Ying-Hwa Chen

Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients

OBJECTIVE—Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeats in the promoter of human HO-1 gene has been shown to modulate gene transcription. The aim of this study was to assess the association of the length of (GT)n repeats in the HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS—We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 986 unrelated individuals who underwent coronary angiography. Serum bilirubin and markers of iron status were evaluated. RESULTS—The distribution of numbers of (GT)n repeats was divided into two subclasses: class S included shorter (<27) repeats, and class L included longer (≥27) repeats. Among those with diabetes, subjects with the L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70 ± 0.22 vs. 0.81 ± 0.24 mg/dl, P = 0.001) and higher serum ferritin values (4.76 ± 0.72 vs. 4.28 ± 1.05 μg/l for log ferritin, P = 0.001). Compared with those carrying the S allele, diabetic subjects with the L/L genotype had an almost threefold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, [95% CI 1.22–6.47], P = 0.015). With adjustment for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared. CONCLUSIONS—Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients, and this effect might be conveyed through its influence on serum bilirubin and ferritin.

Estimation of central systolic blood pressure using an oscillometric blood pressure monitor

Current noninvasive techniques for assessing central aortic pressure require the recording of an arterial pressure wave using a high-fidelity applanation tonometer. We therefore developed and validated a novel method to estimate the central aortic systolic pressure using an oscillometric blood pressure monitor alone. Invasive high-fidelity right brachial and central aortic pressure waves, and left-brachial pulse volume plethysmography from an oscillometric blood pressure monitor, were obtained at baseline and 3 min after administration of sublingual nitroglycerin in 100 patients during cardiac catheterization. In the initial 50 patients (Generation Group), Central systolic blood pressure was predicted by a multi-variate prediction model generated from the comprehensive analysis of the invasive brachial pressure wave, including brachial late-systolic shoulder pressure value and parameters related to wave reflection and arterial compliance. Another prediction model was similarly constructed from the noninvasively calibrated pulse volume plethysmography. Both models were validated in the subsequent 50 patients (Validation Group) with results: r=0.98 (P<0.001) and mean difference=0.5±4.5 (95% confidence interval −8.3 to 9.3) mm Hg for the invasive model, and r=0.93 (P<0.001) and mean difference=−0.1±7.6 (95% confidence interval −15.0 to 14.8) mm Hg for the noninvasive model. Thus, our results indicate that central aortic systolic blood pressure could be estimated by analysis of the noninvasive brachial pressure wave alone from an oscillometric blood pressure monitor.

Pulsatility of Ascending Aorta and Restenosis After Coronary Angioplasty in Patients >60 Years of Age With Stable Angina Pectoris

A recent study has demonstrated that the pulsatility of the ascending aorta is a strong predictive factor for restenosis after coronary angioplasty. However, whether the pulsatility of the ascending aorta is still a significant predictor for restenosis in elderly patients with a stiffer aorta is unknown. We investigated the relation between arterial pulsatility in the ascending aorta and restenosis after coronary angioplasty in patients aged > 60 years. Eighty-seven consecutive patients (80 men, aged 72.5 +/- 5.1 years) with stable angina were included. Before angioplasty, the arterial systolic, diastolic, and mean pressure waveforms of the ascending aorta were measured. We used fractional pulse pressure (PPf, the ratio of pulse pressure to mean pressure) and pulsatility index (PI, the ratio of pulse pressure to diastolic pressure) to estimate the pulsatility of the ascending aorta. Angiographic restenosis occurred in 39 patients. Pulse pressure, PPf, and PI were significantly higher in patients with restenosis after coronary angioplasty (restenosis vs without restenosis: pulse pressure, 77.6 +/- 12.2 vs 66.1 +/- 15.4 mm Hg [p < 0.001]; PPf, 0.80 +/- 0.09 vs 0.69 +/- 0.11 [p < 0.001]; PI, 1.19 +/- 0.20 vs 0.98 +/- 0.21 [p < 0.001]). After multivariate stepwise adjustment of risk factors of restenosis and using receiver-operating characteristic analysis, the odds ratio (OR) of restenosis was: pulse pressure > 66 mm Hg, OR 5.88 (95% confidence interval [CI] 2.17 to 15.93); PPf > 0.72, OR 13.71 (95% CI 4.81 to 39.05); PI > 1.06, OR 13.56 (95% CI 4.67 to 39.38). Moreover, among patients aged > 70 years (n = 60), the predictive values of PPf and PI were even higher than those in patients aged < or = 70 years (n = 27). Thus, in elderly patients with stable angina, the pulsatility of the ascending aorta is a powerful predictor of restenosis after coronary angioplasty.

