	This issue of Cardiology Review features an important study in the combined arrhythmia and hypertension sections, where Dr. Pierre-Frederic Keller and colleagues from Canada report that angiotensin-converting enzyme inhibitors may have potent antiarrhythmic properties, especially with regard to preventing atrial fibrillation. Dr. Joseph T. Dell’Orfano comments on this study and the need for additional data from a prospective trial.

	A combined article in the diabetes and heart failure sections by Drs. Joshua Barzilay and Richard Kronmal correlates the level of fasting blood glucose with the subsequent development of congestive heart failure in 829 diabetic adults 65 years of age or older. A positive relationship was found, even in the absence of coronary artery disease. In her commentary, Dr. RoseMarie Pasmantier points out that this evidence speaks strongly for the presence of diabetic cardiomyopathy, which she believes is an underdiagnosed condition.

	In the stroke section, the risk of stroke in relation to the serum homocysteine concentration was evaluated by Dr. Hiroyasu Iso from Japan in a prospective case-control study of 11,614 subjects without prior history of stroke or coronary artery disease. Japanese men and women with higher homocysteine levels had higher stroke rates. Can the stroke rate be reduced by treatment with folic acid? This is just one of the intriguing questions posed by Dr. Robert A. Levine in his commentary.

	In the hypertension section, Dr. Giuseppe Schillaci and associates from Italy determined the prognostic significance of finding the metabolic syndrome (a cluster of cardiovascular risk factors closely linked to insulin resistance) in 1,742 hypertensive patients without overt cardiac disease. The patients were followed for a mean of 4.1 years (range 1—10.5), and the cardiovascular event-free survival rate was significantly lower in the subgroup with the metabolic syndrome. Dr. Wendy S. Post comments on these findings.

	In a combined article in the lipid disorders and coronary artery disease sections, Drs. John W.G. Yarnell and Christopher C. Patterson from the United Kingdom compared the predictive values of plasma lipids and three inflammatory/hemostatic coronary artery disease risk factors. The study population consisted of 4,860 men, of whom 525 had a subsequent cardiac event. Their provocative conclusions are discussed by Drs. Rhondalyn C. McLean and Roger S. Blumenthal in their commentary.

	Finally, Dr. Stephen P. Glasser presents another installment in his series on clinical research.

Articles

Cardiology Review Online

Do ACE inhibitors have  antiarrhythmic properties?

	In the previous installments of this series on clinical research, I introduced the different study designs and included a brief description of each. In this installment, I build on the major clinical research designs and address the strengths and weaknesses of each.

	Ecologic studies use available population data to determine associations among diseases, rates, and exposures in the population. Their main use is for hypothesis generation because they cannot address causality to any important degree. The ability to access existent, readily available data means that the study should be relatively inexpensive, quick, and simple. Thus, if an association has not been explored in the literature, this design might be appropriate as an early study to support future efforts. The weaknesses beyond the study’s inability to address causation, however, are numerous and include: (1) the fact that population information may not readily apply to individuals, (2) there is almost no ability to control for other variables that might influence the association, (3) there is little or no control of data quality, and (4) the concept of the ecologic fallacy is always present. What is the ecologic fallacy? It relates to the aforementioned issue that observations in the aggregate do not necessarily hold true for an individual. For example, one might want to assess the association between cigarette smoking and suicide. Indeed, one may find that the sale of cigarettes is highest in those states with the highest suicide rates. However, it may not be true that the suicides are occurring in the cigarette smokers.

	The study design of case reports and case series is obvious, and their main weakness is, again, the inability to address causality. They should not be discounted and deemed unimportant, however. It was a case series of echocardiographic findings in patients who had taken fen-phen that set into motion the whole debate regarding the association of valvular abnormalities with combination appetite suppressant therapy.

	In cross-sectional studies, one defines and describes disease status (or outcome), exposures, and other characteristics at a point in time to evaluate associations among them. The operative phrase for cross-sectional studies is at a point in time. Cross-sectional studies contrast with cohort studies in that cohort studies observe the association between exposure and outcome (for example, from health to disease or from disease to an event). This, in turn, contrasts with a case-control study, wherein the investigator identifies a certain outcome in the population, matches that “diseased group” to a “healthy group,” and identifies differences in exposures between the two groups. Cohort studies similarly attempt to find an association between an exposure and ultimate outcome. One example of how cohort studies differ from case-control studies is that with case-control studies, outcome is identified and exposure is sought, whereas in cohort studies, exposure is identified and outcome is sought (Figures 1—3).

	Figure 1 is a diagram of a typical cross-sectional study. In a target population, the exposure and outcomes are determined, and the four possibilities are analyzed. In this example, the exposures to electromagnetic energy and cancer at a point in time are examined for a relationship. In Figures 2 and 3, the diagram shows that persons exposed to electromagnetic energy and those who were not are followed for a period of time, and cancer rates are determined in the two groups (or cancer cases and exposure are retrospectively analyzed).

	In the randomized-controlled trial (RCT), the exposure is controlled by the investigator, which contrasts it with all the other study designs (Figure 4).

	As previously mentioned, the differences among the various study designs will be discussed in more detail later. For now, however, one should be able to begin to understand the key differences and therefore the limitations of each study design and the circumstances in which one design might be preferable over another.

	If we use the example of exposure to electromagnetic energy and cancer (eg, leukemia) in a cross-sectional study, a population is identified (target population), cancer rates are determined, and exposure and lack of exposure to electromagnetic energy are ascertained. One then analyzes the exposure rates in the cancer-free and cancer-present subjects and whether the cancer rate is higher in those who were exposed; a hypothesis regarding the association is then generated. This would be a relatively inexpensive way to begin to look at the possible association among these variables, but limitations should be obvious. Because there is no time determination in cross-sectional studies and because exposure to electromagnetic energy, if it did cause cancer, would likely have to occur over a period of time, one could easily miss an association.

