US researchers reveal a prognostic value for monocyte chemoattractant protein 1 in acute and chronic phases after acute coronary syndrome
The novel biomarker monocyte chemoattractant protein (MCP)-1 demonstrates prognostic value in both the acute and chronic phases after acute coronary syndrome (ACS), according to latest findings from the University of Texas (TX, USA).
This study sought to determine whether MCP-1 adds prognostic value to standard risk assessment tools and biomarkers after ACS. MCP-1 was measured at baseline (n = 4244), 4 months (n = 3603) and 12 months (n = 2950), and correlated with clinical events in the Z phase of the A to Z (Aggrastat to Zocor) trial, which compared early intensive versus delayed and less intensive statin therapy after ACS.
The team, led by James de Lemos (University of Texas, TX, USA), found that higher MCP-1 levels at both baseline and 4 months were associated with an increased risk for long-term death and major adverse cardiac events, independent of standard risk factors and established biomarkers including C-reactive protein (CRP) and BNP.
However, the results showed that MCP-1 levels did not identify patients most likely to benefit from statin therapy. The authors say further studies are needed to confirm whether MCP-1 should be included in multiple biomarker panels for risk stratification and to test its use as a marker for antiatherosclerotic therapies.
Furthermore, patients with MCP-1 levels above the cut-off value of 238 pg/ml were at significantly increased risk for mortality (p < 0.0001) and each of the secondary end points (p < 0.01).
After adjusting for baseline variables, index diagnosis, creatinine clearance, LDL-cholesterol, CRP and BNP levels, MCP-1 levels greater than 238 pg/ml were significantly associated with mortality (hazard ratio [HR]: 2.16) as well as each of the secondary end points.
Furthermore, addition of MCP-1 increased the C-statistic of this fully adjusted mortality model from 0.76 to 0.78 (p < 0.0001). MCP-1 levels greater than 238 pg/ml at 4 months were also independently associated with mortality (HR: 1.76), and addition of MCP-1 levels to the 4-month mortality model increased the C-statistic from 0.72 to 0.73.
Patients in the early intensive statin arm had similar responses to treatment irrespective of whether their baseline and 4-month MCP-1 levels were greater than 238 pg/ml or lower, leading the authors to state, “MCP-1 is not useful for identifying patients who benefit from aggressive statin regimens after ACS.”
Writing in the Journal of the American College of Cardiology, the researchers conclude “MCP-1 provides independent prognostic value in the acute and chronic phases after ACS and merits further evaluation as a prognostic marker and potential therapeutic target.”
Source: de Lemos JA, Morrow DA, Blazing MA et al.: Serial measurement of monocyte chemoattractant protein-1 after acute coronary syndromes: results from the A to Z trial. J. Am. Coll. Cardiol. 50, 2117–2124 (2007).
Vitamin E may demonstrate cardiovascular benefits in diabetic patients with oxidative stress
Researchers from Israel have revealed a benefit of Vitamin E in reducing cardiovascular events in diabetes patients carrying a genetic variant that increases oxidative stress.
Clinical trials of vitamin E had failed to demonstrate a decrease in cardiovascular events. However, previous studies had not addressed possible benefit to subgroups with increased oxidative stress.
Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus. This latest study examined diabtetes patients with the Hp genotype Hp 2-2. The Hp gene has a polymorphism with two common alleles, Hp 1 and Hp 2, and the Hp 2 allelic protein product provides inferior antioxidant protection to that of Hp 1. This difference is profoundly accentuated in the diabetic state, such that diabetes patients with the Hp 2-2 genotype have a marked increase in oxidative stress, explain lead investigator Andrew Levy (Technion-Israel Institute of Technology, Israel) and colleagues.
Levy and colleagues sought to test the hypothesis that vitamin E could reduce cardiovascular events in diabetic individuals with the Hp 2-2 genotype, a subgroup that comprises 2–3% of the general population. They suspected that high-dose antioxidant therapy may only benefit particular groups of patients suffering from very high levels of oxidative stress. Having previously demonstrated an interaction between the Hp genotype and diabetes on the development of cardiovascular events, the researchers tested the effects of vitamin E supplements in diabetic patients with the Hp 2–2 genotype.
A total of 1434 Hp 2–2 diabetic patients aged 55 years or older were randomly assigned to receive either vitamin E 400 U/day or placebo, with a follow-up period of 18 months. Those patients taking vitamin E were found to have a significantly lower rate of myocardial infarction (MI), stroke and cardiovascular death than those taking the placebo, at 2.2% versus 4.7% (p = 0.01). This was largely owing to the significant reduction in nonfatal MI, at seven (1%) events in the vitamin E group versus 17 (2.4%) in the placebo group, and led to early termination of the study.
The authors believe that a pharmacogenomic approach to determine which patients should receive vitamin E “appears warranted based on several meta-analyses showing that vitamin E may be harmful when given indiscriminately to all individuals.”
