Chii-Ming Lee

The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis

It is not clear to what extent methylenetetrahydrofolate reductase (MTHFR) gene and hyperhomocysteinemia effect the severity and extent of coronary atherosclerosis in Asian populations. We examined the MTHFR genotypes and plasma homocysteine (HCY) concentrations in 192 Taiwanese and investigated their relationship with coronary artery disease (CAD), and the severity and extent of coronary atherosclerosis. The distribution of MTHFR genotypes was similar in 116 CAD patients and 76 non-CAD subjects. Homozygosity was noted in 8% of CAD patients and 13% of non-CAD subjects (P=0.33; 95% CI, 0. 2-1.6). The geometric mean of HCY values was higher in CAD patients (11.10+/-1.51 micromol/l) than in non-CAD subjects (9.21+/-1.55 micromol/l) (P=0.003). HCY levels were higher in patients with multi-vessel disease (P<0.05) or in patients with > or = 90% stenotic lesions (P=0.005), compared with non-CAD subjects. The CAD risks in the top two HCY quartiles (> or = 14.0 and 10.1-13.9 micromol/l) were 4.0 (95% CI, 1.7-9.2) and 3.2 (95% CI, 1.4-7.4) times higher than in the lowest quartile (< or = 7.9 micromol/l) (P=0.001 and 0.007, respectively). Linear regression analysis showed significant correlations between HCY concentrations and the severity and extent of atherosclerosis (P=0.0001 for both). In conclusion, hyperhomocysteinemia appears to have a graded effect on the risk of CAD as well as the severity and extent of coronary atherosclerosis. Our findings do not support the homozygous genotype of MTHFR as a genetic risk factor for CAD in this Taiwanese population. Perhaps a further study including assessment of vitamin status is needed to better clarify the relationship between MTHFR genotypes and CAD.

Homocysteine inhibits arterial endothelial cell growth through transcriptional downregulation of fibroblast growth factor-2 involving G protein and DNA methylation

Homocysteine (Hcy) contributes to atherogenesis and angiostasis by altering the phenotype of arterial endothelial cells (ECs). The present study was aimed at elucidating potential mechanisms by which Hcy can slow EC proliferation and induce EC apoptosis, thereby disrupting endothelial integrity. Given the strong mitogenic and antiapoptotic properties of fibroblast growth factor (FGF)2, we examined whether Hcy can modulate its expression. In cultured human coronary and bovine aortic ECs, Hcy exerted time- and concentration-dependent (0 to 500 &mgr;mol/L) reduction of the mRNA and protein levels of FGF2, whereas vascular endothelial growth factor expression was not affected until Hcy reached a proapoptotic 500 &mgr;mol/L. By testing a panel of signal transduction inhibitors, we found that the Hcy-induced downregulation of FGF2 was specifically attenuated by pertussis toxin, an inhibitor of Gi protein signaling. Hcy induced cell cycle arrest at the G1/S transition and increased TUNEL-positive apoptotic cells in a graded manner. These effects were effectively counteracted by exogenous FGF2. Reporter gene assays showed that Hcy downregulated FGF2 by transcriptional repression of the gene promoter encompassed in a CpG dinucleotide-rich island. This region was heavily methylated at the cytosine residues by Hcy despite decreased methylation potential (S-adenosylmethionine to S-adenosylhomocysteine ratio). Normal levels of FGF2 transcription were restored to ECs simultaneously exposed to Hcy and 5-aza-deoxycytidine. We conclude that homocysteine disrupts the growth and survival of ECs through a G protein–mediated pathway associated with altered promoter DNA methylation and the transcriptional repression of FGF2.

Home-based exercise increases exercise capacity but not quality of life in people with chronic heart failure: a systematic review

QUESTIONS Does home-based exercise improve exercise capacity and quality of life in people with chronic heart failure? Is it safe? DESIGN Systematic review with meta-analysis. PARTICIPANTS Adults with heart failure > 3 months duration. INTERVENTION Home-based aerobic exercise with or without resistance exercise. OUTCOME MEASURES Exercise capacity (measured at the impairment level by peak VO2 and at the activity level by 6-min Walk Test), quality of life (measured by disease-specific scales), and adverse events (measured as death, hospitalisation). RESULTS 10 randomised controlled trials with 648 participants of New York Heart Association Class II or III were included. Most participants were male > or = 50 years old with an ejection fraction < or = 40%. The exercise programs ranged from 6 weeks to 9 months at low to moderate intensity (40-70% of maximum heart rate or heart rate at 70% peak VO2. Home-based exercise increased 6-min walking distance by 41 m (WMD, 95% CI 19 to 63) and peak VO2 by 2.71 ml/kg/min (WMD, 95% CI 0.67 to 4.74) more than usual activity. It did not improve scores on the Minnesota Heart Failure Questionnaire (WMD 0.5 points out of 105, 95% CI -4.4 to 5.4) or increase the odds of hospitalisation (OR 0.75, 95% CI 0.19 to 2.92) more than usual activity. CONCLUSIONS Home-based exercise increased exercise capacity safely but did not improve quality of life in patients with chronic heart failure. It could therefore be used to improve the management of people with chronic heart failure who do not have access to hospital-based exercise.