	With cohort studies, the time issue is addressed because subjects who are exposed are followed and the development of disease (outcomes) is ascertained in the exposed versus the unexposed. A cohort study is close to an experimental design (RCT), except that the exposure occurs in nature and is therefore not controllable by the investigator. One of the other major limitations of this design is that the assumption is made that the subject under study is free of the outcome in question at the study’s onset. Clearly, this assumption may be inaccurate, particularly for diseases that have longer incubation periods and asymptomatic states (eg, coronary artery disease).

	In the next installments, I will delve deeper into RCTs and begin to address the very important issue of causation.

Part 3: Overview of study designs

	Yarnell and Patterson (page 37) provide a provocative report on the findings of a prospective cohort study of the association between inflammatory markers and the incidence of myocardial infarction. In this study, 4,325 men who were followed for 10 years underwent a baseline cardiovascular examination and laboratory studies. Based on an initial coronary heart disease (CHD) risk profile, the patients were characterized as being at high or low risk for future cardiac events.  

	The investigators performed logistic regression analyses, comparing a classic model of CHD risk factors to that of a model incorporating the following nonlipid risk factors: leukocyte count, serum viscosity, and fibrinogen level. The absolute risk for this hemostatic model was 35% in the high-risk group compared with 2% in the low-risk group, a finding comparable to that predicted in the lipid model (36% and 3%, respectively).

	The investigators conclude that the use of inflammatory mediators, in addition to traditional risk factors for CHD, is as predictive of a cardiac event as a model incorporating lipids.  

	These findings highlight the growing role of inflammatory markers in CHD risk prediction. A meta-analysis of prospective data compiled in 1998 demonstrated a modest but highly statistically significant increase in risk of CHD for those subjects with higher baseline blood levels of fibrinogen, white blood cell count, and high- sensitivity C-reactive protein (hs-CRP).1

	Based on the previously characterized pathophysiology of stress responses, it is not surprising that acute-phase reactants, such as fibrinogen and leukocyte count, would be elevated in the setting of an acute coronary syndrome. It is also biologically plausible that chronic elevation of these markers may be associated with an increased risk for future CHD events. Perhaps higher baseline blood levels of inflammatory mediators indicate a low level of chronic inflammation, a marker of plaque instability, and an increased risk of anatherothrombotic event. However, a pattern of causality is impossible to establish in observational studies alone.  

	While further studies are necessary to clarify the nature of the association between CHD and inflammatory mediators, the ease with which these inflammatory markers are determined in the laboratory and the relatively low cost of obtaining such tests may have important implications for monitoring those at risk for CHD. Additionally, fol-

	lowing blood levels of inflammatory markers may have therapeutic implications. For example, a well-publicized analysis by Ridker and colleagues showed that patients with lower CRP levels after HMG-CoA reductase inhibitor (statin) therapy had better clinical cardiovascular outcomes than those with higher CRP levels irrespective of  low-density lipoprotein cholesterol (LDL-C) levels achieved.2 This work supports the concepts that inflammation is a determinant of plaque stability and that statins have anti-inflammatory effects.

	In addition, Nissen and colleagues performed an angiographic ultrasound study of 502 patients and found that a decrease in hs-CRP levels is independently and significantly correlated with the rate of atheroma progression.3 Patients with reductions in both LDL-C and CRP that were greater than the median had slower rates of progression than subjects with LDL-C and hs-CRP reductions that were less than the median. Thus, the reduced rate of progression was related to greater reductions in both atherogenic lipoproteins and hs-CRP.

	The aforementioned studies offer compelling evidence that inflammatory markers can potentially be used at all stages of disease for risk stratification. Future studies will help determine if atherosclerosis should be added to the list of organ-specific autoimmune diseases.4 In the future, it may be possible to create anti-inflammatory agents that are tailored to specific immunologic abnormalities in the atheroma. Determining the precise mechanisms of actions of statins will help us in future drug development.5

Inflammatory markers and  the risk of coronary heart disease

	I read with interest the article by Horwich and Fonarow1 and the accompanying commentary by Borzak (October 2004).2 Most studies extol the benefits of HMG-CoA reductase inhibitors (statins) in the treatment of coronary disease and other atherosclerotic vessels with objective evidence of plasma cholesterol/low-density lipoprotein (LDL) reduction, but none have shown any concomitant effect on the plasma level of coenzyme Q10 (CoQ10). I agree that retrospective studies are limited and that more effective medical regimens and new devices are available, which have proven to have a positive impact on heart failure (HF) outcome.

	Cholesterol is a steroid. It is synthesized in the liver, intestines, skin, adrenal cortex, testes, and aorta. These alone should give us pause, especially when the National Cholesterol Education Program is recommending aggressive reduction of LDL. To refresh our memory, the first stage in the biosynthesis of cholesterol is the formation of mevalonate from acetyl CoA catalyzed by HMG-CoA reductase (site of statin inhibition). The second stage is the formation of isoprenoid units from mevalonate, which are the building blocks of  the “steroid skeleton.” The condensation of these units, the third stage, will eventually lead to cholesterol. However, the isoprenoid unit is also the side chain of CoQ10.1-3

	CoQ10 plays a vital role in the mitochondrial respiratory chain with electron and proton transfer during adenosine triphosphate (ATP) generation. It also acts as an antioxidant and stabilizes membrane function.4 Cells with a large ATP requirement tend to have more mitochondria. Heavily utilized muscles, such as cardiac and skeletal muscles, have cells containing large numbers of mitochondria adjacent to the contractile elements. Proper myocardial function then is ATP dependent.5 A decreased CoQ10 will have an adverse effect in energy generation and may have a role in the pathogenesis of HF when a statin is used.6,7 Another study has shown left ventricular diastolic function with Doppler echocardiography before and after statin treatment with worsening after and reversal with CoQ10 supplementation.8 The mortality rate is increased in patients with low cholesterol and advanced HF.9 It is possible that the low cholesterol reflects a declining CoQ10.

