News and Notices

The News and notices section is published in every issue of the Cell Proliferation. It provides readers with details of current affairs, the best of what is being published in other journals and upcoming events for your diaries. Readers are invited to submit material, upcoming events and training opportunities to the News Editors.

Newsworthy

Nonvalidation of genetic risks for acute coronary syndromes

A genetic basis of atherosclerotic heart disease and acute coronary syndromes (ACS) has been implicated in a number of small studies, but there has been little consistency in the associated gene variants across studies. Morgan and colleagues performed a systematic literature review and identified 85 variants in 70 genes that have been previously reported as associated with ACS. The authors sought to replicate these findings in a cohort study of 811 patients with ACS and 650 age-matched and sex-matched controls. The authors report that they could not unequivocally validate any of the 85 genetic variants previously implicated as susceptibility factors for ACS.

Morgan TM, et al. Nonvalidation of reported genetic risks factors for acute coronary syndrome in a large-scale replication study. JAMA 2007; 297:1551-1561.

Corticosteroids for the prevention of atrial fibrillation after cardiac surgery

Atrial fibrillation (AF) is the most common arrhythmia to occur after cardiac surgery. An exaggerated inflammatory response has been proposed to be one etiological factor.

To test whether intravenous corticosteroid administration after cardiac surgery prevents AF after cardiac surgery, a double-blind, randomized multicenter trial was conducted in three university hospitals in Finland.

A total of 241 consecutive patients, without prior AF or flutter and scheduled to undergo first on-pump coronary artery bypass graft surgery, aortic valve replacement, or combined coronary artery bypass graft surgery and aortic valve replacement, were randomized to receive either 100 mg hydrocortisone or matching placebo as follows the first dose in the evening of the operative day, then one dose every 8h during the next 3 days. In addition, all patients received oral metoprolol (50-150 mg/day) titrated to heart rate.

Occurrence of AF during the first 84 h after cardiac surgery was the main outcome measure. The incidence of postoperative AF was significantly lower in the hydro-cortisone group [36/120 (30%)] than in the placebo group [58/121 (48%); adjusted hazard ratio, 0.54; 95% confidence interval, 0.35-0.83; P = 0.004; number needed to treat, 5.6]. Compared with placebo, patients receiving hydrocortisone did not have higher rates of superficial or deep wound infections, or other major complications.

Therefore, intravenous hydrocortisone reduced the incidence of AF after cardiac surgery and did not increase the risk of superficial or deep wound infections.

Halonen J, et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery. JAMA 2007; 297:1562-1567.

Effect of reconstituted high-density lipoprotein infusions on coronary atherosclerosis. A randomized controlled trial

High-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression.

To investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS), a randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2-3 weeks after the last study infusion.

Between July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks.

Sixty patients were randomly assigned to receive four weekly infusions of placebo (saline), 111 to receive 40mg/kg of reconstituted HDL (CSL-111) and 12 to receive 80mg/kg of CSL-111. The primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points.

The higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was −3.4% with CSL-111 and −1.6% for placebo (P =0.48 between groups, P < 0.001 vs. baseline for CSL-111). The nominal change in plaque volume was −5.3 mm³with CSL-111 and −2.3 mm³ with placebo (P =0.39 between groups, P < 0.001 vs. baseline for CSL-111). The mean changes in plaque characterization index on IVUS (−0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (−0.039 mm for CSL-111 and −0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = 0.01 and 0.03, respectively). Administration of CSL-111 (40mg/kg) was associated with mild, self-limiting transaminase elevation but was clinically well tolerated.

In conclusion, short-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography.

Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted.

Tardif JC, et al. Effect of reconstituted high-density lipoprotein infusions on coronary atherosclerosis. A randomized controlled trial. JAMA 2007; 297:1675-1682.

Inotropic support in decompensated heart failure

Positive inotropic agents, such as dobutamine or milrinone, in patients with acute decompensated heart failure have been associated with an increased risk of death and other cardiovascular events, and there is a need for medications that improve hemodynamics and relieve symptoms without compromising survival. In the clinical trial Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE), patients were randomly assigned to receive short-term intravenous infusion of either levosimendan or dobutamine. Mebazaa and colleagues report that neither the primary trial outcome (all-cause mortality at 180 days) nor secondary outcomes, including mortality at 31 days and patient-assessed symptom relief at 24 h, differed among patients receiving levosimendan vs. dobutamine.

Mebazaa A, et al. Levosimendan vs. dobutamine for patients with acute decompensated heart failure. The survive randomized trial. JAMA 2007; 297:1883-1891.

