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Circumferential pulmonary vein ablation for chronic atrial fibrillation

A randomized, controlled trial of circumferential pulmonary vein ablation for the treatment of chronic atrial fibrillation was conducted in this study. A total of 146 patients with a mean (± SD) age of 57 ± 9 years who had chronic atrial fibrillation were randomly assigned to receive amiodarone and undergo two cardioversions during the first 3 months alone (the control group) or in combination with circumferential pulmonary vein ablation. Cardiac rhythm was assessed with daily telephonic transmissions for 1 year. The left atrial diameter and the severity of symptoms were assessed at 12 months.

Among the 77 patients assigned to undergo circumferential pulmonary vein ablation, ablation was repeated because of recurrent atrial fibrillation in 26% of patients and atypical atrial flutter in 6%. An intention-to-treat analysis showed that 74% of patients in the ablation group and 58% of those in the control group were free of recurrent atrial fibrillation or flutter without anti-arrhythmic-drug therapy at 1 year (P = 0.05). Among the 69 patients in the control group, 53 (77%) crossed over to undergo circumferential pulmonary vein ablation for recurrent atrial fibrillation by one year and only three (4%) were in sinus rhythm without antiarrhythmic-drug therapy or ablation. There were significant decreases in the left atrial diameter (12 ± 11%, P >0.001) and the symptom severity score (59 ± 21%, P >0.001) among patients who remained in sinus rhythm after circumferential pulmonary vein ablation. Except for atypical atrial flutter, there were no complications attributable to circumferential pulmonary vein ablation.

Therefore, sinus rhythm can be maintained long-term in the majority of patients with chronic atrial fibrillation by means of circumferential pulmonary vein ablation independent of the effects of antiarrhythmic drug therapy, cardioversion, or both. The maintenance of sinus rhythm is associated with a significant decrease in both the severity of symptoms and the left atrial diameter.

Catheter ablation for chronic atrial fibrillation is at that interim stage of clinical development between demonstrating its promise and defining its role in clinical practice. Although it is possible to use catheter ablation to eliminate chronic atrial fibrillation, it is premature to recommend this procedure for all patients. A large, prospective clinical trial comparing the short and long-term outcomes among patients undergoing catheter ablation with those receiving antiarrhythmic drug therapy or drug therapy to control the heart rate is needed to define the role of catheter ablation in various populations of patients. Until such trials are performed, younger patients who are refractory to medical treatment and who have limited or no structural heart disease may be most likely to benefit from this procedure. Ablation procedures are not yet widely used for chronic atrial fibrillation and are still rapidly evolving. Further technical advances are being made that are likely to improve procedural outcomes. Catheter ablation is not first-line therapy for chronic atrial fibrillation. Physicians considering this therapy for their patients should refer them to experienced centers and recognize that the elderly and those with severe structural heart disease may not be good candidates for ablation.

Hakan Oral, MD, et al. Circumferential pulmonary vein ablation for chronic atrial fibrillation. N Engl J Med 2006; 354:934–941.

Effects of ACAT inhibition on the progression of coronary atherosclerosis

The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiathero-sclerotic effects.

We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis.

The primary efficacy variable analyzing the progression of atherosclerosis—the change in percent atheroma volume—was similar in the pactimibe and placebo groups (0.69% and 0.59%, respectively; P = 0.77). Both secondary efficacy variables assessed by means of intravascular ultrasonography, however, showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (– 5.6mm³, P = 0.001) but not in the pactimibe group (–1.3 mm³, P = 0.39; P = 0.03 for the comparison between groups). The atheroma volume in the most diseased 10mm subsegment regressed by 3.2mm³ in the placebo group, as compared with a decrease of 1.3 mm³ in the pactimibe group (P = 0.001). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P = 0.53).

In conclusion, for patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis.

Steven E. Nissen, MD, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 2006; 354:1253–1263.

Sequence variations in PCSK9, low LDL, and protection against coronary heart disease

A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.

We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.

Of the 3363 black participants examined, 2.6% had nonsense mutations in PCSK9; these mutations were associated with a 28% reduction in mean LDL cholesterol and an 88% reduction in the risk of CHD (P = 0.008 for the reduction; hazard ratio, 0.11; 95% confidence interval, 0.02–0.81; P = 0.03). Of the 9524 white subjects examined, 3.2% had a sequence variation in PCSK9 that was associated with a 15% reduction in LDL cholesterol and a 47% reduction in the risk of CHD (hazard ratio, 0.50; 95% confidence interval, 0.32–0.79; P = 0.003).

These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.

This study has public health implications. It strongly suggests that earlier initiation of therapy to lower LDL cholesterol levels, which is potentially achievable through lifestyle interventions or the use of medications, would provide benefit.