	We need prospective clinical trials in order to better assess the long-term effect of statins on cardiac function before an epidemic of HF follows aggressive lipid-lowering therapy. Thank you.

	We appreciate the interest of Dr. Rectra in our study of statin therapy in HF1 and agree that randomized controlled trials are needed before statins can definitively be recommended as a therapy for HF. Several large trials of statin therapy in HF are currently under way.

	The abundance of scientific and clinical data on statin therapy does not support Dr. Rectra’s concern that statin therapy may produce an “epidemic of HF.” Reduction of coenzyme Q10 levels, in theory, could adversely affect cardiac function and exercise tolerance in HF, and this deserves further study. However, there are also multiple biologic mechanisms by which statins could improve symptoms and survival in HF. In addition to anti-ischemic

	actions, statins may decrease sympathetic activation, improve endothelial function, and decrease inflammatory cytokine activity.2 In animal models of HF, as well as small trials in humans with HF, statin therapy has been shown to reverse pathologic myocardial remodeling and improve systolic function.3

	Confirming our initial findings, other investigators have now also observed improved survival in HF patients treated with statins.4,5 Despite the association between low cho-

	lesterol and increased HF mortality, the association between statins and improved survival in HF appears to be independent of baseline cholesterol levels.1 Large randomized stat-in trials in coronary artery disease have shown that statins reduce the incidence of HF and improve survi-val in those with asymptomatic left ventricular dysfunction.6,7 Taken to-gether, these data suggest that statin therapy at least is safe for patients with HF.

	Ischemic events increase the risk of HF hospitalization and mortality; autopsy studies have revealed that acute coronary syndromes may be a more frequent cause of death than previously realized in both ischemic and nonischemic HF.8 In light of the well-established cardiovascular protective properties of statins and the current state of evidence on statins and HF, statin therapy in ischemic HF should be strongly considered, as we await the more definitive answers from randomized trials.

	    Tamara B. Horwich, MD    Gregg C. Fonarow, MD    Ahmanson UCLA Cardiomyopathy Center, David Geffen School of Medicine at UCLA Los Angeles, California

 Statin therapy in heart failure

	A recent study reported in Cardiology Review showed that classic risk factors—cholesterol levels, blood pressure, and smoking habit&mdash;accounted for at least 75% of major coronary artery disease (CAD) events during 10 years of follow-up in a large British cohort.1 In our studies based on two British cohorts, we evaluated the contribution to subsequent risk of additional lipids (high-density lipoprotein [HDL] cholesterol and triglycerides2) and inflammatory markers (fibrinogen, viscosity, and white blood cell count). Our initial study showed that total cholesterol, HDL cholesterol, and triglycerides act largely independently of each other in predicting subsequent CAD risk.2 Our recent study compared the predictive value of lipid markers with inflammatory markers, both in addition to smoking habit, blood pressure, and body mass index. Those findings are reviewed in this article.

	Two populations from the West of England and from South Wales, United Kingdom, were examined using a common protocol between 1979 and 1983. Men were selected from the general population and were 45 to 63 years of age when first examined. About 90% of patients were eligible for the study, or a total of 4,860 men.

	A standard (epidemiological) cardiovascular examination was performed and a venous blood sample taken after an overnight fast. Suitable samples were available from 4,641 men.

	The follow-up procedure consisted of a repeated cardiovascular examination at 5-year intervals for one population and 3-year intervals for the other. Hospital admissions in the survey district were used to check major coronary events, and the validity of clinical diagnoses was checked using hospital notes. Death certificates for men who died during the 10-year follow-up period were obtained from the National Health Service Central Register. In addition to fatal and nonfatal coronary events, silent myocardial infarctions were ascertained from electro-cardiograms done at follow-up examinations according to World Health Organization criteria.3

	Full details of the laboratory analyses done at the time of the baseline examinations have been reported previously.2,4 Calculations of the laboratory precision and biological variability of these assays were also performed. Regression dilution effects were calculated by the parametric method of Rosner and colleagues5 using samples taken in an identical manner to those taken at baseline examination (early morning after an overnight fast) from subjects rescreened at 5 years in one of the study populations. Details of all statistical methods used to evaluate risks at 10 years of follow-up are reported elsewhere.

	In the examined study population of 4,325 men, 525 (12%) had experienced a major CAD event during 10 years of follow-up. Of 1,006 men who had clinical or historical evidence of CAD at baseline screening, 234 (23%) had had a CAD event during 10 years of follow-up. Among the 3,319 men without evidence of CAD at baseline, 291 men (9%) experienced a major CAD event.

	The distributions of the clinical risk factors, lipids, and inflammatory markers differed in the expected directions between those who had had a major CAD event and those who had not. All risk factors showed statistically significant differences in the two groups when adjusted for age and area (study population). These data are shown in Table 1.

	Relative odds (risk) of a major CAD event by 10 years were calculated from logistic regression analyses comparing a model incorporating total cholester-ol, HDL cholesterol, triglycerides, and standard nonlipid clinical risk factors (age, preexisting CAD, blood pressure, smoking habit, and body mass index) with a model incorporating these same nonlipid risk factors and three hemostatic factors (fibrinogen, viscosity, and white blood cell count). Two methods were then used to compare the risk prediction derived from these models: (1) risk scores were calculated for each individual from regression coefficients and used to construct receiver operating characteristic (ROC) curves, with the area under this curve providing a measure of usefulness for prediction (0.5 indicated no better prediction than expected by chance, and 1.0 indicated perfect prediction); and (2) absolute risk in 10 subgroups of men defined by the deciles of predicted risk according to each model.