Temporal trends in clinical outcomes in acute coronary syndromes

Using data from the multinational observational cohort study Global Registry of Acute Coronary Events, Fox and colleagues assessed whether changes in hospital management of patients with acute coronary syndromes between 1999 and 2006 were associated with improvements in clinical outcomes. The authors, report that between 1999 and 2006, the use of interventional therapies increased and changes in pharmacological medications were made consistent with trial evidence and professional guidelines. Rates of new heart failure, mortality, and incidence of stroke and myocardial infarction after discharge declined from 1999 through 2006.

Fox KAA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006. JAMA 2007; 297:1892-1900.

Trans-fatty acids in erythrocytes linked to increased coronary heart disease risk

Trans-fat, primarily found in partially hydrogenated vegetable oils, is produced by the food industry to create solid fats from liquid oils. These fats increase the shelf life of food products and improve the stability of frying oils. Trans-fat accounts for 2-3% of total energy intake in the US populations. Of all types of fatty acids, trans-fatty acids have been demonstrated to have the strongest effect in raising the serum total cholesterol to high-density lipoprotein ratio, a known predictor of coronary heart disease (CHD) risk. Reported intake has been demonstrated to correlate with CHD risk but the effect size may be underestimated or overestimated because of measurement errors associated with dietary assessment. Biomarkers of trans-fat intake have the advantages of freedom from reporting errors and the ability to assess different isomers of trans-fatty acids. In the Nurses’ Health Study, there were 166 incident cases of CHD during 6 years of follow-up, who were matched with 327 controls, to investigate the associations between trans-fatty acid content in erythrocytes and risk of CHD. As humans cannot synthesize trans-fatty acids, the amount of trans-fat in red blood cells is an appropriate biomarker of trans-fat intake. In multivariable analysis, the risks of CHD from the lowest to highest quartiles of total erythrocyte trans-fatty acid content were 1.0, 1.6, 1.6, and 3.3, after adjustment for age, smoking, and other cardiovascular risk factors (P for trend < 0.01). These biomarker data provide further evidence that high trans-fat consumption is a significant risk factor for CHD.

Sun Q, et al. A prospective study of trans-fatty acids in erythrocytes and risk of coronary heart disease. Circulation 2007; 115:1858-1865.

No prognostic benefit of percutaneous coronary intervention in stable coronary artery disease

In acute coronary syndromes percutaneous coronary intervention (PCI) reduces mortality and myocardial infarction (MI) in patients who present with acute coronary syndromes. Most interventions, however, are undertaken electively in patients with stable coronary artery disease in which similar benefit has not been shown. A recent study, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, was designed to determine whether PCI coupled with optimal medical therapy reduced the risk of death and nonfatal MI in patients with stable coronary artery disease, compared with optimal medical therapy alone. In this US and Canadian study, 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease were randomized to either undergo PCI with optimal medical therapy (PCI group) or to receive optimal medical therapy alone (medical therapy group). The primary outcome was death from any cause and nonfatal MI during a follow-up period of 2.5-7.0 years (median, 4.6). Two hundred and eleven primary events in the PCI group and 202 events in the medical-therapy group were present. PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. A decrease in the rate of angina, however, was seen at 1 and 3 years with PCI, with 66 vs. 58% free from angina at 1 year (P < 0.001) and 72 vs. 67% at 3 years (P = 0.02). By 5 years, however, this difference had disappeared and the authors note that angina symptoms were substantially improved in both groups overall. Accordingly, PCI in stable coronary disease should be used to treat symptoms only, but the procedure does not prevent major cardiovascular events.

Boden W et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356:1503-1516.

New findings on survival in heart failure and/or left ventricular dysfunction - still as poor as cancer?

Echocardiographic Heart of England Screening Study (ECHOES) screened a total of 6162 men and women aged ≥ 40 years living in the West Midlands, UK, who were randomly selected from four cohorts: the general population; diuretic users; patients with a prior clinical diagnosis of heart failure; and those at high risk of heart failure owing to previous myocardial infarction, angina, hypertension, or diabetes. About 2.3% (92) patients from the general population were diagnosed with heart failure and 1.8% (72) with left ventricular systolic dysfunction (LVSD). The 5-year survival rate in all four groups, with a mean age of 64 years, was 69% among those with LVSD without heart failure, 62% among those with heart failure and no LVSD, and 53% in those with heart failure and LVSD, compared with 93% in the general population. The median survival time of patients shown to have definite heart failure was 6 years. The study confirms the poor prognosis of patients suffering from heart failure across the community and provide a generalizable mortality risk estimate of 9%/year, lower than the rates suggested from hospital-diagnosed heart failure populations or LVSD alone, but much higher than in the general population. Survival improved significantly with increasing ejection fraction, but even borderline systolic dysfunction carried an impaired prognosis according to this study.

Hobbs FDR, et al. Prognosis of all-cause heart failure and borderline left ventricular systolic dysfunction: 5-year mortality follow-up of the Echocardiographic Heart of England Screening Study (ECHOES). Eur Heart J 2007 Apr 25 [Epub ahead of print].