2016 Consensus statement on prevention of atherosclerotic cardiovascular disease in the Hong Kong population.

INTRODUCTION: In Hong Kong, the prevalence of atherosclerotic cardiovascular disease has increased markedly over the past few decades, and further increases are expected. In 2008, the Hong Kong Cardiovascular Task Force released a consensus statement on preventing cardiovascular disease in the Hong Kong population. The present article provides an update on these recommendations. PARTICIPANTS: A multidisciplinary group of clinicians comprising the Hong Kong Cardiovascular Task Force-10 cardiologists, an endocrinologist, and a family physician-met in September 2014 and June 2015 in Hong Kong. EVIDENCE: Guidelines from the American College of Cardiology/American Heart Association, the European Society of Hypertension/European Society of Cardiology, and the Eighth Joint National Committee for the Management of High Blood Pressure were reviewed. CONSENSUS PROCESS: Group members reviewed the 2008 Consensus Statement and relevant international guidelines. At the meetings, each topical recommendation of the 2008 Statement was assessed against the pooled recommendations on that topic from the international guidelines. A final recommendation on each topic was generated by consensus after discussion. CONCLUSIONS: It is recommended that a formal risk scoring system should be used for risk assessment of all adults aged 40 years or older who have at least one cardiovascular risk factor. Individuals can be classified as having a low, moderate, or high risk of developing atherosclerotic cardiovascular disease, and appropriate interventions selected accordingly. Recommended lifestyle modifications include adopting a healthy eating pattern; maintaining a low body mass index; quitting smoking; and undertaking regular, moderate-intensity physical activity. Pharmacological interventions should be selected as appropriate after lifestyle modification.

Subclinical atrial fibrillation and the risk of stroke.

BACKGROUND: One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation. METHODS: We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. RESULTS: By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P=0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. CONCLUSIONS: Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT ClinicalTrials.gov number, NCT00256152.).

Fish-oil supplement has neutral effects on vascular and metabolic function but improves renal function in patients with Type 2 diabetes mellitus.

AIMS: Increased dietary fish-oil consumption is associated with a reduced risk of coronary heart events and has pronounced effects on dyslipidaemia. However, the effects of fish-oil supplement on vascular function and metabolic profile in patients with Type 2 diabetes mellitus (DM) are unclear. METHODS: In a double-blind placebo-controlled trial, we randomized 97 Type 2 DM patients without prior cardiovascular disease to fish-oil (4 g/day, n = 49) or olive-oil (with equivalent calories, as placebo, n = 48) supplements for 12 weeks. Assessment of vascular function with brachial artery flow-mediated dilation (FMD) and circulating levels of endothelial progenitor cells (EPCs), and metabolic parameters, high-sensitivity C-reactive protein (hsCRP), oxidative stress markers and renal function were examined before and after the supplement. RESULTS: Despite a significant reduction in serum triglycerides (-0.47 mmol/l, P < 0.01), 12-week supplement of fish oil did not improve vascular function as determined by FMD (+0.16%, P = 0.83) and circulating EPC count (+4 cells/microl, P = 0.78). Furthermore, fish-oil supplement did not have any significant treatment effects on hsCRP, oxidative stress, low- and high-density lipoprotein and glycated haemoglobin (HbA(1c)) (all P > 0.05). In contrast, serum creatinine was lower (-4.5 micromol/l, P = 0.01) in fish-oil-treated patients as compared with control subjects. CONCLUSIONS: This study demonstrated that 12 weeks of fish-oil supplement had no significant beneficial effect on vascular endothelial function, but improved renal function without changes in endothelial function, metabolic profiles, blood pressure, inflammation or oxidative stress in patients with Type 2 DM.

Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the prevalence and pattern of arterial calcification in patients with rheumatoid arthritis (RA). BACKGROUND: Patients with RA are prone to premature atherosclerosis; nonetheless the prevalence and extent of atherosclerosis in different vascular beds and their relationship to each other remain unknown. METHODS: We studied the distribution and extent of arterial calcification in 85 RA patients and 85 age-and sex-matched controls. Arterial calcification as determined by calcium score (CS) were measured using multi-detector computed tomography in thoracic aorta, coronary and carotid arteries. RESULTS: Compared with controls, RA patients had a significantly higher average CS and prevalence of CS > 0 in aorta, coronary and carotid arteries and overall arteries (all P < 0.05). After adjusting for age and sex, RA patients had a significantly higher relative risk of developing calcification in the aorta [Odds Ratio (OR) = 19.5, 95% Confidence Interval (CI): 8.0-47.6], followed by the carotid arteries (OR = 5.7, 95% CI:1.7-18.7) and coronary arteries (OR = 5.0, 95% CI:2.2-11.1) compared with controls (all P < 0.01). Amongst RA patients aged >60, 90% had diffuse arterial calcification, especially over the thoracic aorta, compared with 55% of controls who had arterial calcification clustered in the coronary arteries (P < 0.05). RA patients with total CS > 0 were older with a higher urea level and C-reactive protein than those without arterial calcification, no factor was found to be independently predictive for arterial calcification (all P > 0.05). CONCLUSIONS: Our results demonstrated that RA patients had earlier onset, more diffuse arterial calcification over multiple vascular beds and more preferential involvement of thoracic aorta, rather than coronary artery when compared with control.

