	The incidence of atrial fibrillation (AF) following coronary artery bypass graft (CABG) surgery averages between 28% and 40% and is associated with an increased incidence of stroke in elderly patients and a prolonged hospital stay.1 Several mechanisms have been proposed to explain the increased incidence of AF following CABG surgery. Kalman and colleagues found higher postoperative norepinephrine levels in patients with AF following CABG surgery, suggesting that increased sympathetic activation may be an important mechanism.2 Attempting to blunt the sympathetic response with beta blocking agents has been shown to decrease AF in some series, but the incidence is still greater than 20%. There is some evidence to suggest that atrial ischemia during cardioplegic arrest may be an important factor because of less effective cooling of atrial tissue.3,4 However, the incidence of AF does not appear to be lower in patients treated with warm blood cardioplegia techniques or off-pump CABG surgery, in which no cardioplegia is given. Decreased glycogen levels have been found in the atria of patients undergoing mitral valve replacement, suggesting that substrate deficiency may be an important mechanism.5 Indeed, in our own studies with glucose-insulin-potassium (GIK) solutions, my colleagues and I found that the use of GIK significantly decreased the incidence of AF in both diabetic and nondiabetic CABG surgery patients.6,7

	In their study of left atrial function using intraoperative transthoracic echocardiography in 300 elective CABG patients, Leung and Bellows (page 36) propose another mechanism for the development of AF in the CABG patient. They found that patients who developed postoperative AF had larger left atrial and appendage areas, lower left atrial ejection fractions before bypass, and decreased atrial systolic function and abnormal left ventricular relaxation after bypass. Patient age was also a significant factor for the development of postoperative AF. They conclude that the structural and functional changes seen in elderly patients with chronic AF are also found in CABG patients with postoperative AF and that the presence of these changes may serve as a guide as to which CABG patients should receive prophylactic therapy to prevent AF.

	I agree with the authors’ conclusions that changes in left atrial structure and dimensions can be a contributing factor in the development of postoperative AF. Although my colleagues and I found GIK may have decreased AF due to enhanced substrate utilization, another explanation is its ability to prevent diastolic dysfunction, thus reducing atrial dilation resulting from impaired postoperative ventricular compliance.8 In addition to GIK, earlier use of diuretics, beta blockers, and angiotensin-converting enzyme (ACE) inhibitors may also help to improve ventricular compliance, thereby decreasing atrial distention and ultimately AF.

	duce the incidence of AF from 35% to between 16% and 20%, a significant percentage of CABG patients may

	still develop postoperative AF. Should patients with abnormal left atrial function assessed by intraoperative trans-thoracic echocardiography be given prophylactic therapy with antiarrhythmics, such as amiodarone (Cordarone or Pacerone)? Daoud and colleagues treated elective CABG and valve surgery patients with amiodarone for 1 week before surgery and reduced the incidence of AF from 53% to 25%.9 However, the 25% incidence was not different from the 28% incidence reported by Leung and Bellows in the absence of prophylactic therapy. Furthermore, earlier studies in which CABG patients received preoperative amiodarone therapy reported a higher incidence of postoperative pulmonary edema, pacing, and the need for in-

	tra-aortic balloon and inotropic support.10 Moreover, there is no evidence that the incidence of postoperative AF can be decreased in those patients with abnormal intraoperative left atrial function. A prospective, randomized study will need to be undertaken to determine whether early postoperative prophylactic use of amiodarone will decrease the incidence of AF in these patients.

	Until these data are available, treatment of patients with abnormal intraoperative left atrial function under-going CABG surgery should include early initiation of beta blockers and ACE inhibitors as well as more aggressive diuresis in an attempt to decrease left atrial distention and improve ventricular compliance.

Articles

Cardiology Review Online

Linking left atrial function and  postoperative atrial fibrillation 

	A 75-year-old white man was scheduled for coronary artery bypass graft (CABG) surgery for three-vessel disease. He had hypertension, non—insulin-dependent diabetes mellitus, stable angina, a preoperative weight of 250 pounds, and a height of 5’ 8”. Preoperative medications included metoprolol (Lopressor Toprol), nitrates, and glyburide (Diabeta, Micronase). Preoperative left ventricular function by ventriculography was 50%.

	The patient underwent three-vessel CABG surgery on cardiopulmonary bypass. Surgery was uneventful, and normal sinus rhythm was achieved with only one attempt at defibrillation after completion of the distal anastomoses. The patient was separated from cardiopulmonary bypass without inotropes and was taken to the intensive care unit (ICU) in stable condition.

	Postoperatively, the patient remained stable and was transferred to the floor on postoperative day 1. On the second postoperative day, he developed a tachycardia associated with diaphoresis. Electrocardiographic telemetry showed a narrow complex tachycardia, with a heart rate of 130 beats per minute. Metoprolol, 5 mg intravenously, was administered, and an irregularly irregular rhythm consistent with atrial fibrillation was evident. The patient was returned to the ICU, with paroxysmal atrial fibrillation in the next few days, which required digitalization and ventricular rate control with a beta-adrenergic blocking agent. The patient was stable by postoperative day 7, with no recurrence of atrial fibrillation. He was discharged in good condition.