Electron Microscopic Studies of Phenotypic Modulation of Smooth Muscle Cells in Coronary Arteries of Patients With Unstable Angina Pectoris and Postangioplasty Restenosis

BACKGROUND Proliferation and matrix protein secretion of coronary smooth muscle cells (SMCs) have been suggested as one of the mechanisms responsible for the development of postangioplasty restenosis and an alternative cause of unstable angina. Phenotypic modulation of SMCs may produce a pool of cells potentially responsive to growth stimulation that can synthesize abundant extracellular matrix. This study tested the hypothesis that phenotypic modulation of SMCs occurred during the evolution of postangioplasty restenosis and unstable angina. METHODS AND RESULTS The SMCs of coronary atherectomy specimens from 24 patients were identified under electron microscope. Volume fractions of synthetic organelles (VFSOs) and other features related to phenotypic modulation of SMCs were measured. The results showed that the VFSO in SMCs from 5 patients with unstable angina (group 2) resembled those from 9 patients with postangioplasty restenosis (group 3; 0.42 +/- 0.13 versus 0.36 +/- 0.10; P = NS), and both were significantly higher than those from 6 patients with stable angina (group 1; 0.21 +/- 0.11). Four patients with restenosis lesions who underwent angioplasty > 6 months ago (group 4) also had a low VFSO in SMCs (0.19 +/- 0.05). This value was significantly less than those in groups 2 and 3 (P < .05) but similar to that in group 1. CONCLUSIONS The coronary lesions from patients with unstable angina resembled those from patients with postangioplasty restenosis in terms of the phenotypic modulation and VFSO in SMCs. Our findings therefore suggest that after phenotypic modulation, the SMCs may become responsive to growth stimulation, with an ability to massively proliferate and synthesize abundant extracellular matrix. These processes may lead to plaque expansion and eventually to the development of unstable angina and restenosis.

Impaired forearm reactive hyperemia is related to late restenosis after coronary stenting

To investigate whether systemic endothelial function on forearm resistance vessels is related to angiographic restenosis after coronary stenting, 47 men who underwent elective coronary stenting were divided into 2 groups according to the presence (n = 20) or absence (n = 27) of in-stent restenosis 6 months after the procedure. Another 19 risk factor-matched men with normal coronary angiograms served as the control group. Forearm blood flow was assessed by venous occlusive plethysmography. Basal forearm blood flow was similar between restenosis, nonrestenosis, and control groups (2.63 +/- 0.19, 2.58 +/- 0.14, and 3.23 +/- 0.13 ml/100 ml forearm tissue per minute, respectively). In all 3 groups, forearm blood flow increased significantly during reactive hyperemia (5.75 +/- 0.7, 11. 32 +/- 1.23, and 14.52 +/- 1.36 ml/100 ml forearm tissue per minute, p <0.05, respectively) and remained unchanged after sublingual administration of nitroglycerin. The percentage change of forearm blood flow during reactive hyperemia was significantly lower in the restenosis group (117.3 +/- 18.3%) than in the nonrestenosis group (354.2 +/- 46.5%, p <0.01). This difference was still present after sublingual nitroglycerin (37.6 +/- 21.2% vs 226.4 +/- 40.5%, p <0. 01). In contrast, percentage change of hyperemic forearm blood flow was significantly lower in patients with angina (117.5 +/- 49.5%) than in those without angina (290.1 +/- 37.4%, p <0.05) at follow-up. In all patients, the angiographic loss index was correlated negatively to the percentage change of hyperemic forearm blood flow (r = -0.33, p <0.01) and positively to the percentage change of forearm vascular resistance during reactive hyperemia (r = 0.33, p <0.01). In patients with angiographic restenosis after coronary stenting, forearm reactive hyperemia was more impaired compared with those without angiographic restenosis. Systemic endothelial dysfunction might be either a marker or one of the confounding factors in the development of late restenosis after coronary stenting.