Radix Astragali and Radix Rehmanniae, the principal components of two antidiabetic foot ulcer herbal formulae, elicit viability-promoting effects on primary fibroblasts cultured from diabetic foot ulcer tissues.

Over 194 million people suffer from diabetes worldwide. The improper control of diabetes may result in diabetic foot ulcer or even amputation. Herbal medicine provides a means for treating diabetic foot ulcers for a large population in developing countries. The wound healing-enhancing activities of the principal herbs, Radix Astragali (RA) and Radix Rehmanniae (RR) in two clinically efficacious Chinese herbal formulae were studied in primary fibroblasts from diabetic foot ulcer patients. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that RA and RR significantly enhanced the viability of fibroblasts isolated from foot ulcers of diabetic patients, even from those with no response to insulin treatment. The results in this study indicate that fibroblast viability enhancement effects of RA and RR likely underlie the healing effects of F1 and F2 in diabetic foot ulcers.

The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels.

BACKGROUND AND PURPOSE: Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels. EXPERIMENTAL APPROACH: Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes. KEY RESULTS: Ketanserin blocked hERG current (I(hERG)) in a concentration-dependent manner (IC50=0.11 microM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 microM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K+ concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC50s of 0.84 +/- 0.2 and 1.7 +/-0.4 microM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2-59 fold) by ketanserin. CONCLUSIONS AND IMPLICATIONS: These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin.

Relationship between the metabolic syndrome and the development of hypertension in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2).

BACKGROUND: The metabolic syndrome is a predictor of diabetes and coronary events. We hypothesized that it also predicts hypertension. METHODS: A total of 1,944 subjects (901 men and 1,043 women; age 46 +/- 12 years) from the Hong Kong Cardiovascular Risk Factor Prevalence Survey were recruited in 1995-1996 and restudied in 2000-2004. The prevalence of hypertension and factors predicting its development were determined. RESULTS: In 2000-2004, hypertension was found in 23.2% of the men and 17.2% of the women. Of the 1,602 subjects who were normotensive at baseline, 258 subjects developed hypertension after a median interval of 6.4 years. According to the National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria, the hazard ratios associated with the metabolic syndrome were 1.89 (95% confidence interval (CI): 1.41-2.54) and 1.72 (95% CI: 1.24-2.39), respectively. The positive and negative predictive values of the metabolic syndrome for identifying subjects who will develop hypertension in this population were 34.7 and 85.4% (NCEP criteria), and 33.1 and 85.5% (IDF criteria), respectively. The development of hypertension was related to the number of components of the metabolic syndrome (other than raised blood pressure), present in men (P = 0.003) and in women (P = 0.001). Using multivariate analysis, age, baseline systolic blood pressure (SBP), body mass index (BMI), and the triglycerides/high-density lipoprotein (HDL) ratio were found to be significant predictors of the development of hypertension. Compared with optimal blood pressure, the hazards of developing hypertension associated with normal or high-normal blood pressure were 2.31 (95% CI: 1.68-3.17) and 3.48 (95% CI: 2.52-4.81), respectively. CONCLUSIONS: Blood pressure, when not optimal, is the predominant predictor of hypertension. The metabolic syndrome contributes to the risk, especially when blood pressure is optimal.

A randomized comparison of sirolimus-eluting versus bare metal stents in the treatment of diabetic patients with native coronary artery lesions: the DECODE study.