	Preoperatively, given the patient’s history, how would you advise this patient of his risk of postoperative atrial fibrillation? Is there any additional information that could be obtained, either before or during surgery, by way of monitoring that might further stratify his risk of postoperative atrial fibrillation? Are prophylactic antiarrhythmic medications indicated for this patient? If so, which medication is indicated?

	Based on results from our study, this patient is at high risk for developing postoperative atrial fibrillation, given his age, body size, and race. Intraoperatively, transesophageal echocardiography may provide additional information on his left atrial dimension. An enlarged left atrium will further increase his risk of postoperative atrial fibrillation. After cardiopulmonary bypass, if the patient develops further evidence of a reduction in left atrial function and diastolic filling abnormalities, then institution of prophylactic antiarrhythmic medication may be indicated. Amiodarone (Cordarone) and rate control with beta blocking agents may be considered. Medications that may optimize atrial loading conditions, such as angiotensin-converting enzyme inhibitors and diuretics, may also prove to be worthwhile, but further research is necessary to show their efficacy in the treatment of postoperative atrial fibrillation.

Atrial fibrillation after bypass surgery

	Following cardiac surgery, 10% to 50% of patients develop atrial fibrillation,1,2 which has been shown to result in increased hospital costs.1,3 The causes of atrial fibrillation after surgery are not clear, although the

	condition is common. Atrial hypertrophy, atrial dilatation, and patchy fibrosis, with damage to the sinoatrial node, have been shown to occur as a result of aging.4 The effect of age on the development of atrial fibrillation may be better understood by assessing the function and measurements of the atria.

	Left atrial function is usually described as consisting of three elements—a reservoir, a conduit function, and a booster function. During ventricular systole, blood accumulates and is stored in the reservoir. During the conduit function, blood travels from the pulmonary veins to the left ventricle throughout passive ventricular filling in early diastole. During the booster function, left ventricular filling at end diastole is supplemented by contraction of the atrium.5,6 Irregularity in any of these functions results in dysfunction of the left atrium.

	We hypothesized that patients who develop atrial fibrillation after surgery had preexisting structural remodeling, and the trauma of surgery caused atrial function to diminish, resulting in atrial fibrillation. Through the use of echocardiography, these changes can be measured noninvasively.

	Patients who underwent coronary artery bypass graft (CABG) surgery elec-

	tively were included in the study. These patients did not undergo any other procedures at the time of their surgery. Patients with a preoperative pacemaker, cur-

	rent atrial fibrillation, recent atrial fibrillation (within a week of the surgery),

	or inadequate or unavailable echocardiographic studies were not included in

	The anesthetic management and surgical procedures were conducted according to our customary procedures and were not controlled. Measurements were

	taken throughout the surgery using transesophageal echocardiography, as well as after the surgery. Doppler echocardiography was used to assess mitral inflow measurements. The measurements included peak velocity during early filling (E), late filling from atrial contraction (A), and deceleration time. In addition, pulmonary vein diameter and pulmonary venous flow velocities were measured. Other measurements included left atrial area, left atrial length, left atrial appendage area, left atrial appendage peak velocity, left ventricular ejection fraction, and hepatic vein size and velocity.

	Left atrial reservoir function was estimated by left atrial ejection fraction (LAEF), which was determined by the following formula: LAEF = (left atrial maximal area — left atrial minimal area) left atrial maximal area ¥ 100%. Dividing the E wave velocity time in-tegral (VTI) by the A wave VTI provided an estimate for left atrial conduit function. Left atrial systolic function was estimated by the atrial filling

	A wave VTI by the total VTI of mitral inflow.7 The peak velocity of the A wave was used to estimate the left atrial booster pump function.8 Hemodynamic and echocardiographic data were measured simultaneously to provide information on loading conditions. Other potential predictors of postoperative atrial fibrillation, including patient demographic and surgical data, were recorded. We used continuous electrocardiographic te-lemetry to monitor for the development of atrial fibrillation in all patients. Two blinded investigators validated all episodes of atrial fibrillation from echocardiographic printouts.

	The association of potential clinical echocardiographic predictors with the occurrence of postoperative atrial fibrillation was evaluated using multivariate logistic regression. Group-by-time interaction and repeated measures analysis of variance were used to analyze hemodynamic information. The Mann-Whitney test was used to compare echocardiographic information before and after surgery.

	None of the patients developed atrial fibrillation intraoperatively. Postoperative atrial fibrillation occurred in 84 (28%) of the 300 patients. As shown in Table 1, those with postoperative atrial fibrillation were older than those who did not develop atrial fibrillation. There also was a correlation between postoperative atrial fibrillation and use of antiarrhythmic agents postoperatively, postoperative mediastinal exploration, race, body surface area, and a history of atrial fibrillation. The risk of developing postoperative atrial fibrillation was higher for whites and Asians compared with African Americans and Hispanics. Compared with patients who did not develop atrial fibrillation after surgery, hospital stay was significantly longer for patients who developed atrial fibrillation after surgery (median days, 4.5 versus 6.0 respectively; P < .001).