Prostaglandin E2 Potentiates Mesenchymal Stem Cell–Induced IL-10+IFN-γ+CD4+ Regulatory T Cells To Control Transplant Arteriosclerosis

Mesenchymal stem cells (MSCs) are known for their immunomodulatory functions. We previously demonstrated that bone marrow–derived MSCs effectively control transplant arteriosclerosis (TA) by enhancing IL-10+ and IFN-γ+ cells. The objective of this study is to elucidate the mechanism by which MSCs induce IL-10+IFN-γ+CD4+ regulatory T type 1 (TR1)–like cells. In an MLR system using porcine PBMCs, MSC-induced IL-10+IFN-γ+CD4+ cells, which confer resistance to allogeneic proliferation in an IL-10–dependent manner, resemble TR1-like cells. Both cyclooxygenase-derived PGE2 and IDO help to induce TR1-like cells by MSCs. MSCs constitutively secrete PGE2, which is augmented in allogeneic reactions. However, TR1-like cells were deficient in PGE2 and 4-fold less potent than were MSCs in suppressing MLR. PGE2 mimetic supplements can enhance the immunosuppressive potency of TR1-like cells. In a porcine model of allogeneic femoral arterial transplantation, MSC-induced TR1-like cells combined with PGE2, but not either alone, significantly reduced TA at the end of 6 wk (percentage of luminal area stenosis: TR1-like cells + PGE2: 11 ± 10%; PGE2 alone: 93 ± 8.7%; TR1-like cells alone: 88 ± 2.4% versus untreated 94 ± 0.9%, p < 0.001). These findings indicate that PGE2 helps MSC-induced IL-10+IFN-γ+CD4+ TR1-like cells inhibit TA. PGE2 combined with MSC-induced TR1-like cells represents a new approach for achieving immune tolerance.

Low incidence of transplant coronary artery disease in chinese heart recipients

OBJECTIVES This study sought to assess the incidence of transplant coronary artery disease (CAD) in Chinese heart recipients. BACKGROUND The prevalence of transplant CAD detected by angiography at 1, 2 and 4 years after heart transplantation was 11%, 22% and 45%, respectively. The incidence of transplant CAD in Chinese heart recipients has not been reported. METHODS For those recipients surviving for more than 1 year after transplantation, coronary angiography was performed annually for surveillance of transplant CAD. The recipient characteristics, donor characteristics, rejection episodes, medication and human leukocyte antigen (HLA) mismatches were recorded. RESULTS Fifty patients were included in this study. Thirteen (26%) recipients had ischemic heart disease. Two patients (4%) had active cytomegalovirus (CMV) infection after transplantation. The mean number of rejection episodes in the 1st year after transplantation was 1.15. Among 47 patients with complete data of donor and recipient histocompatibility antigens, there were seven patients (14.9%) with two or fewer HLA mismatches. Among 74 angiograms of 50 patients reviewed, only one patient had discrete stenosis less than 50% in the middle portion of the left anterior descending artery at 1 year after transplantation. The cumulative incidence of transplant CAD was 2% at 1 year and 2% at 2 and 4 years after transplantation. CONCLUSIONS The incidence of transplant CAD was low in Chinese heart transplant recipients. Low percentage of ischemic heart disease in recipients, low occurrence of active CMV infection and rejection episodes after transplantation, less racial disparity, and lower HLA mismatches may be the important factors.

