortality were significantly higher in patients with high baPWV (1708.0 cm/s). In multivariable Cox regression analysis, high baPWV (hazard ratio: 2.55; 95% confidence interval: 1.03–6.30, P=0.043) was an independent predictor of MACE even after adjusting for possible confounders. Conclusion Our findings indicate that baPWV was a strong independent prognostic factor of MACE in patients with NSTEMI. This suggests that baPWV can be a useful prognostic factor in the clinical setting for easier and less invasive prediction of MACE in patients with NSTEMI.

Prognostic value of computed tomographic coronary angiography and exercise electrocardiography for cardiovascular events

Background/Aims: This study is a head-to-head comparison of predictive values for long-term cardiovascular outcomes between exercise electrocardiography (ex-ECG) and computed tomography coronary angiography (CTCA) in patients with chest pain. Methods: Four hundred and forty-two patients (mean age, 56.1 years; men, 61.3%) who underwent both ex-ECG and CTCA for evaluation of chest pain were included. For ex-ECG parameters, the patients were classified according to negative or positive results, and Duke treadmill score (DTS). Coronary artery calcium score (CACS), presence of plaque, and coronary artery stenosis were evaluated as CTCA parameters. Cardiovascular events for prognostic evaluation were defined as unstable angina, acute myocardial infarction, revascularization, heart failure, and cardiac death. Results: The mean follow-up duration was 2.8 ± 1.1 years. Fifteen patients experienced cardiovascular events. Based on pretest probability, the low- and intermediate-risks of coronary artery disease were 94.6%. Odds ratio of CACS > 40, presence of plaque, coronary stenosis ≥ 50% and DTS ≤ 4 were significant (3.79, p = 0.012; 9.54, p = 0.030; 6.99, p < 0.001; and 4.58, p = 0.008, respectively). In the Cox regression model, coronary stenosis ≥ 50% (hazard ratio, 7.426; 95% confidence interval, 2.685 to 20.525) was only significant. After adding DTS ≤ 4 to coronary stenosis ≥ 50%, the integrated discrimination improvement and net reclassification improvement analyses did not show significant. Conclusions: CTCA was better than ex-ECG in terms of predicting long-term outcomes in low- to intermediate-risk populations. The predictive value of the combination of CTCA and ex-ECG was not superior to that of CTCA alone.

Cardiac arrest due to coronary embolism from a metastatic sarcoma recovered through aspiration thrombectomy

Coronary embolism in patients with metastatic cancer is an uncommon cause of acute myocardial infarction (1,2). Aspiration thrombectomy becomes necessary in specific conditions, especially in cases of large thrombus or coronary embolism. Some cases of cancer embolism, with restoration of coronary flow through percutaneous coronary intervention (PCI) using aspiration thrombectomy were reported in the literature (3,4). We report on a rare and lethal case of cardiac arrest due to acute myocardial infarction owing to coronary embolism. Coronary flow was restored and histologic confirmation was made after removal of emboli via aspiration thrombectomy.

TICAGRELOR VERSUS CLOPIDOGREL IS ASSOCIATED WITH BETTER RECOVERY OF LV FUNCTION AFTER ACUTE MYOCARDIAL INFARCTION

Background: Recovery of LV function following AMI is associated with the risk of long-term CV mortality and CHF progression. We sought to evaluate the predictors of recovery of LV function in AMI patients. Methods: AMI patients treated with uneventful PCI were prospectively enrolled (n=224). At 30-

Enhanced Pulmonary Vasodilator Reserve and Abnormal Right Ventricular

Background— Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results— In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV d P /d t max/IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P <0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions— Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration— URL: . Unique identifier: [NCT01418248][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01418248&atom=%2Fcirchf%2F8%2F3%2F542.atomBackground—Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during &bgr;-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results—In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV dP/dtmax/IP and s′) and diastolic function (higher RV &tgr;) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P<0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions—Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to &bgr;-adrenergic stimulation in HFpEF than controls, suggesting a potential role for &bgr;-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01418248.

Enhanced Pulmonary Vasodilator Reserve and Abnormal Right VentricularCLINICAL PERSPECTIVE: Pulmonary Artery Coupling In Heart Failure With Preserved Ejection Fraction

Background— Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results— In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV d P /d t max/IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P <0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions— Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration— URL: . Unique identifier: [NCT01418248][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01418248&atom=%2Fcirchf%2F8%2F3%2F542.atomBackground—Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during &bgr;-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results—In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV dP/dtmax/IP and s′) and diastolic function (higher RV &tgr;) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P<0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions—Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to &bgr;-adrenergic stimulation in HFpEF than controls, suggesting a potential role for &bgr;-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01418248.