	As shown in Table 2, compared with patients who did not develop postoperative atrial fibrillation, the LAEF was lower and the left atrial appendage area and left atrial area were larger in patients who developed atrial fibrillation postoperatively.

	The only surgical variable that correlated with developing postoperative atrial fibrillation was return to the operating room for mediastinal exploration, and this was only slightly so. In the final model, this variable was not shown to portend postoperative atrial fibrillation. Aortic cross-clamp time, cardiopulmonary bypass time, number of grafts, inotropic drugs, magnesium sulfate and beta blocker use post-CABG, return to cardiopulmonary bypass, use of intra-aortic balloon pump, intraoperative defibrillation, and postoperative myocardial infarction were not associated with postoperative atrial fibrillation.

	There was no difference between patients with and without postoperative atrial fibrillation in the subjective assessment of myocardial protection. For patients who developed postoperative atrial fibrillation, mean systolic blood pressure was the only hemodynamic factor that was considerably greater preoperatively (130 ± 26 mm Hg versus 113 ± 20 mm Hg; P = .082), although there were no echocardiographic changes when this occurred.

	As shown in Table 3, in addition to age, race, and body surface area, atrial filling fraction (lowest 1st quartile) and mitral inflow duration (highest 4th quartile) following surgery were independent predictors of postoperative atrial fibrillation, based on multivariate analysis.

	The results of our study showed that patients who developed postoperative atrial fibrillation were more likely to be older, to have increased body surface area, and to be white or Asian. As a result of a reduction in myocardial fibers and increased fibrosis, aging may result in atrial remodeling.9,10 In the Framingham study, it was recently reported that the excess risk of atrial fibrillation associated with obesity appears to be mediated by left atrial dilatation,11 which was also shown in our study. In addition, we found that Hispanics and possibly African Americans were not as likely as whites to develop postoperative atrial fibrillation. Two previous studies of nonsurgical patients similarly showed that African Americans were not as likely as whites to develop atrial fibrillation.12,13 The reasons for these associations with race are still not clear.

	In addition to these clinical factors, our study also showed that those

	who developed atrial fibrillation postoperatively had signs of structural remodeling preoperatively, as shown by a larger left atrium and a tendency toward having a reduced LAEF and a larger left atrial appendage measurement. Compared with patients who did not develop postoperative atrial fibrillation, those who did had evidence of left ventricular relaxation impairment, increased atrial conduit function, and decreased atrial systolic function.

	In our study, there was a decrease in the atrial filling fraction and an increase in the VTI E/A fraction among those who developed atrial fibrillation after surgery, which are indices of atrial systolic function and left atrial conduit function (analogous to stroke volume), respectively. The increase in left atrial stroke volume may be secondary to an increase in autonomic nervous system activity.14 The decrease in atrial filling fraction and increase in left atrial conduit function may be an indication of increased left atrial afterload, possibly as a result of the increased left ventricular stiffness, as shown by abnormal ventricular relaxation in our study. Furthermore, an increase in left atrial volume15 and dilatation of the left atrium and pulmonary veins may result from abnormal relaxation of the left ventricle, which might result in higher atrial pressures during atrial diastole. This hypothesis is supported by our findings that patients with postoperative atrial fibrillation had larger pulmonary veins, left atrial appendages, and left atria. There is also evidence of an increase in right atrial pressure, as reflected by an increase in hepatic vein velocity, in these patients.

	Are these changes in atrial function related to atrial stunning or ischemia after open-heart surgery, or both? Because the atrial functional abnormalities occur predominantly after cardiopulmonary bypass, the evidence indirectly suggests that surgery or cardiopulmonary bypass, or both, may have been an inciting factor. How-

	of atrial protection during cardiopulmonary bypass because the adequacy of myocardial protection as assessed

	by the surgeons subjectively was similar between patients with and with-

	out postoperative atrial fibrillation in our study.

	The findings from our study provide evidence that patients who develop atrial fibrillation after bypass surgery have some of the same functional and structural alterations in the atria as those found in elderly patients with long-term atrial fibrillation. Furthermore, the development of atrial fibrillation after cardiac surgery is probably preceded by atrial dysfunction.

	Because prophylactic antiarrhythmic therapy may be prohibitive in cost and may have unwanted side effects, carefully choosing patients for therapeu-

	tic intervention before cardiac surgery based on the prediction of clinical risk should be explored as an alternative approach. Some of the risks identified in our study include a decrease in atrial systolic function and diastolic filling as shown on Doppler echocardiogram, white race, body surface area above 2.12 m2, and age older than 70 years. Additionally, future studies should evaluate methods to improve left ventricular diastolic filling and decrease left atrial size. Studies focusing on how atrial function is affected by loading conditions may also provide insight into how atrial dysfunction prior to surgery influences the occurrence of atrial fibrillation after cardiac surgery.