Far infra-red therapy promotes ischemia-induced angiogenesis in diabetic mice and restores high glucose-suppressed endothelial progenitor cell functions

BackgroundFar infra-red (IFR) therapy was shown to exert beneficial effects in cardiovascular system, but effects of IFR on endothelial progenitor cell (EPC) and EPC-related vasculogenesis remain unclear. We hypothesized that IFR radiation can restore blood flow recovery in ischemic hindlimb in diabetic mice by enhancement of EPCs functions and homing process.Materials and methodsStarting at 4 weeks after the onset of diabetes, unilateral hindlimb ischemia was induced in streptozotocine (STZ)-induced diabetic mice, which were divided into control and IFR therapy groups (n = 6 per group). The latter mice were placed in an IFR dry sauna at 34°C for 30 min once per day for 5 weeks.ResultsDoppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio in the thermal therapy group was significantly increased beyond that in controls, and significantly greater capillary density was seen in the IFR therapy group. Flow cytometry analysis showed impaired EPCs (Sca-1+/Flk-1+) mobilization after ischemia surgery in diabetic mice with or without IFR therapy (n = 6 per group). However, as compared to those in the control group, bone marrow-derived EPCs differentiated into endothelial cells defined as GFP+/CD31+ double-positive cells were significantly increased in ischemic tissue around the vessels in diabetic mice that received IFR radiation. In in-vitro studies, cultured EPCs treated with IFR radiation markedly augmented high glucose-impaired EPC functions, inhibited high glucose-induced EPC senescence and reduced H2O2 production. Nude mice received human EPCs treated with IFR in high glucose medium showed a significant improvement in blood flow recovery in ischemic limb compared to those without IFR therapy. IFR therapy promoted blood flow recovery and new vessel formation in STZ-induced diabetic mice.ConclusionsAdministration of IFR therapy promoted collateral flow recovery and new vessel formation in STZ-induced diabetic mice, and these beneficial effects may derive from enhancement of EPC functions and homing process.

Estimation of central aortic systolic pressure from the second systolic peak of the peripheral upper limb pulse depends on central aortic pressure waveform morphology

Background: Direct identification of second systolic peaks of peripheral upper limb pulses (pSBP2) has been used to represent central systolic blood pressure (cSBP), but its accuracy at low SBP was questioned. Objectives: We investigated the relationship of pSBP2 with characteristics of central pressure waveforms. Methods: High-fidelity central aortic and right brachial pressure waveforms were simultaneously recorded using a custom-made dual pressure sensor catheter in 78 patients (65.9 ± 12.9 years) during catheterization for 285 measurements. Results: Overall agreement between cSBP and pSBP2 was good (mean difference −0.9 ± 4.8, r = 0.98), with a systematic bias at low SBP. We examined agreements of different waveform types according to the relationship of the second systolic peak of aortic pressure waveforms (cSBP2) to cSBP. Of type A (positive late systolic augmentation) and type B (zero augmentation) aortic pressure waveforms, in which cSBP = cSBP2, agreement between pSBP2 and cSBP was excellent (mean difference −0.4 ± 4.1, r = 0.99). There were 40 type C aortic pressure waveforms (negative augmentation; cSBP > cSBP2) with cSBP 107.2 ± 13.9 mmHg. Their cSBP2, compared with cSBP, showed closer agreement (mean difference −0.6 ± 3.2 vs. −4.0 ± 7.2 mmHg) and better correlation (r = 0.97 vs. 0.85, P = 0.03) with pSBP2. Conclusion: pSBP2 can be used with type A and B aortic pressure waveforms for estimation of cSBP. However, it should not be used with type C aortic pressure waveforms, typically at low SBP, because pSBP2 is closer to cSBP2 than cSBP. This explains why pSBP2 underestimates cSBP at low SBP.