US population studies such as the National Health and Nutrition Examination Surveys indicate that levels of total cholesterol and LDL cholesterol decreased substantially between the 1960s and the early 1990s, in association with a reduction in the dietary intake of saturated fat and cholesterol. In the 1990s, however, these beneficial changes slowed markedly, and further reductions in LDL cholesterol levels were restricted primarily to older persons, in association with an increased use of statins. The new findings suggest the need to redouble our efforts to reduce LDL cholesterol levels in younger persons by promoting healthy diets and reducing obesity. Even small successes will probably be leveraged for later gains in lowering the risk of cardiovascular disease.

Jonathan C. Cohen, PhD, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264–1272.

Rapidly declining CHD mortality in Ireland: due to improvement in risk factors and in medical treatment

In only just over 15 years, between 1985 and 2000, CHD mortality rates in Ireland fell by 47% in men and women aged 25–84 years. By using IMPACT, a previously validated model, a group of researchers combined and analysed data on the use and effectiveness of specific treatments in coronary heart disease as well as trends in risk factors. The data sources used were published trials and meta-analyses, official statistics, clinical audits, and observational studies. By using the model they found that some 44% of the observed decrease in mortality could be attributed to treatment effects and 48% to favourable population risk factor trends; specifically declining smoking prevalence (26%), mean cholesterol concentrations (30%), and blood pressure levels (6%), but also that these favourable developments were offset by increases in adverse population trends related to obesity, diabetes, and inactivity (– 14%), indicating that the decline in CHD mortality might theoretically have been even greater, if increases in obesity and a sedentary lifestyle had not occurred. A great part of the effect of therapy was due to secondary preventative therapies and treatment of heart failure, whereas revascularization by CABG surgery or angioplasty accounted for only 5% of the total mortality decrease. The authors note that this is a disappointingly small contribution given the large financial resources allocated to these interventions. Still, the results emphasize the importance of a comprehensive strategy maximizing uptake of effective treatments, and at the same time actively promoting primary prevention, particularly less smoking and a healthy diet.

Bennett K, et al. Explaining the recent decrease in coronary heart disease mortality rates in Ireland, 1985–2000. J Epidemiol Community Health 2006; 60:322–327.

Declining CHD mortality not universal: South America lags behind

CHD mortality has declined sharply in the US over the past four decades. The situation in Latin America is less clear, with great heterogeneity between various countries. T. Rodíguez (Universidad Pública de Navarra, Pamplona, Spain) and colleagues examined data from 10 countries in Latin America for 1970–2000. In general, the magnitude of changes was related to the initial CHD mortality. Only Argentina, which had high rates in the 1970s, had falls in rates comparable with those reported in North America. Declines were smaller in Puerto Rico, Chile, Cuba, and Brazil. CHD trends were unfavourable in other Latin American countries, particularly Costa Rica, Ecuador, and Mexico, characterized by the lowest rates in the 1970s. Accordingly, over more recent calendar years CHD mortality varied less between countries of the Americas than in the past, reflecting a more uniform pattern of lifestyle habits and risk factor exposure across various American countries.

Rodíguez T, et al. Trends in mortality from coronary heart and cerebrovascular diseases in the Americas: 1970–2000. Heart 2006; 92:453–460.

Early return to work after myocardial infarction

Return to work sooner than 8 weeks after an acute myocardial infarction (AMI) is usually not recommended, mainly because of concerns regarding getting patients back to their preinfarction activities before the infarct is completely healed. Detailed clinicopathologic work has demonstrated that small infarcts are almost completely healed after 5 weeks and large infarcts are completely healed or undergo no further discernible change after 2 months. In an era with more active early treatment and risk stratification, however, current recommendations may not be firmly underbuilt. In a randomized controlled trial conducted in Australia patients were randomized to return to normal activities at 2 weeks or to undergo standard cardiac rehabilitation and return to normal activities at 6 weeks after AMI before discharge. Patients were considered to be randomized if they had no angina, had left ventricular ejection fraction >40%, a negative result from a symptom-limited exercise stress test for ischemia (>2mm ST depression) at 1 week, and achieved more than seven METs. Patients with left ventricular ejection fraction under 40% were included only if they did not have inducible ventricular tachycardia at electrophysiologic studies. Seventy-two patients were randomized to return to normal activities at 2 weeks and 70 patients to undergo standard cardiac rehabilitation. There were no deaths or heart failure in either group. After 6 months, there were no significant differences between the groups in the incidence of reinfarction, revascularization, left ventricular function, lipids, body mass index, smoking, or exercise test results. Bearing in mind that this was a comparatively small study, and that patients were carefully selected, early return to work is probably safe in low-risk patients willing to do so. The authors point out, however, that before this strategy can be widely recommended, its safety must be confirmed in larger prospective clinical trials.

Kovoor P, et al. Return to full normal activities including work at two weeks after acute myocardial infarction. Am J Cardiol 2006; 97:952–958.