Impairment of left atrial function  and postoperative atrial fibrillation

	Jennings and Kamarck (page 28) prospectively studied the progression of carotid artery atherosclerosis in a cohort of patients from the Kuopio Ischemic Heart Disease (KIHD) study. The original KIHD study was an epidemiologic investigation conducted over a 5-year period (1984—1989) that evaluated cardiovascular risk factors in 2,682 men from Kuopio, Finland. In this study, 756 men were followed up for assessment of intima-media thickness (IMT) through the common carotid arteries by high-resolution B-mode ultrasonography at baseline, 4 years, and 11 years. The mean IMT, the maximum IMT, and the plaque height (defined as the difference between maximum and minimum thickness) were reported.

	An automated test sequence composed of four standardized computer-based tasks that evaluated memory and reaction time, including a computerized version of the Stroop Color-Word Task, was used as a measure of cardiovascular reactivity. The level of difficulty was adjusted to maintain a success rate of approximately 60%. Automated measurements of blood pressure and heart rate were taken in the dominant arm at 90-second intervals. Regression of blood pressure and heart rate responses on IMT were calculated, with adjustments being made for age and educational level, two factors known to influence cardiovascular responses.

	As expected, IMT increased over the 7-year period. When analyzed as a function of systolic blood pressure, the mean carotid IMT was 0.035 mm thicker for each standardized unit of change in systolic blood pressure induced by mental stress, which was approximately 7 mm Hg. The association persisted in a subsample

	of 195 patients who had no known cardiovascular disease, including hypertension, and who did not take any cardiac medications. Each standardized unit of change in systolic blood pressure response to mental stress was associated with a 7-year progression of 0.02 mm of thickening. Smoking status did not affect the association statistically.

	To examine psychological stress, Jennings and Kamarck used tasks of varying difficulty to determine cardiovascular responses. Although this method may create mental stress in a controlled setting, it fails to simulate the unpredictable nature of everyday life. Furthermore, responses to these tasks may simply be surrogate markers of the subject’s underlying personality.1 Associations between type A personality and exaggerated cardiovascular responses to laboratory tasks have been demonstrated.2 Conversely, submissive, type B behavior was protective against both nonfatal and fatal myocardial infarctions (MI), mainly in women.3 The current study falls short of evaluating the clinically relevant end points, such as MI and mortality. Previous studies have documented an increased risk of acute MI for each 0.1-mm increment in carotid IMT.4 Although the study by Jennings and Kamarck is suggestive, it remains unclear whether the observed 0.02-mm increase in IMT per standardized unit change in systolic blood pressure would lead to any increase in acute MI or mortality in this population.

	Causal links between psychological stress and MI in humans have been difficult to demonstrate.5 Limited animal studies have demonstrated positive results similar to this study. Manuck and colleagues studied the development of atherosclerosis with respect to heart rate responses to a standardized stress in monkeys on an atherogenic diet.6 The animals were categorized as high and low reactors based on heart response. Coronary intimal lesions were found to be twice as extensive in the high-reactor group. The use of beta blockade with a 20% heart rate reduction in the high-reactor group led to a statistically significant decline in atherosclerosis.7 This suggests that the physiologic responses triggered by stressor events (ie, adrenergic or other biochemical mediators are released) enhance atherosclerosis. Observational studies have shown that psychologic stress is associated with an acceleration of coronary artery disease (CAD).8 Biochemical parameters linking acute stress exposure to CAD have been identified, including interleukins, such as interleukin-1 beta and interleukin-2, and intercellular cell adhesion molecule-1. Stress may further enhance CAD risk through upregulation of the renin-angiotensin-aldosterone hormonal axis, direct endothelial damage, and aggravation of common risk factors, such as smoking, hypertension, and hypercholesterolemia.9

	If the increased risk of CAD with hard end points, including MI, can be demonstrated in human subjects with higher reactor response, the traditional CAD risk factors may need to be treated more aggressively in this subset. This study should be applauded for contributions in this arena, where information is still scarce. Further long-term studies using clinical end points such as MI and mortality are still required.

Exaggerated blood pressure  responses during mental stress and carotid atherosclerosis progression

	Mr. Jones is a hypothetical 55-year-old patient with some common cardiovascular risk factors (smoking, moderate obesity, borderline high cholesterol, prehypertension) but with no personal or family history of coronary heart disease. He has a demanding lifestyle, and he reports a number of chronic financial and interpersonal

	stressors, such as uncertainty at work (a number of his colleagues have suffered layoffs and transfers), financial problems, and caretaking responsibilities for his spouse, who has significant medical problems. A number of indications suggest that Mr. Jones may have a hyperdynamic circulation, for example, his blood pressure readings at several consecutive office visits are quite variable, and, on ambulatory blood pressure monitoring, he shows wide fluctuations in cardiovascular activity that appear to be related to periods of mental stress during the day.

	Given his unremarkable risk factor profile, however, he is not currently being treated for risk factor management. Findings such as those presented in the feature (page 28) suggest that the risk for cardiovascular events in such a patient may be greater than would otherwise be suspected based upon his age and risk factor profile, and that efforts at aggressive risk factor modification may be warranted. Although this decision strategy is consistent with results from the current report, further research is needed to extend the use of a mental stress battery to clinical practice.