OBJECTIVE: To compare the effects of sirolimus-eluting (SES) versus bare metal stents (BMS) on 6-month in-stent late luminal loss (LLL) and 1-year major adverse cardiac events (MACE) in diabetics undergoing percutaneous coronary interventions. BACKGROUND: In studies of unselected patients, coronary restenosis rates have been lower with SES than with BMS. Comparisons of SES versus BMS in diabetics with more than one stenosis or more than one vessel disease are few. METHODS: This open-label trial randomly assigned 200 diabetics with de novo coronary artery stenoses to receive up to three SES versus BMS in a 2:1 ratio. The patients underwent repeat coronary angiography at 6 months after the index procedure and were followed-up for 1 year. The primary study endpoint was in-stent LLL at 6 months. RESULTS: Between August 2002 and May 2004, 83 patients (mean age = 60 years) with 128 lesions (mean = 1.5 per patient) were enrolled at four U.S. and seven Asian medical centers. Enrollment was terminated early by the Safety Monitoring Board because of a statistically significant difference in rates of clinical endpoints. The mean in-stent LLL at 6 months was 0.23 mm in SES versus 1.10 mm in BMS recipients (P < 0.001). At 12 months, 8 patients (15%) assigned to SES had experienced MACE versus 12 patients (41%) assigned to BMS (P = 0.006). CONCLUSIONS: In diabetics, the mean 6-month in-stent LLL was significantly smaller, and 12-month MACE rate significantly lower, after myocardial revascularization with SES than with BMS.

A 3-year study of medication incidents in an acute general hospital.

BACKGROUND AND OBJECTIVE: Inappropriate medication use may harm patients. We analysed medication incident reports (MIRs) as part of the feedback loop for quality assurance. METHODS: From all MIRs in a university-affiliated acute general hospital in Hong Kong in the period January 2004-December 2006, we analysed the time, nature, source and severity of medication errors. RESULTS: There were 1278 MIRs with 36 (range 15-107) MIRs per month on average. The number of MIRs fell from 649 in 2004, to 353 in 2005, and to 276 in 2006. The most common type was wrong strength/dosage (36.5%), followed by wrong drug (16.7%), wrong frequency (7.7%), wrong formulation (7.0%), wrong patient (6.9%) and wrong instruction (3.1%). 60.9%, 53.7% and 84.0% of MIRs arose from handwritten prescription (HP) rather than the computerized medication order entry in 2004, 2005 and 2006 respectively. In 43.1% of MIRs, preregistration house officers were involved. Most errors (80.2%) were detected before any drug was wrongly administered. The medications were administered in 212 cases (19.7%), which resulted in an untoward effect in nine cases (0.8%). CONCLUSIONS: The most common errors were wrong dosage and wrong drug. Many incidents involved preregistration house officers and HPs. Our computerized systems appeared to reduce medication incidents.

Incremental predictive value of vascular assessments combined with the Framingham Risk Score for prediction of coronary events in subjects of low-intermediate risk.

BACKGROUND: In patients with low-intermediate risk, the use of the Framingham Risk Score (FRS) may not allow accurate prediction of the occurrence of coronary events. OBJECTIVE: To determine whether non-invasive vascular sonographic assessments add value to the FRS for prediction of coronary events. METHODS: Brachial artery flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) and the presence of carotid plaque in 70 male subjects (mean (SD) age 62 (9) years) with a low-intermediate FRS who presented with a recent coronary event were evaluated and compared with those in 35 male controls matched for age (mean age 60 (9) years). RESULTS: Patients with a recent coronary event had a significantly higher FRS than controls. They had a significantly lower FMD (3.56 (2.41)% vs 5.18 (2.69)%, p = 0.003) and significantly higher prevalence of carotid plaque (67% vs 40%, p = 0.008), but there was no significant difference in mean maximum IMT between the two groups (1.01 (0.28) vs 0.96 (0.14) mm, p = 0.32). Multivariate analysis revealed that FMD < or =4.75% was an independent predictor of an acute coronary event. Of the three vascular markers, FMD < or =4.75% and presence of carotid plaque provided the best diagnostic accuracy for a coronary event, with area under the curve (AUC) of 0.70 and 0.64 (p = 0.001 and p = 0.033), respectively, based on receiver operating characteristic curve analysis. Furthermore, incorporating carotid plaque or FMD < or =4.75% into the FRS (AUC = 0.72 and AUC = 0.78) provided incremental benefit in risk stratification over FRS alone (AUC = 0.66) (p = 0.008 and p = 0.007, for comparison of difference in two receiver operating characteristic curves). CONCLUSIONS: Incorporating a measure of FMD or carotid plaque burden with FRS significantly increases the accuracy of predicting coronary events in subjects of low-intermediate risk and hence should be considered as additional investigations to improve coronary risk assessment.

Caecal metastasis from a primary small-cell lung carcinoma.