	Relative odds of a major CAD event at 10 years were statistically significant in both lipid and hemostatic models with the exception of body mass index, which failed to achieve significance. Correction for regression dilution tended to increase the relative odds for the continuously distributed variables (with the exception of body mass index), but decreased the relative odds for some categorical defined variables.

	Results for the predictions derived from areas under the ROC curves are shown in Table 2. For the whole cohort, the prediction derived from the lipid model was similar to that derived from the hemostatic model, but the combined model was statistically significantly better for prediction than either of the separate models. When men without evidence of CAD at baseline were considered, a similar pattern was shown in the results, but the predictive ability was reduced.

	Absolute risks were calculated for 10 subgroups of men defined from the deciles of predicted risk for each of the models—lipid and hemostatic&mdash;when all other nonlipid clinical risk factors were included in the model (as described previously). These analyses are summarized in the Figure and show that men in the highest group based on their lipid values actually had a 34.3% chance of a major CAD event by 10 years (35.5% predicted) compared with 3.2% for those men in the lowest risk group (3.1% predicted). Absolute risks for the hemostatic model were similar (34.5% for men in the highest risk group and 2.1% for men in the lowest risk group).

	Three main points can be highlighted from these results: (1) in these particular British populations, three inflammatory markers predict CAD as well as three lipid markers, taking into account all other established risk factors; (2) prediction of events from either of these models is relatively weak; in men in the top 10th of the distribution of either of these classes of risk factors, just over one third of the CAD events occurred, although the majority of the events occurred at lower levels of these risk factors. When this was repeated for fifths of the distribution of risk

	factors, up to half of CAD events occurred in the top fifth of men for the lipid, hemostatic, or combined model; and (3) adjustment for regression dilution does not result in any improvement in risk prediction, at least when assessed in the same dataset that was used to derive the logistic model. These three points are addressed in the following discussion.

	1. In countries such as Japan and China, the prevalence of CAD is low; a large prospective study from Shanghai showed that there was a graded relationship between the incidence of CAD and the level of serum cholesterol in men or women at recruitment, although the population levels of cholesterol were low by Western standards.6 In the present study, cholesterol levels were relatively high at baseline recruitment (≥ 6.0 mmol/L), and it is possible that inflammatory markers may be either less or more predictive with lower population levels of cholesterol. This can only be tested in prospective studies in different populations at different levels of lipid risk factors.

	2. These data broadly support the view that risk factor thresholds may not be relevant for reporting risk of CAD7 and also show that risk factor scores fall considerably short of perfect prediction of risk during a 10-year period of follow-up. The claim that 75% of major CAD events could be accounted for by smoking habit, serum cholesterol levels, and blood pressure by the authors of the British Regional Heart Study report1 is dependent on the choice of cut points; if low threshold values for risk factors are used, then a higher percentage of events will be attributed to these risk factors. In particular, the data, although similar

	to those reported in the British Regional Heart Study1 and with similar levels of serum cholesterol, show that the general level of risk prediction,

	taking into account all known risk factors, is relatively poor. This is likely to indicate the existence of unknown

	psychosocial stressors. Some indica-tion of the importance of the latter, although in a limited case-control design, has been shown in the INTERHEART Study in 52 countries across the globe8; it seems important to attempt to reproduce these findings in prospective studies.

	3. The model that had been corrected for regression dilution bias was no better for prediction than the uncorrected model. Rather than assessing it on the original dataset that was used in its derivation, it may have performed better had it been applied to a new dataset or to a dataset incorporating repeated assessments of risk factors to minimize their measurement error.

	These data support the view that inflammatory factors are important in the pathogenesis of CAD. It has been suggested that statins, in addition to lowering cholesterol, also have antiatherothrombotic properties9 and can lower plasma viscosity.10 Laboratory evaluation of inflammatory markers, such as those described in this article, is inexpensive and may be helpful in risk prediction, although this should be assessed in future prospective studies.

Inflammatory markers  versus lipid levels in  the risk of CAD 

	In this issue, Keller and colleagues (page 12) summarize their study of 5,463 hypertensive patients taking angiotensin-converting enzyme (ACE) inhibitors matched with patients taking calcium channel blockers. After a 4-year follow-up, they found a significantly lower rate of new-onset atrial fibrillation in the ACE inhibitor group. There also was a significant reduction in the rate of atrial-fibrillation—related hospitalizations. This finding is consistent with several previous reports, including a substudy of the Studies Of Left Ventricular Dysfunction trial1 and another study, which showed that ACE inhibitors reduced the incidence of atrial fibrillation following acute myocardial infarction (MI).2

	The beneficial effects of ACE inhibitors cannot be explained by improvements in hypertension since both groups were being treated for hypertension. The authors imply that there is a direct antiarrhythmic action, although it is also possible that ACE inhibitors prevent the atria from remodeling. Studies have demonstrated that atrial fibrillation can cause changes in the atrial tissue, making it more likely to fibrillate (hence “atrial fibrillation begets atrial fibrillation”).3 ACE inhibitors appear to help prevent this remodeling process. In a study examining the effect of adding ACE inhibitors to antiarrhythmic drug treatments in patients undergoing cardioversion, there was a reduction in the number of admissions for atrial fibrillation, as found in the present study.4 In addition, signal-averaged P-wave duration, a measure of atrial remodeling, was significantly shorter, even after 1 year of treatment with ACE inhibitors. These findings suggest that ACE inhibitors may help to prevent atrial remodeling.

	How do we apply these findings to our patients? Many patients with structural heart disease already have an indication for ACE inhibitors. In patients with congestive heart failure and MI, ACE inhibition has been conclusively shown to improve survival. The study by Keller and colleagues tells us that ACE inhibitors may help to prevent atrial fibrillation in patients with hypertension. Thus, ACE inhibitors should be offered in all of these groups.