Levy concluded that the study results suggest that genetic testing for the Hp 2–2 genotype, which is commercially available and hoped to decrease in cost considerably, could “identify a large group of diabetes individuals who could potentially derive cardiovascular benefit from a very inexpensive treatment.”
Source: Milman U, Blum S, Shapira C et al.: Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both Type 2 diabetes mellitus and the haptoglobin 2–2 genotype. A prospective double-blinded clinical trial. Arterioscler. Thromb. Vasc. Biol. (2007) (Epub ahead of print).
Low testosterone levels linked to increased cardiovascular risk in men
Latest study findings from the UK indicate a possible link between low testosterone levels in otherwise healthy men and an increased risk for cardiovascular and all-cause death.
“The magnitude of the relationship of endogenous testosterone levels with cardiovascular disease (CVD) mortality was comparable in size – but independent of – the classical risk factors such as blood pressure and cholesterol,” noted lead author Kay-Tee Khaw (Addenbrooke‘s Hospital, Cambridge, UK).
Khaw and colleagues conducted a nested case-control study of 11,606 men aged 40–79 years who were surveyed between 1993 and 1997 and followed up in 2003. Testosterone levels were analyzed in men who were free from known CVD at the beginning of the study, of whom 825 subsequently died; 1489 were still alive at follow-up and served as controls.
Mean testosterone levels were found to be significantly lower in those men who died of any cause (CVD or cancer) compared with controls, at 15.6, 15.8 and 15.7 versus 16.7 nmol/l, respectively (p < 0.001). Furthermore, testosterone concentration was inversely related to all-cause mortality and CVD death. For example, men with testosterone levels in the highest quartile (≥19.6 nmol/l) had a 41% lower relative risk for all-cause mortality compared with those whose levels were in the lowest quartile (≤12.5 nmol/l).
Multivariable analysis using testosterone as a continuous variable revealed that, for every 6-nmol/l increase in serum testosterone, all-cause mortality decreased by 14% (odds ratio [OR]: 0.86, p < 0.001). The effect size was similar for CVD death (OR: 0.83, p < 0.01), and changed little after adjustment for cardiovascular risk factors and sex hormone binding globulin, or after the exclusion of deaths within 2 years.
Khaw speculated that testosterone supplementation could reduce CVD and all-cause mortality risk in men with low endogenous levels.
If the findings are confirmed, testosterone could be considered an additional risk factor to help assess an individual‘s cardiovascular risk and, therefore, guide preventive treatment.
Source: Khaw KT, Dowsett M, Folkerd E et al.: Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men. European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation (2007) (Epub ahead of print).
New study calls into question UK guidelines for chronic atrial fibrillation
The departure from recommending digoxin as the first-line treatment in patients with chronic atrial fibrillation (AF) by current UK guidelines is premature, investigators have concluded in a review published in the British Medical Journal.
The UK NICE last year published guidelines that replaced digoxin with β-blockers or calcium antagonists as the recommended initial monotherapy for the control of heart rate in patients with chronic AF.
“Digoxin has been the mainstay of treatment for many years, so new recommendations relegating digoxin should be evidence-based and safe,” write Theodora Nikolaidou and Kevin Channer (Royal Hallamshire Hospital, Sheffield, UK). But the reviewers found little evidence to support replacing digoxin with either of the other treatments as monotherapy. Rather, they found that improvements in both heart rate variability and exercise tolerance have been shown only with the combination of digoxin and a β-blocker or calcium-channel blocker. Indeed, they found some evidence that β-blockers used alone may worsen exercise capacity.
A total of 57 studies were reviewed, including 25 randomized double blind controlled trials, assessing digoxin, β-blockers, calcium antagonists and combinations for rate control in chronic AF. β-blocker monotherapy was found to be better than digoxin alone at controlling heart rate at rest in just one out of ten studies. In additionn, in six other studies, β-blocker use alone did not improve exercise capacity.
Several studies demonstrated that the combination of β-blocker and digoxin gave greater improvements in heart rate control at rest and during exercise compared with digoxin alone. The combination‘s effect on exercise capacity was inconsistent, causing deterioration in some studies, but improvement or no change in others.
In five studies, the calcium-channel blocker, diltiazem, was found to be better than digoxin at controlling heart rate during exercise, but not during rest, and it failed to improve exercise capacity. However, most of the eleven studies assessing the combination of diltiazem and digoxin showed that it provided better heart rate control at rest and during exercise than digoxin alone, and two studies demonstrated that the combination gave improved exercise tolerance.
They conclude: “We believe that the combination of digoxin and a β-blocker or calcium antagonist should be recommended as first-line management. We would emphasize that it is safest to start treatment with digoxin first.”
Source: Nikolaidou T, Channer KS: Rate control in permanent atrial fibrillation. Br. Med. J. 335, 1057–1058 (2007).