A patient in need of aggressive  risk factor modification

	Psychological stress is frequently assumed to contribute to cardiovascular disease, but empirical support for this belief is just beginning to emerge.1 One approach to stress examines the cardiovascular responses to challenging tasks presented in laboratory settings. Individual differences in such cardiovascular reactivity are correlated with the current and future occurrence of a number of cardiovascular diseases.1 “Preclinical”2 indices of cardiovascular disease have typically been employed because such indices can be examined in community samples, permitting identification of disease in its early stages. Carotid intima-media thickness (IMT), for example, is related to systemic and coronary atherosclerosis as well as incidence and prevalence of myocardial infarction and stroke.3,4

	We previously observed that the amplitude of blood pressure reactions to laboratory challenges were associated with carotid IMT measurements  collected concurrently in the population-based Kuopio Ischemic Heart Disease (KIHD) study.5 We now report on the same measures of blood pressure reactivity as predictors of 7-year progression of carotid IMT.6

	Participants. KIHD is an epidemiologic investigation sampling the community of Kuopio, Finland—a relatively high-risk geographical region.7 KIHD is composed of four cohorts of men aged 42, 48, 54, and 60 years at the time of study initiation. Between 1991 and 1993, we tested 901 men from this study with both a standardized laboratory stress reactivity battery and with carotid ultrasound. Seven years later, between 1999 and 2001, 756 of these men participated in a carotid artery ultrasound follow-up.

	Carotid atherosclerosis. High-resolution B-mode ultrasonography was used to assess right and left common carotid arteries (CCAs) in a 1.0- to 1.5-cm section at the distal end of the CCA, proximal to the carotid bulb. A Biosound Phase 2 scanner equipped with a 10-MHz annular array probe was employed in both initial and follow-up examination.8 Prosound software (University of Southern California, Los Angeles, CA) provided a computerized analysis of the videotaped ultrasound images, using an edge-detection algorithm.9 This permitted assessment of IMT at approximately 100 points in both the right and left CCAs. In addition, lipoproteins and glucose were assessed with standard techniques.

	Cardiovascular reactivity testing. An automated test battery assessed individual differences in cardiovascular reactivity. This consisted of four standardized computer-based tasks, each 9 minutes long (memory task, reaction time task, tracing task, and computerized version of the Stroop Color-Word task).10 Tasks were separated by a 9-minute baseline (rest and recovery) period. The computer maintained difficulty of the tasks at approximately 60% success. Maintaining a consistent challenge contributed to the ability of this battery to show consistent individual differences in cardiovascular reactivity over repeated assessments.10

	A two-lead electrocardiogram was continuously assessed and blood pressure measurements (Dinamap Vital Signs Monitor) were taken every 90 seconds during the baseline and task periods. Heart rate, systolic, and diastolic blood pressures were averaged separately across the 9-minute period for each rest period and each task. Reactivity was then scored by subtracting the average rest period values from each averaged task score and averaging standardized measures across tasks.

	Three measures of IMT were used: (1) mean IMT, the mean of all IMT estimates from the right and left CCAs; (2) maximum IMT, the mean of the points of maximum thickness from

	the right and left CCAs; and (3) plaque height, the mean of right and left CCA measurements of plaque height, measured by the difference between maximum and minimum thickness.

	Analyses. Blood pressure and heart rate responses were used in regression analyses to predict IMT. Age and educational level (factors known to influence cardiovascular responses) were entered with the physiological responses initially, and then IMT from the initial assessment was added. Finally, analyses were repeated including standard risk factors (smoking status, low-density lipoprotein, high-density lipoprotein, serum triglyceride, fasting serum glucose, and resting systolic and dia-stolic blood pressures). Separate analyses were conducted for younger and older age groups and for participants reporting no cardiovascular disease

	or cardiovascular medication usage at the initial assessment.

	Seven-year prospective relations between reactivity and carotid measures. Enhanced blood pressure reactions to mental stress at the initial testing were related both to greater atherosclerosis 7 years later and to the increase in atherosclerosis over these 7 years. Controlling only for age and education, systolic blood pressure reactions were significantly related to degree of mean and maximal IMT as well as the plaque score (P < .001). This relationship remained after controlling for the carotid IMT at initial testing, thus assessing progression of IMT thickening (P < .008). Diastolic blood pressure responses to the mental stress challenges showed the same pattern of results, albeit with less statistical significance (P < .02 with age and education covaried; P < .08 with initial IMT added).

	Heart rate responses were unrelated to IMT measures. Figure 1 presents the relationship between systolic blood pressure reactivity at initial testing and carotid IMT assessed 7 years later. For illustrative purposes, values of systolic blood pressure reactivity are separated into quintiles, and the younger and older two cohorts are presented separately to illustrate the change in IMT with age and the applicability of our finding to both age groups. Figure 2 presents the relationship between quintiles of systolic blood pressure reactivity and progression of thickness of carotid IMT over 7 years. The Figures further illustrate the possibility, which we cannot yet interpret, that the relationship between systolic blood pressure reactivity and carotid IMT may not be strictly linear.