	Should ACE inhibitors be used in patients without structural heart disease (ie, lone atrial fibrillation)? The authors point out the need for a prospective controlled trial. Such a trial would add to our understanding of the role of ACE inhibition in the treatment of lone paroxysmal atrial fibrillation. There are few data

	on the use of ACE inhibitors in lone atrial fibrillation. Animal studies suggest that ACE inhibitors may be effective if administered early in the course of atrial fibrillation.5 A recent study demonstrated this in patients with atrial fibrillation treated with antiarrhythmic agents and ACE inhibitors.6 Unfortunately, this study was retrospective and did not examine patients with lone atrial fibrillation. Nonetheless, it adds support to the role of ACE inhibitors in the treatment of atrial fibrillation.

	A growing body of literature supports the use of ACE inhibitors in patients with atrial fibrillation. Most patients with structural heart disease already have an indication for treatment with ACE inhibitors. More data are needed to support the use of these agents in patients with lone paroxysmal atrial fibrillation.

ACE inhibition and atrial fibrillation: Improving the substrate

	A 59-year-old man had occasional heart palpitations over the past 2 months. He had been feeling well, had no relevant medical or surgical history, and was not taking any medication. He was physically active (tennis, golf, and bicycle riding) and had no limitations. Specifically, he had no cardiovascular risk factors except for high blood pressure as measured during a medical visit 1 year earlier. Despite dietary modifications, his blood pressure remained high when measured in pharmacies (155/95 mm Hg). His palpitations started 2 months earlier and occurred four to five times per week, mostly during the day and rarely during the night, without any relationship to physical activity. The palpitations were often associated with mild dyspnea, and each episode was self-limited and lasted 15 to 20 minutes.

	Results of the physical examination showed a man in good general condition. His blood pressure was high, at 160/95 mm Hg, and his heart rate was 70 beats per minute and was regular. Heart sounds were normal, without gallop or murmur, and the rest of the physical examination was normal. His electrocardiogram was normal, with sinus rhythm. Echocardiographic findings were also normal. Results of ambulatory Holter monitoring showed two short episodes of symptomatic atrial fibrillation.

	This patient was hypertensive despite 1 year of diet modification. He presented with paroxysmal atrial fibrillation. Anticoagulant and antihypertensive therapy were initiated. In light of our recent study on the subject, the patient was prescribed an angiotensin-converting enzyme inhibitor as antihypertensive therapy to decrease blood pressure and prevent recurrent atrial fibrillation.

A hypertensive patient with  atrial fibrillation

	Hospital admissions for atrial fibrillation, which is the most significant cardiac arrhythmia, have increased markedly over the past few years.1 Because of the aging population and because the prevalence of atrial fibrillation is age-related,2 the incidence of atrial fibrillation is expected to increase further. Atrial fibrillation is also associated with significant morbidity (mainly stroke-related) and mortality (the rate doubles compared with patients in sinus rhythm).3 In addition to causing stroke, atrial fibrillation may decrease functional status and quality of life because of symptoms of heart failure due to increased heart rate, atrioventricular asynchrony, and left atrial or left ventricular dysfunction and because some patients experience significant discomfort as a result of irregular rhythm.

	Standard therapies include chemical and electrical cardioversion and antiarrhythmic drugs for maintenance of sinus rhythm. However, the recurrence rate of atrial fibrillation after successful cardioversion is as high as 50% at 1 year for patients who are prescribed long-term antiarrhythmic drugs, which are associated with significant side effects. An interventional approach to atrial fibrillation is showing promising preliminary results in selected patients using radiofrequency catheter ablation around the junction of the pulmonary veins in the left atrium. Several catheter ablations are often needed because of recurrences, however, and rare but clinically significant complications do occur with this strategy.

	New insights into the pathophysiology of atrial fibrillation have emerged from basic science and animal models. These data indicate that the renin-angiotensin system may play a role in the pathogenesis of atrial fibrillation. Specifically, angiotensin II (AT-II) appears to be implicated in structural and electrophysiological remodeling of the atria, therefore contributing to atrial fibrillation. AT-II shortens the effective refractory period and lengthens intra-atrial conduction time favoring fibrillation, possibly through mechanical stretch of the atria.4,5 In addition,

	AT-II is a potent promoter of fibrosis through reduced collagenase activity, cardiac myoblast proliferation, and activation of extracellular signal-regulated and mitogen-activated protein kinases.6,7 Atrial fibrosis is frequently found

	the characteristic conduction disturbances and persistent susceptibility. Consequently, the angiotensin-converting enzyme (ACE) inhibitor enalapril (Vasotec) and the A-II receptor blocker (ARB) candesartan (Atacand) were studied in dog models with favorable results for the prevention of atrial structural and electrical remodeling, with a subsequent decrease in the occurrence of atrial fibrillation.8-10 Early clinical trials evaluating the preventive effect of ACE inhibitors in patients with reduced left ventricular function after myocardial infarction11 and ARBs in patients with atrial fibrillation who underwent successful cardioversion have shown significant reductions in the recurrence of atrial arrhythmias.12 More recently, our group found a beneficial effect with enalapril for the

	prevention of atrial fibrillation in pa-

	Hypertension is known as the most prevalent and potentially modifiable risk factor for atrial fibrillation. It affects approximately 20% of the adult population worldwide. Cardiac adaptive responses to hypertension, such as left ventricular hypertrophy, left atrial enlargement, modifications in mechanical function of the atria, and increased filling pressures, have been found to independently predict development of atrial fibrillation.14 Because experimental and early clinical studies have suggested a role for ACE inhibitors in the prevention of atrial fibrillation and because they are among the most frequently prescribed antihypertensive medications, we assessed the effect of this class of drugs on the occurrence of atrial fibrillation in a large cohort of hypertensive patients. We used long-acting calcium channel blocking agents as the blood pressure—lowering comparator because they represent the most frequently prescribed antihypertensive drug class after ACE inhibitors and because it has been suggested that they have antiarrhythmic properties.