Comparison of the predictive value of EuroSCORE, SYNTAX score, and clinical SYNTAX score for outcomes of patients undergoing percutaneous coronary intervention for unprotected left main coronary artery disease†

Objectives: We aimed to assess the prognostic values of the EuroSCORE, SYNTAX score, and the novel Clinical SYNTAX score (CSS) for 30‐day and 1‐year outcomes in patients undergoing left main (LM) percutaneous coronary intervention (PCI). Background: PCI has become an alternative treatment for LM coronary artery disease, and risk scoring system might be beneficial for pre‐PCI risk stratification. Methods and Results: We enrolled 198 consecutive patients with unprotected LM disease undergoing PCI (mean age 71.5 ± 10.7 years). The CSS was calculated by multiplying the SYNTAX Score to (age/left ventricular ejection fraction +1 for each 10 mL the estimated glomerular filtration rate <60 mL/min per 1.73 m2). The endpoints were 30‐day, and 1‐year all‐cause death and major adverse cardiovascular events (MACE), which were defined as all‐cause death, nonfatal MI, and clinical‐driven target vessel revascularization. Comparing with the SYNTAX score, the predictive accuracy of CSS for 30‐day and 1‐year all‐cause death and MACE were significantly higher (c‐statistics, CSS versus SYNTAX score: P < 0.01 for 30‐day and 1‐year all‐cause death; P < 0.05 for 30‐day and 1‐year MACE, respectively). Furthermore, in the multivariate Cox regression analysis, both EuroSCORE and CSS were identified as the independent predictors of 30‐day and 1‐year all‐cause death and MACE, but the SYNTAX score was not. Conclusions: In the general practice among a high‐risk population undergoing LM PCI, EuroSCORE and CSS might be independent predictors for 30‐day and 1‐year all‐cause death and MACE. Furthermore, the CSS had a superior discriminatory ability in predicting the 30‐day and 1‐year clinical outcomes comparing with the SYNTAX score.

Application of the Sequential Organ Failure Assessment score for predicting mortality in patients with acute myocardial infarction

BACKGROUND Thrombolysis in Myocardial Infarction (TIMI) score and Global Registry of Acute Coronary Events (GRACE) score have been validated as predictors of death in patients with acute myocardial infarction (AMI). This study was undertaken to determine whether the Sequential Organ Failure Assessment (SOFA) score had good accuracy for predicting mortality in AMI patients, and to compare the discriminatory performance of the 3 risk scores (RSs). METHODS This was a retrospective study. We calculated the TIMI RS, GRACE RS, and SOFA score for 726 consecutive AMI patients. The study endpoint was all-cause mortality. All patients were followed up for at least 3 years or until the occurrence of death. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive ability of each score at different time points. RESULTS For in-hospital death, the AUC were 0.67 for TIMI RS, 0.73 for GRACE RS, and 0.79 for SOFA score (P<0.001, respectively). However, the SOFA score and GRACE RS were significantly better for predicting the 1-year (P<0.001, respectively) and 3-year (P<0.001, respectively) mortality than the TIMI RS was. Multivariate Cox regression analysis revealed that the SOFA score was an independent predictor of long-term mortality in AMI patients [hazard ratio (HR), 1.313; 95% CI, 1.191-1.447]. CONCLUSIONS The SOFA score provides potentially valuable prognostic information on clinical outcome when applied to patients with AMI. Compared with TIMI RS, both SOFA score and GRACE RS provide better discrimination for long-term mortality in patients presenting with AMI.

Anti-inflammatory strategies for homocysteine-related cardiovascular disease.

Homocysteine may induce vascular damage for atherosclerosis. Vitamin/folate supplementation has been proposed to reduce the cardiovascular disease risk. Nevertheless, there is no randomized clinical trial clearly proving the efficacy of reducing the homocysteine as a means of lowering the incidence of cardiovascular disease. Homocysteine induces oxidative stress leading to endothelial dysfunction. In addition, homocysteine-induced oxidative stress favors lipid peroxidation and induces production of inflammatory factors, thus accelerating atherosclerosis. In this paper, we reviewed the available evidence concerning the association between homocysteine and cardiovascular disease, with the objective of discussing the pertinence of screening, treatment, and prevention of hyperhomocysteinemia-related cardiovascular disease. Our previous findings also indicated the significant role of mononuclear cells activation in homocysteine-induced endothelial dysfunction; treatment with statins attenuated homocysteine-induced endothelial adhesiveness, indicating the novel endothelial protection effects of statins in the presence of homocysteine. Since inflammation and oxidative stress are critical to homocysteine-induced vascular damage, the improvement of endothelial dysfunction and the inhibition of mononuclear cell activation by anti-inflammatory and/or antioxidative drugs/agents may serve as the potential therapeutic strategy for hyperhomocysteinemia-related cardiovascular disease.