	An important issue is whether traditional risk factors may explain the relationship between blood pressure reactivity to laboratory challenge and progression of carotid artery disease. In fact, covarying known risk factors did not significantly modify the positive relationship between systolic blood pressure reactions and carotid IMT or its progression. The Table shows the results of this analysis. Diastolic blood pressure relationships were eliminated when risk factors were covaried. The Table presents standardized beta values in order to permit direct comparison of the strength of relationship between risk factors.

	Analyses of healthy individuals not taking medications at the time of initial testing (n = 195) continued to support the relationship between systolic blood pressure reactivity and subsequent carotid IMT (P < .02), but covarying the initial carotid IMT reduced the significance to P < .10. Analyses covarying and blocking on age did not demonstrate any age differences in the effects of blood pressure reactivity on IMT (despite such a finding in our initial cross-sectional report5).

	Systolic blood pressure reactivity to mental stress was observed to be positively and prospectively related to carotid artery IMT measures taken

	7 years later. Mean carotid IMT was 0.035 mm thicker for each standardized unit of mental-stress induced change of systolic blood pressure (approximately 7 mm Hg of change in blood pressure). This prospective relationship was not altered when both the preexisting carotid artery values and recognized risk factors were taken into account. A change of approximately 7 mm Hg of blood pressure reactivity to stress was related to a progression over 7 years of 0.02 mm of thickening of the carotid IMT. Based on previous work, this would translate into an increase of approximately 1% every 3 years in risk for myocardial infarction.4,11 This magnitude of association may have public health significance and possibly clinical significance when considered in concert with other independent risk factors.

	The results reported here provide substantial support for the hypothesis that cardiovascular reactivity is re-

	lated to the progression of the atherosclerosis. The current results are based on a larger sample and more thorough measurements than previous work.12-15 The current results are consistent with these studies and, taken together, suggest the predictive validity of magnitude of systolic blood pressure responses to laboratory challenges regardless of gender and nature of the sample, eg, community versus clini-cal sample.

	A number of limitations of this study should be noted. The sample was all men and from a high-risk area of eastern Finland. This limits generalization. We did not study mortality or morbidity of myocardial infarction or stroke. The methods are correlational and unknown/unmeasured factors related to blood pressure reactivity might account for the results. Finally, the results do not illuminate any mechanism for the relationship of reactivity and atherosclerosis (although a number of mechanisms have been proposed1). We do claim that relative to our prior cross-sectional findings,5 these prospective results more strongly support a role for cardiovascular reactivity in the atherosclerotic process.

Stress-induced blood pressure  reactions: A pathway to coronary artery disease?

	The article by Mozaffarian and colleagues (page 20) details results of a prospective dietary study in 4,778 individuals aged 65 and older, which is in its conception both insightful and gratifying. The study concludes that risk of stroke, particularly ischemic stroke, can be reduced by up to 30% by modest weekly intake of “fatty” (eg, tuna, salmon) unfried fish. This study is somewhat unique in that it restricts its cohort to individuals who are primarily at risk for stroke, namely the elderly. Fully two thirds of all strokes occur after age 65, and the risk after this age increases throughout late life.1 Moreover, the study is especially powerful because it is prospective, and it follows the cohort over a sufficiently long period to accumulate relatively large numbers of stroke end points.

	Previous studies on this issue have had some conflict in their results. An excellent meta-analysis of the nine cohort studies that have been undertaken calculated pooled relative risks to be at least 32% less for those who consumed fish at least once a month.2 Two large studies3,4 did not demonstrate this benefit, but the numbers of stroke end points were very low in both, suggesting that the participants were not followed into late life. In fact, the famed Physicians’ Health Study4 followed 21,185 men with an average age of only 51 for a mere 4 years. It should not be surprising, then, that only 173 strokes were observed in this setting. The authors concluded that fish consumption was not protective for stroke (or cardiovascular disease). An equally pertinent, if cynical, conclusion might have been that for younger individuals such as those in this cohort with an approximate annual stroke risk of 0.2%, the point is moot. Moreover, the putative beneficial mechanisms of the n-3 fatty acids in fatty fish include platelet inhibition and improvement of vascular reactivity.5,6 Unlike an intervention that would (only) inhibit chronic atherogenesis, these benefits would seem to confer a more immediate protection from platelet aggregation and ischemia in an aging—and potentially already atherosclerotic&mdash;cerebral circulation.

	The study by Mozaffarian and colleagues included 4,778 men and women free of cerebrovascular disease at baseline, who filled out dietary questionnaires which stratified fish intake by frequency as well as type—particularly fried versus broiled/baked fish, and tuna. A subset of participants was shown to have correlation between n-3 fatty acid plasma concentration with intake of the broiled/baked/tuna fish but not fried fish. In 12 years of follow-up, 626 incident strokes were documented, of which 537 (86%) were ischemic. This implies an approximate stroke incidence of 3.2% per year, consistent with data from the Framingham study.1 The relative risk of overall and especially ischemic stroke was reduced by at least 26% with the consumption of broiled/baked/tuna fish but not fried fish/fish sandwich consumption. No significant benefit (or risk) was conferred by any fish for hemorrhagic stroke. Given the putative mechanisms of n-3 fatty acids, I wonder if the end points were further stratified to include ischemic stroke subtypes, if fish consumption would have shown even greater protection against atherothrombotic ischemic stroke.