	We performed a retrospective, longitudinal cohort study to assess the effects of ACE inhibitors on atrial fibrillation in patients with hypertension compared with long-acting calcium channel blocking agents. We used an integrated medical and pharmacy claims database of more than 8 million people in the United States. To be eligible, patients had to be diagnosed with hypertension from one or more medical visits during the period 6 months before and after the index prescription of ACE inhibitors or calcium channel blocking agents. Any additional antihypertensive medication prescribed during the follow-up period was permitted to be taken, except calcium channel blocking agents for the patients taking ACE inhibitors and ACE inhibitors for the patients taking calcium channel blocking agents. The index prescriptions for ACE inhibitors or calcium channel blocking agents were filled between January 1, 1995, and June 30, 1999, and the final cohorts were evaluated until June 30, 2002, with an average length of follow-up of 4.6 years for the ACE inhibitor group versus 4.2 years for the calcium channel blocker group. Propensity scoring and logistic regression were used to match cohorts and minimize potential baseline differences that could bias final outcomes.

	Of 10,926 patients, 5,463 eligible patients were matched in each group. The major baseline characteristics

	showed a mean age of 65 years in both groups, a 3.7% versus 3.6% prevalence of congestive heart failure, a 9.9% versus 10.1% prevalence of diabetes, a 6.4% versus 6.7% prevalence of stroke, and a previous history of atrial fibrillation in 2.3% versus 2.4% of patients in the ACE inhibitor

	and calcium channel blocking agent groups, respectively. About 48% of patients in both groups received at least one other antihypertensive medication, with a higher rate of thiazides being taken in the ACE inhibitor group and a higher rate of beta blocking agents being taken in the calcium channel blocking agent group (17.6% versus 12.4% for thiazides and 15.5% versus 19.6% for beta blocking agents in the ACE inhibitor versus calcium channel blocking agent groups, respectively).

	The incidence rate of new-onset atrial fibrillation was significantly lower in the group treated with ACE inhibitors than in the group treated with calcium channel blocking agents (hazard ratio, 0.85; 95% confidence interval [CI], 0.74—0.97). The average number of months to the first onset

	of atrial fibrillation was 29.5 versus 26.1 (difference, 3.4 months; 95%

	CI, 0.72—6.04) in the ACE inhibitor versus calcium channel blocking agent groups, respectively. Time to occurrence using the Kaplan-Meier method showed a significant decrease in new-onset atrial fibrillation with the ACE inhibitor over the whole observation period (P = .018; Figure 1).

	The potential benefit of treatment with ACE inhibitors over calcium channel blocking agents in patients with hypertension was also assessed by analyzing the rate of atrial fibrillation— related hospitalization. The rate of hospitalization related to atrial fibrillation was 8.5 per 1,000 patient-years for patients taking ACE inhibitors compared with 11.9 per 1,000 patient-years for patients taking calcium channel blocking agents, with an incidence ratio for patients treated with an ACE inhibitor of 0.74 (95% CI, 0.62–0.89; Figure 2). Further analysis showed an incremental benefit of ACE inhibitors over calcium channel blocking agents in patients with a previous history of atrial fibrillation compared with patients without a previous episode of atrial fibrillation. The incidence ratio for patients with a previous history of atrial fibrillation treated with ACE inhibitors after the entire follow-up period was 0.55 (95% CI, 0.38–0.78) compared with an incidence ratio of 0.82 for patients without a history of atrial fibrillation (95% CI, 0.67–1.01). Therefore, ACE inhibition was associated with a reduced incidence of atrial fibrillation and related hospitalizations for hypertensive patients in a managed care setting.

	ACE inhibitors are extensively prescribed to lower blood pressure in hypertensive patients and, for patients with impaired left ventricular function, to control neurohormonal activation and remodeling and to decrease mor-

	tality. Recent developments in our understanding of the pathophysiology of atrial fibrillation have allowed their evaluation as antiarrhythmic drugs. This study, as well as others, strongly suggests that ACE inhibitors have significant antiarrhythmic properties, especially with regard to atrial fibrilla-

	tion, that distinguish them from other antihypertensive drugs. They are now emerging as a potential adjunct to the current treatment options for atrial fibrillation. The socioeconomic effect of these results warrants a dedicated prospective randomized trial. Because of the high prevalence of hypertension and atrial fibrillation, any class of drugs that can normalize blood pressure and prevent atrial fibrillation is likely to have a significant impact on health care.

	Our study showed that hypertensive patients taking ACE inhibitors had a lower incidence of atrial fibrillation than those who were taking calcium channel blocking agents. These findings indicate that ACE inhibitors have considerable antiarrhythmic properties, especially with regard to atrial fibrillation.

Reducing the incidence  of atrial fibrillation by inhibiting  angiotensin-converting enzyme

	Dual antiplatelet therapy with clopidogrel (Plavix) and aspirin produces a more rapid reduction in asymptomatic embolization compared with aspirin alone in patients with recently symptomatic carotid stenosis.

	Asymptomatic microembolic signals (MES) detected by transcranial Doppler ultrasound serve as a surrogate marker for the risk of future stroke or transient ischemic attack (TIA).

	The findings emerged from an international study called Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis (CARESS), a randomized, double-blind clinical trial assessing the efficacy of antiplatelet agents in reducing the incidence of MES in the middle cerebral artery as detected by transcranial Doppler. The investigational team was led by Hugh S. Markus, FRCP, professor of neurology at St. George’s Hospital Medical School in London, United Kingdom.