Small bowel metastases from a primary lung carcinoma are rare. We report a case of a 59-year-old male with a primary small-cell lung carcinoma who developed anaemia and bowel symptoms. On colonoscopic examination he was found to have a tumour in the caecum near the ileocaecal valve, which was biopsied, revealing small neuroendocrine tumour cells. The patient then underwent systemic chemotherapy, which achieved a reduction in the size of the primary lung tumour and an improvement in his bowel symptoms. It is important that such a rare condition be recognised early as complicated intestinal metastases from a lung carcinoma can lead to high mortality rates and poor short-term outcome. With advances in chemotherapy and palliative care, patients with metastatic lung carcinoma can sometimes survive more than a year with reasonable quality of life.

Progression of Device-Detected Subclinical Atrial Fibrillation and the Risk of Heart Failure.

BACKGROUND: Long-term continuous monitoring detects short-lasting, subclinical atrial fibrillation (SCAF) in approximately one-third of older individuals with cardiovascular conditions. The relationship between SCAF, its progression, and the development of heart failure (HF) is unclear. OBJECTIVES: This study examined the relationship between progression from shorter to longer SCAF episodes and HF hospitalization. METHODS: Subjects in ASSERT (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial) were ≥65 years old, had history of hypertension, no prior clinical AF, and an implanted pacemaker or defibrillator. We examined patients whose longest SCAF episode during the first year after enrollment was >6 min but ≤24 h (n = 415). Using time-dependent Cox models, we evaluated the relationship between subsequent development of SCAF >24 h or clinical AF and HF hospitalization. RESULTS: Over a mean follow-up of 2 years, 65 patients (15.7%) progressed to having SCAF episodes >24 h or clinical AF (incidence 8.8% per year). Older age, greater body mass index, and longer SCAF duration within the first year were independent predictors of SCAF progression. The rate of HF hospitalization among patients with SCAF progression was 8.9% per year compared with 2.5% per year for those without progression. After multivariable adjustment, SCAF progression was independently associated with HF hospitalization (hazard ratio [HR]: 4.58; 95% confidence interval [CI]: 1.64 to 12.80; p = 0.004). Similar results were observed when we excluded patients with prior history of HF (HR: 7.06; 95% CI: 1.82 to 27.30; p = 0.005) or when SCAF progression was defined as development of SCAF >24 h alone (HR: 3.68; 95% CI: 1.27 to 10.70; p = 0.016). CONCLUSIONS: In patients with a pacemaker or defibrillator, SCAF progression was strongly associated with HF hospitalization.

Cell cycle-dependent expression of potassium channels and cell proliferation in rat mesenchymal stem cells from bone marrow.

OBJECTIVE: Recently, our team has demonstrated that voltage-gated delayed rectifier K(+) current (IK(DR)) and Ca(2+)-activated K(+) current (I(KCa)) are present in rat bone marrow-derived mesenchymal stem cells; however, little is known of their physiological roles. The present study was designed to investigate whether functional expression of IK(DR) and I(KCa) would change with cell cycle progression, and whether they could regulate proliferation in undifferentiated rat mesenchymal stem cells (MSCs). MATERIALS AND METHODS: Membrane potentials and ionic currents were recorded using whole-cell patch clamp technique, cell cycling was analysed by flow cytometry, cell proliferation was assayed with DNA incorporation method and the related genes were down-regulated by RNA interference (RNAi) and examined using RT-PCR. RESULTS: It was found that membrane potential hyperpolarized, and cell size increased during the cell cycle. In addition, IK(DR) decreased, while I(KCa) increased during progress from G(1) to S phase. RT-PCR revealed that the mRNA levels of Kv1.2 and Kv2.1 (likely responsible for IK(DR)) reduced, whereas the mRNA level of KCa3.1 (responsible for intermediate-conductance I(KCa)) increased with the cell cycle progression. Down-regulation of Kv1.2, Kv2.1 or KCa3.1 with the specific RNAi, targeted to corresponding gene inhibited proliferation of rat MSCs. CONCLUSION: These results demonstrate that membrane potential, IK(DR) and I(KCa) channels change with cell cycle progression and corresponding alteration of gene expression. IK(DR) and intermediate-conductance I(KCa) play an important role in maintaining membrane potential and they participate in modulation of proliferation in rat MSCs.

Burden of carotid atherosclerosis in patients with stroke: relationships with circulating endothelial progenitor cells and hypertension.