PET Assessment of Myocardial Perfusion Reserve Inversely Correlates with Intravascular Ultrasound Findings in Angiographically Normal Cardiac Transplant Recipients

Cardiac allograft vasculopathy (CAV) is the major determinant of long-term survival after heart transplantation. We aimed to evaluate the efficacy of PET as a noninvasive way to assess the early stages of CAV. Methods: Twenty-seven consecutive patients (20 men and 7 women; mean age ± SD, 46 ± 12 y) who had normal results on coronary angiography and normal left ventricular systolic function (ejection fraction ≥ 60%) were enrolled at 2.5 ± 2.1 y after transplantation. Myocardial blood flow (MBF) was assessed using dynamic 13N-ammonia PET at rest and during adenosine-induced hyperemia, and myocardial perfusion reserve (MPR) was calculated as the ratio of hyperemic MBF to resting MBF. Regional 13N-ammonia PET was assessed using a 5-point scoring system. The intravascular ultrasound (IVUS) measurements for the extent of intimal hyperplasia, including plaque volume index (calculated as [total plaque volume/total vessel volume] × 100%) and maximum area of stenosis, were compared with MPR by linear regression analysis. Results: In 27 angiographically normal cardiac transplant recipients, MBF at rest and during adenosine stress and MPR of the left anterior descending artery distribution correlated strongly with the other 2 coronary artery distribution territories (r ≥ 0.97, P < 0.0001). Summed stress score and summed difference score showed a moderate inverse correlation with MPR (r = −0.41 and −0.49, respectively; P < 0.05) but not with IVUS measurements. MPR correlated inversely with plaque volume index (r = −0.40, P < 0.05) but not with maximal luminal stenosis as assessed by IVUS. In addition, MPR and IVUS measurements gradually inversely changed after heart transplantation (all P < 0.05). Conclusion: This study confirms that CAV is a progressive process, diffusely involving the epicardial and microvascular coronary system. Plaque burden as determined by IVUS agrees well with MPR as assessed by PET in recipients with normal coronary angiography results. This finding suggests that dynamic 13N-ammonia PET is clinically feasible for the early detection of CAV and can be used as a reliable marker of disease progression.

Dyslipidemias Have a Detrimental Effect on Left Ventricular Systolic Function in Patients With a First Acute Myocardial Infarction

Several large-scale clinical trials have shown that lipid-lowering interventions are associated with reduced coronary events and mortality. However, whether dyslipidemias have a detrimental effect on the evolution of myocardial infarction (MI) is still unknown. To examine whether dyslipidemias can aggravate myocardial vulnerability following MI, 165 patients with a first MI were studied. All patients underwent measurements of serum lipid profiles 1 week and 3 months after MI, a radionuclide ventriculographic study, and a coronary angiographic study. The patients were divided into 3 groups according to their 3-month serum cholesterol levels (group 1, <200 mg/dl; group 2, 200 to 240 mg/dl; group 3, >240 mg/dl). Groups 1, 2, and 3 consisted of 66, 59, and 40 patients, respectively. Group 3 had a higher Gensini score than groups 1 and 2, although this was not statistically significant (p = 0.13). The postinfarct left ventricular ejection fraction (LVEF) was highest in group 1 (53 +/- 13%), at mid level in group 2 (43 +/- 14%), and lowest in group 3 (35 +/- 11%) (p < 0.0001). A significant negative correlation between 3-month low-density lipoprotein (LDL) cholesterol (r = -0.55, p < 0.0001) and the postinfarct LVEF was found. The product of peak creatine kinase (CK(MAX)) and time to CK(MAX) (p = 0.001), and patency of the infarct-related artery (p = 0.009), rather than variables of coronary atherosclerosis, were also independent predictors of the postinfarct LVEF. Increases in 1-week LDL cholesterol and decreases in 1-week high-density lipoprotein cholesterol were associated with a higher CK(MAX) and a lower patency rate of the infarct-related artery, respectively. This study revealed that dyslipidemias per se, especially LDL cholesterol, had a detrimental effect on the postinfarct LVEF; this effect might be independent of the atherogenic properties of dyslipidemias.

Autologous mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-γ, and indoleamine 2,3-dioxygenase.