	There are many strengths of this study, particularly in terms of its prospective nature and the cohort, as noted above. Further, the n-3 fatty acid correlation substudy is reassuring, as are the analyses adjusting for confounding factors such as education, smoking, or aspirin use. There may, of course, be other “unmeasured or imprecisely measured” confounders such as elements of a healthy lifestyle, for example, increased exercise and moderate wine intake in those who enjoy baked/broiled fish, versus sedentary lifestyle and higher consumption of other fatty foods in those who do not enjoy these foods. This seems to be at least suggested in the higher relative risks of those in the study who consumed fried fish/fish sandwiches. However, these considerations are largely outweighed by the consistency of results after other adjustments in the study, and with the results of other large studies.

	The results of the study by Mozaffarian and colleagues apply to precisely that population in which primary stroke prevention is of greatest importance. Furthermore, the results are easily and immediately applicable to this population, particularly as the interven-tion only involves eating at least one meal of fatty fish per week. In summary, this study is very generalizable, highly believable from a biological standpoint, and readily usable in practice. For the majority of my stroke-prone patients, and certainly for those of any elderly caregiver, it is the catch of the day.

Fish consumption and stroke  risk in elderly individuals:  The catch of the day

	A 71-year-old woman arrived at her physician’s office for a follow-up visit. She had a history of hypertension, which was well-controlled with a diuretic and an angiotensin-converting enzyme inhibitor. She had smoked cigarettes for more than 30 years in the past, but quit on her 65th birthday and had not smoked since. She did not have diabetes and was not obese. She was independent and active, walking 20 to 30 minutes daily most days of the week. Her total serum cholesterol level was modestly elevated, but her total cholesterol to high-density lipoprotein cholesterol ratio was within the optimal range. One year earlier, she had a transient ischemic attack, with evaluation at that time revealing 30% to 40% carotid atherosclerosis bilaterally and modest left ventricular hypertrophy with preserved systolic function. Since that time, she had been taking one aspirin, 325 mg, daily. On physical examination, she was an alert elderly woman, with a heart rate of 70 beats per minute, a blood pressure of 128/65 mm Hg, and unremarkable cardiac, pulmonary, and neurologic examinations.

	At this visit, she related that her first cousin recently had a “massive” stroke. This cousin had previously been living independently, playing golf, and traveling, but now had complete left-sided hemiparesis and lived in a nursing home. She was concerned about her own risk of stroke and wished to know what she could do to reduce her risk further. She had heard that fish might be good for the heart and wondered if fish intake might have any effect on stroke risk, particularly at her age. Also, if there was a potential benefit from fish intake, she wished to know how frequently she should consume fish to obtain that benefit and whether the type of fish meal consumed or the method of preparation make a difference.

	Based on the current evidence, she was advised to consume at least one serving per week of fatty or oily fish, such as salmon, herring, or tuna, and informed that intake of lean (white) fish might not provide similar benefits, particularly if fried.

Can fish intake reduce stroke risk? 

	Cardiovascular disease is the leading cause of death and disability in older adults, the most rapidly growing segment of the population. While n-3 fatty acids in fish have several effects that may reduce stroke risk,1-4 results of previous studies of fish intake and stroke incidence have been inconsistent,5-10 and none have focused on elderly individuals, in whom disease burden may be high and dietary habits may have less influence. Health effects of fish intake may also vary with the type of fish meal consumed, with effects differing for intake of tuna or other broiled or baked fish compared with fried fish.11 We evaluated the relationship between fish consumption and risk of stroke in the Cardiovascular Health Study, a population-based, longitudinal cohort study of older adults.

	We studied 4,778 men and women aged 65 or older who were free of known cerebrovascular disease at baseline. Subjects were randomly selected and enrolled from Medicare eligibility lists in four US communities from 1989 to 1990. Medical history and cardiovascular risk factors were ascertained, and subjects underwent physical examination and laboratory testing. Usual dietary intake was assessed at baseline using a food frequency questionnaire, including questions on tuna fish, other fish (broiled or baked), and fried fish or fish sandwiches (fried fish burgers). In a subset of participants, intake of tuna/other fish correlated with plasma phospholipid concentrations of long-chain n-3 fatty acids (r = 0.59; P < .001), while intake of fried fish/fish sandwiches did not (r = 0.04; P = .78),11 consistent with the lean, white fish (eg, cod) typically used for these fried fish meals.

	Incident strokes were identified during annual examinations, phone contacts, and reviews of hospital discharge records and centrally adjudicated using medical records, death certificates, medical examiner forms, Centers for Medicare and Medicaid Services hospitalizations, and available computed tomography or magnetic resonance imaging scans. Cox proportional-hazards models were used to evaluate the associations between fish intake and risk of stroke. Statistical tests were two-tailed (a = 0.05).