	[17]:2233-2240), CARESS enrolled 107 participants at 11 medical centers in France, Germany, Switzerland, and the United Kingdom. All patients had 50% or greater carotid stenosis. To be eligible, patients had to have suffered a stroke or TIA within the 3 months before enrollment. They were randomly assigned to 7 days of aspirin monotherapy, 75 mg/day, or aspirin plus clopidogrel, a 300-mg loading dose on day 1 followed by 75 mg/day.

	Recent studies have suggested that the risk of a very early recurrent stroke after a minor stroke or TIA may be as high as 8% to 12% at 7 days.

	“The risk is particularly high in patients with narrowed carotid arteries, which suggests that more aggressive anticlotting therapy may be indicated in this patient group,” according to Dr. Markus.

	After 7 days, MES were detected in 43.8% of the patients receiving dual therapy compared with 72.7% of the group treated with aspirin only—a relative risk reduction of 39.8% (P = .005).

	“The results demonstrate the power of the technique to detect treatment effects in relatively small groups of patients, far less than those required with the use of clinical end points such as stroke, and suggest this technique may help screen different drug combinations for further testing in large and expensive clinical trials,” he added.

	A secondary end point—MES frequency per hour&mdash;was reduced by 61.4% with dual therapy at day 7 (P = .001) and by 61.6% at day 2 (P = .005).

	No significant difference in bleeding was observed between the two groups, with no episodes of life-threatening, major, or intracerebral hemorrhage in either group. There were three minor bleeding events—two in the group assigned to dual therapy and one in patients assigned to aspirin alone.

	Although aspirin is commonly prescribed to prevent recurrent strokes or TIAs caused by emboli, it prevents recurrent strokes in only about one fifth of the patients treated.

	A recent clinical trial found no additional benefit of dual therapy over monotherapy in the secondary prevention of stroke over 18 months of follow-up in patients with either large-vessel or small-vessel disease, but patients were recruited several weeks after the acute phase of their strokes, the CARESS authors note. “The results of CARESS suggest that dual antiplatelet therapy with clopidogrel and aspirin is likely to be more effective in patients with large-vessel atherosclerotic stroke in the acute phase,” they write.  

Dual antiplatelet therapy superior to monotherapy  in reducing embolization in stroke patients

	Fish oil supplements appear to confer their cardioprotective effect by improving autonomic function as measured by a significant increase in heart rate variability (HRV), thereby reducing the risk of fatal arrhythmias, according to research published in Chest (2005;127[4]:1102-1107). In the same study, soy oil was associated with a lesser but significant increase in HRV.

	Researchers led by Fernando Holguin, MD, assistant professor of medicine at Emory University School of Medicine, Atlanta, measured HRV in 52 nursing home residents for 2 months before they were randomly assigned to fish oil or soy oil supplements (to establish baseline measures), and then every other day for 4 months after the supplements were started. Subjects assigned to fish oil received 2 g/day in divided doses; each capsule contained 83.2% of omega-3 fatty acids (docosahexaenoic acid and eicosopentanoic acid). Those assigned to soy oil capsules received 2 g/day in divided doses, with each capsule containing 6.78% of alpha-linolenic acid, 16.3% of saturated fat, and 52.7% of linoleic acid (omega-6).

	All HRV parameters increased significantly from baseline in the group assigned to the fish oil capsules. All HRV parameters except the low-frequency (LF) component increased significantly from baseline in the soy oil group. After adjusting for age and mean heart rate, total HRV, the high-frequency (HF) and LF components, the standard deviation of normal RR intervals increased significantly from baseline in subjects assigned to fish oil, whereas soy oil supplementation was associated with a significant increase in the standard deviation of normal RR intervals and only marginally significant increases in the HF and LF components.

	Patients assigned to fish oil experienced an increase in HRV within the first 2.7 weeks, contradicting the previous notion that the benefits of fish oil supplementation are not apparent in the short term. It took 8.1 weeks for HRV to increase significantly in the group assigned to soy oil.

	Compliance with supplementation was greater than 90% in each group. No significant clinical adverse events occurred, but belching was more common in the fish oil group compared with the soy oil group (41% versus 16%).

	Increasing HRV may be an effective form of primary and secondary prevention of cardiovascular mortality, given that reduced HRV predicts mortality and arrhythmic complications after myocardial infarction and in apparently healthy middle-aged and older persons, note the authors.

	They write, “a diet supplemented with omega-3 fatty acids derived from either soy oil or fish oil in conjunction with other factors known to increase HRV such as exercise, weight loss, stress reduction, and restoration of normal sleep could be part of an effective way to improve cardiac autonomic function.”

	They add that the population studied had a low dietary intake of omega-3 fatty acids, so extrapolating the findings to populations with higher fish intake may not be possible.

	In an editorial that accompanied the study, Hussam Abuissa, MD, and colleagues note the potent antiarrhythmic effects of omega-3 fatty acids in animal and human experiments. The largest randomized controlled trial on the effects of omega-3 fatty acids—the GISSI-Prevenzione Trial&mdash;demonstrated a 45% reduction in sudden death and a 20% reduction in all-cause mortality after 3.5 years among patients with known coronary heart disease (CHD) who were randomized to receive 850 mg/day of omega-3 fatty acids compared with placebo.

	The favorable effect of marine omega-3 fatty acids may also lie in their ability to lower heart rate, according to Dr. Abuissa, preventive cardiology fellow at the Mid-America Heart Institute in Kansas City, Missouri. Heart rate is positively associated with the risk of sudden death; in one study of 18 CHD patients, omega-3 fatty acid supplementation lowered the resting heart rate by 4 beats per minute.

Fish oil supplements may lower cardiac risk  by increasing heart rate variability

	Despite their safety and efficacy, HMG-CoA reductase inhibitors (statins) are underutilized in the African American population with dyslipidemia, according to a review in the March/April 2005 issue of the ABC Digest of Urban Cardiology.