Transplant arteriosclerosis (TA) remains the major limitation of long-term graft survival in heart transplantation despite the advances in immunosuppressants. Mesenchymal stem cells (MSCs) have been demonstrated to suppress allogeneic immune responses by numerous in vitro studies. However, the immunomodulatory effects of MSCs in vivo are controversial and the underlying molecular mechanisms are not conclusive. In this study, we investigated the therapeutic potential of autologous bone marrow-derived MSCs on TA in a porcine model of femoral artery transplantation. MSCs or saline were injected into the soft tissue surrounding the arterial grafts immediately postanastomosis. Four weeks after transplantation, neointimal formation increased significantly in untreated allografts compared with the MSC-treated grafts as assessed by intravascular ultrasound (maximum luminal area stenosis: 40 ± 12% vs. 18 ± 6%, p < 0.001). Grafts harvested at 4 weeks showed dense perivascular lymphocyte infiltration accompanied by significant intimal hyperplasia in the untreated but not in the MSC-treated allografts. Serial angiographic examination showed that all of the untreated allografts became occluded at the 8th week whereas the majority of the MSC-treated grafts remained patent at the 12th week posttransplantation (n = 12 each group, p < 0.001). Quantitative PCR analysis revealed that Foxp3 expression was comparable between the untreated and the MSC-treated groups. However, expression of interleukin-10 (IL-10), interferon-γ (IFN-γ), and indoleamine 2,3-dioxygenase (IDO) was increased significantly in the MSC-treated allografts compared with that in the allograft controls (p = 0.021 for IL-10, p = 0.003 for IFN-γ, and p = 0.008 for IDO). In conclusion, local delivery of autologous MSCs alleviates TA by inducing allograft tolerance via enhanced expression of IL-10, IFN-γ, and IDO but not Foxp3-positive cells in the vessel wall. These results suggest that MSCs induce immune tolerance by activating the type 1 regulatory T-like cells.

Effectiveness of a self-care program in improving symptom distress and quality of life in congestive heart failure patients: a preliminary study.

Background:Prevalence of heart failure is increasing among older adults. Most heart failure patients experience distressing symptoms that lead to decreased physical functioning, poor quality of life, and a high incidence of rehospitalization. Health education about heart failure self-care (HFSC) is very important during hospitalization for these patients. However, lack of ongoing follow-up after discharge makes evaluation and disease management difficult. This is a significant problem in Taiwan. Purpose:This study was undertaken to determine if participants with heart failure who were managed under the HFSC program had fewer distressing symptoms, better functional status, improved quality of life, and reduced hospital and emergency readmission rates compared with control group participants. Methods:This study used a quasi-experimental design with a control group that received usual care and an intervention group that received usual care plus the HFSC program. Twenty-seven participants were recruited from 2 cardiac general wards at 1 medical center in Taipei City, Taiwan, and were randomized into intervention (n = 14) and control (n = 13) groups. Results:After 3 months, there were significant differences in symptom distress (p < .01), 6-minute walk test results (p < .01), and quality of life (using Short Form 36, Taiwan version, p < .05) between the HFSC and control groups but no significant differences in hospital readmission and emergency department visits. Conclusions/Implications for Practice:The HFSC program for patients with heart failure improved their heart failure symptoms and resulted in increased functional status and better quality of life. HFSC is a workable program in the clinical environment. Advanced nurse practitioners can use HFSC methods and principles to provide improved education and follow-up to heart failure patients.

The effects of dyslipidemia on left ventricular systolic function in patients with stable angina pectoris

Large-scale clinical trials have shown that long-term treatment with lipid-lowering therapy results in a significant reduction in the occurrence of heart failure among patients with coronary artery disease without previous evidence of congestive heart failure, suggesting dyslipidemia may have an adverse effect on left ventricular performance. To examine whether dyslipidemia has a detrimental effect on left ventricular systolic function and whether this effect is dependent on the corresponding severity of coronary atherosclerosis, 114 consecutive patients with stable angina and a positive exercise thallium-201 myocardial perfusion single-photon emission computed tomography were studied. All patients underwent measurement of serum lipid profiles, right-sided heart catheterization, left ventriculography, and selective coronary arteriography. Mean serum levels of total cholesterol and triglycerides were 4.5 and 1.4 mmol/l, respectively. In univariate analysis, a significant positive correlation between serum high-density lipoprotein (HDL) cholesterol and left ventricular ejection fraction (LVEF) (r = 0.49, P<0.0001) was found. Patients in the lower tertile of serum HDL cholesterol had a significantly lower mean LVEF than those in the upper tertile (55.9+/-15.2 vs. 72.8+/-6.8%, P<0.0001). Stepwise multiple linear regression analysis revealed that LVEF significantly correlated with HDL cholesterol (P<0.0001), the Gensini score (P = 0.008), and diabetes mellitus (P = 0.08) (r = 0.55, P<0.0001). In subgroup analysis of patients with angiographically normal coronary arteries, serum HDL cholesterol was still significantly associated with LVEF. The present study demonstrated an independent association between low HDL cholesterol and subclinical left ventricular systolic dysfunction in Chinese patients with stable angina whose serum levels of total cholesterol and triglycerides were relatively low. Moreover, this correlation remained significant even in patients with normal coronary angiograms, suggesting HDL cholesterol might influence left ventricular systolic performance through extra-atherosclerotic mechanisms.