Recent studies suggest that reductions in circulating endothelial progenitor cells (EPCs) may contribute to the development of atherosclerosis. However, whether reduced circulating EPCs contribute to cerebrovascular disease remains undefined. We tested the hypothesis that reduced circulating EPCs was associated with an increased burden of carotid atherosclerosis. The level of circulating CD34+/KDR+ EPCs and the extent of carotid atherosclerosis were determined in 30 patients with a history of atherothrombotic ischaemic stroke and 30 age- and sex-matched controls (mean age: 63+/-2 years; 63% men). Stroke patients, compared with controls, had significantly higher carotid mean maximum intima-media thickness (mmIMT) (1.08+/-0.05 versus 0.90+/-0.02 mm, P=0.002), prevalence of carotid plaque (60.0 versus 23.3%, P=0.004) and a lower number of circulating CD34+/KDR+ EPCs (235.7+/-45.5 versus 400.4+/-56.8 cells/mul, P=0.027). The circulating CD34+/KDR+ EPC count correlated negatively with carotid mmIMT (r=-0.50, P<0.001), and was an independent risk factor for increased carotid mmIMT>1 mm (odds ratio (OR): 7.71; 95% confidence interval (CI): 1.62-36.74, P=0.010) and the presence of carotid plaque (OR: 7.04; 95% CI: 1.95-25.43, P=0.003). Furthermore, stroke patients with low (<25th percentile of controls) as compared to those with normal CD34+/KDR+ EPC count had a significantly greater carotid mmIMT (1.21+/-0.07 versus 0.93+/-0.05 mm, P=0.005) and a significantly higher prevalence of carotid plaque (87.5% versus 28.6%; P=0.001). Our observations suggested that reduced circulating EPC may contribute to the progression of carotid atherosclerosis. Circulating EPC count may provide a novel marker for the burden of carotid atherosclerosis.

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

De novo expression of macrophage migration inhibitory factor in atherogenesis in rabbits.

Macrophage migration inhibitory factor (MIF) has been shown to play an important role in macrophage-mediated diseases. We investigate the potential role of MIF in atherogenesis using a hypercholesterolemic rabbit model. New Zealand White rabbits fed with a 2% cholesterol diet developed hypercholesterolemia and early fatty streaks at 1 month. The lesions became advanced at 3 months and were associated with de novo MIF expression by vascular endothelial cells (VECs) and smooth muscle cells (SMCs), as demonstrated by immunohistochemistry, reverse transcriptase-polymerase chain reaction, and in situ hybridization. By contrast, there was no increase in MIF levels in rabbits fed a normal diet. In early atherogenesis, marked upregulation of MIF mRNA and protein by VECs and some intimal cells were closely associated with CD68(+) monocyte adhesion onto and subsequent migration into subendothelial space. Of significance, the accumulation of macrophages was exclusively localized to areas of strong MIF expression, which may be associated with the macrophage-rich fatty streak lesion formation. Upregulation of MIF by SMCs is transient during atherogenesis. Importantly, strong MIF expression by activated macrophages may be responsible for the development of foam cell-rich lesions. Finally, the ability of MIF to induce intercellular adhesion molecule-1 expression by VECs implicates its pathogenic role in atherogenesis. In conclusion, the present study provides the first demonstration that MIF is markedly upregulated during atherogenesis. Upregulation of MIF by VECs and SMCs may play a role in macrophage adhesion, transendothelial migration, accumulation, and, importantly, transformation into foam cells. Furthermore, strong MIF expression by macrophages may both initiate and amplify the atherogenesis process.

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension.

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29 375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control.

Association of hypertension with single nucleotide polymorphisms in the quantitative trait locus for abdominal obesity-metabolic syndrome on chromosome 17.

Genome scan in Chinese revealed an association of blood pressure with the microsatellite marker D17S1303, which lies in a quantitative trait locus for the abdominal obesity-metabolic syndrome (AOMS2) at 17p12 on chromosome 17. We previously reported that D17S1303 was associated with hypertension and obesity. Therefore, we studied 10 single nucleotide polymorphisms (SNP) within 3 kb of D17S1303. One hundred and eighty hypertensive subjects (91 men, 89 women, age 53+/-12 years) and 180 normotensive matched controls (91 men, 89 women, age 52+/-11) were genotyped using the Sequenom genotyping platform. Allelic frequencies in these Chinese subjects differed from those reported for Caucasians. Three SNPs (rs11656507, rs1357926, rs852319) were homozygous in our subjects. The genotype frequencies of rs852320, rs852321 and rs852322 did not differ between hypertensive and normotensive subjects. However, there were significant differences for rs1525402 (P=0.048), rs2692343 (P=0.022), rs2692344 (P=0.017) and rs2321313 (P=0.028). A four-locus haplotype comprising G at rs1525402, C at rs2692343, C at rs2692344 and G at rs2321313 was associated with lower systolic blood pressure (P=0.023) and normotension (P=0.048). Our results provide further evidence that there is a gene, as yet unidentified, influencing blood pressure in the vicinity of D17S1303 in a quantitative trait locus for abdominal obesity-metabolic syndrome at 17p12.