	African Americans are one group for whom statins should play a key role in coronary heart disease (CHD) risk re-

	duction because CHD affects African Americans disproportionately, writes the ABC expert panel, led by Karol E. Watson, MD, PhD, director of the University of California, Los Angeles, Center for Cholesterol and Hypertension Management. According to the Centers for Disease Control, African Americans have earlier and greater mortality rates from CHD compared with most other US ethnic and racial groups.

	“Statins are generally very well tolerated, and serious adverse effects are rare,” write the authors. “Currently, there appears to be no discernible difference between the statins in the range or severity of adverse effects, although experience is more limited with rosuvastatin.” They note that transaminase elevations may occur, but their clinical significance is uncertain and that progression to liver failure “is exceedingly rare with statins, if in fact it ever happens.”

	The rate of myotoxicity with statins is 1% to 7%. The risk of myopathy appears to be increased by higher statin doses, certain medications taken concomitantly, or the presence of renal impairment. Rhabdomyolysis and myositis are rare, accounting for 0.1% of statin-related adverse effects.

	“The few cases of adverse events in patients being prescribed statin therapy have been unfairly exaggerated,” according to the expert panel. “Fortunately, the one compound that was associated with an unusually high rate of serious side effects, cerivastatin, is no longer available. Statins should be prescribed with confidence.”

	The clinical trial experience with statins in African Americans is limited, but provides evidence of clinical efficacy. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, African Americans made up 38% of the study population. In this group, pravastatin was associated with a significant reduction in the rates of myocardial infarction and stroke compared with usual care, whereas the reduction in these events with pravastatin in the overall population did not reach statistical significance.

	Two trials have tested the lipid-modifying effects of statins exclusively in African Americans. In one study of 245 patients, pravastatin decreased low-density lipoprotein (LDL) cholesterol by 26% but also decreased high-density lipoprotein cholesterol by 0.5%. The African American Rosuvastatin Investigation of Efficacy and Safety compared the effects of mg-equivalent doses of rosuvastatin and atorvastatin in 774 African Americans over 6 weeks. Rosuvastatin, 10 or 20 mg, was associated with a reduction in LDL cholesterol of 37% and 46%, respective-ly, which was significantly greater than the 32% and 39% reductions in LDL cholesterol obtained with atorvastatin, 10 or 20 mg.

	The expert panel calls for greater efforts to ensure access and availability of statins to populations at highest risk, including African Americans.

 Expert panel: African Americans deserve greater statin access

	Orlando—A single session of catheter ablation combined with antiarrhythmic drug therapy is superior to antiarrhythmic drug therapy alone for preventing recurrence of atrial fibrillation (AF) in patients in whom drug therapy has failed previously, said Emanuele Bertaglia, MD, at the American College of Cardiology Annual Scientific Sessions 2005. He presented data from a randomized, controlled, multicenter study of catheter ablation to treat patients with AF.

	“Up to now, the efficacy of catheter ablation of AF was demonstrated only in observational, noncontrolled, nonrandomized studies,” said Dr. Bertaglia, chief of the electrophysiology laboratory at Civic Hospital of Mirano in Venice, Italy. He noted that catheter ablation was still not mentioned in the most recent guidelines for the management of patients with AF.

	In the study, 137 patients with paroxysmal or persistent AF who were intolerant of antiarrhythmic drugs or in whom at least two trials of antiarrhythmic drug therapy had failed were randomly assigned to ablation plus antiarrhythmic drug therapy or to drug therapy alone (control group). Antiarrhythmic drug

	therapy in most patients consisted of amiodarone (Cordarone, Pacerone).

	The efficacy of each treatment was assessed using more than 100 electrocardiograms (ECGs) per patient over the 12 months of follow-up. The assessment included basal ECG and Holter monitoring, in addition to telephonic ECG monitoring during the first 4 months of follow-up. The primary end point was total absence of atrial tachyarrhythmias during this period.

	Ninety-one percent of the control group had at least one AF recurrence compared with 44% of the ablation group (P < .001). In a Cox proportional hazards model, the risk of recurrent AF was 3.2 times greater in the control group.

	The finding in favor of catheter ablation was impressive considering that “these were the worst patients that we could find in our clinical practice,” said Dr. Bertaglia. “Their mean age was 62 years, they had a long history of AF of about 6 years, and in the mean they had failed at least three antiarrhythmic drugs.”

	The rate of major complications was 5.8% in the control group and 5.9% in the ablation group. In the ablation group, there was one stroke, one transient phrenic nerve paralysis, and one pericardial effusion related to the ablation procedure.

	The long-term efficacy of catheter ablation was not affected by the interruption of antiarrhythmic drug therapy, raising the possibility that antiarrhythmic drugs may not be needed in patients with AF who undergo successful ablation, said Dr. Bertaglia. A follow-up trial comparing catheter ablation with or without the help of antiarrhythmic drugs has been started, and results are expected in 2009, he said.

	The strength of the study was the intensive ECG monitoring, which allowed detection of both symptomatic and asymptomatic AF recurrences, whereas previous trials of catheter ablation for AF relied solely on the number of symp-tomatic AF episodes as an end point, commented Jeffrey Goldberger, MD, as-sociate professor, Feinberg School of Medicine, Chicago.

June 2005

Do ACE inhibitors have antiarrhythmic properties?

Part 3: Overview of study designs

Inflammatory markers and the risk of coronary heart disease

Statin therapy in heart failure

Inflammatory markers versus lipid levels in the risk of CAD

ACE inhibition and atrial fibrillation: Improving the substrate

A hypertensive patient with atrial fibrillation

Reducing the incidence of atrial fibrillation by inhibiting angiotensin-converting enzyme

Dual antiplatelet therapy superior to monotherapy in reducing embolization in stroke patients

Fish oil supplements may lower cardiac risk by increasing heart rate variability

Expert panel: African Americans deserve greater statin access

Catheter ablation reduces AF recurrences

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