	Fried fish/fish sandwich consumption was associated with male sex, nonwhite race, and lower education, while tuna/other fish consumption was associated with younger age, female sex, and higher education (Table 1). In general, tuna/other fish consumption was associated with a more favorable cardiovascular risk profile; however, body mass index and low-density lipoprotein (LDL) cholesterol levels were higher with greater intake. Associations with other dietary habits are also shown in Table 1.

	During 12 years of follow-up, 626 incident strokes were documented. The incidence of stroke among subjects who consumed tuna/other fish five or more times a week was 12 per 1,000 person-years compared with 19 per 1,000 person-years among those who consumed this type of fish meal less than once a month (P = .002; Figure). Among those consuming fried fish/fish sandwiches one or more times a week, the incidence of stroke was 17 per 1,000 person-years versus 13 per 1,000 person-years for those who consumed fried fish meals less than once a month (P = .02; Figure).

	After adjusting for potential confounding factors, tuna/other fish intake was inversely associated with risk of stroke, with a trend toward a 13% lower risk with consumption one to three times per month, a 25% lower risk with consumption one to four times a week, and a 26% lower risk with consumption five or more times a week, compared with less than once a month (P for trend = .04; Table 2). When stroke subtypes were separately analyzed, we found an inverse association between tuna/other fish intake and ischemic stroke, with a trend toward a 13% lower risk with consumption one to three times a month, a 27% lower risk with consumption one to four times a week, and a 30% lower risk with consumption five or more times per week, compared with less than once a month (P for trend = .02). Tuna/other fish intake was not significantly associated with risk of hemorrhagic stroke.

	Conversely, fried fish/fish sandwich consumption was associated with a higher risk of stroke. In multivariate-adjusted analyses, consuming fried fish/fish sandwiches at least once a week was associated with 37% higher risk of total stroke and 44% higher risk of ischemic stroke compared with consumption less than once a month (P for trend = .006 for total stroke and .003 for ischemic stroke; Table 2). When evaluated continuously, each one serving per week predicted a 10% higher risk of total stroke (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.02—1.19) and a 13% higher risk of ischemic stroke (HR, 1.13; 95% CI, 1.04–1.22; adjustments as in Table 2).

	Further adjustment for factors that might mediate associations between fish intake and stroke risk (systolic blood pressure, LDL cholesterol, high-density lipoprotein cholesterol, triglycerides, C-reactive protein) or exclusion of participants who used fish oil supplements (n = 178) or who had atrial fibrillation (n = 261) at baseline had little effect on these results (data not shown). Further, there was little evidence that findings varied with age, sex, education, diabetes, prevalent coronary heart disease, treated hypertension, systolic blood pressure, smoking, or aspirin use (P > .05 for each interaction).

	Among these older adults, consumption of tuna or other broiled or baked fish was associated with a lower incidence of stroke. While these observational findings do not prove causality, this relationship was present after adjustment for a variety of demographic, clinical, and lifestyle factors. Furthermore, there are plausible biologic mechanisms that may explain the beneficial effects of tuna/other fish consumption on the incidence of stroke, particularly ischemic stroke. Fish oil has been found to influence blood pressure, serum lipid levels, inflammatory responses, endothelial cell function, and cerebral arteriolar reactivity in experimental studies.1-4 Each of these effects, alone or in combination, may reduce the risk of ischemic stroke.

	Compared with no intake or infrequent intake (less than once a month), frequent intake of tuna/other fish (five or more times a week) was associated with a reduction in risk that was similar to that found with modest intake (one to four times times a week), with an approximately 25% lower risk of total stroke and a 30% lower risk of ischemic stroke. This suggests a potential threshold effect for the benefits of fatty fish intake at approximately one serving a week. Such a threshold effect, also suggested by a previous report,10 is compatible with the time course of incorporation of n-3 fatty acids from fish into cell membranes, whereby a single meal can produce changes lasting for days to weeks.12

	Previous ecologic studies have suggested that high seafood intake is associated with a higher risk of hemorrhagic stroke, possibly because of antithrombotic effects.13 However, we did not observe a higher risk of hemorrhagic stroke with fish intake. Experimental studies suggest that fish oil only affects bleeding times at high doses (3—15 g daily),14 much higher than the typical dietary fish intake. Although the few numbers of hemorrhagic strokes in our study limit definitive conclusions, our results, together with those of prior cohort studies,9-10 suggest that modest tuna/other fish consumption does not significantly increase the risk of hemorrhagic stroke, particularly relative to the potential reduction in ischemic stroke risk.

	Consumption of fried fish/fish sandwiches was associated with a higher risk of stroke, particularly ischemic stroke. These results are consistent with positive associations between fried fish/fish sandwich intake and risk of ischemic heart disease reported previously.11 Given the lack of correlation between fried fish intake and plasma phospholipid n-3 fatty acid levels, it is likely that most of these fish meals were made with lean, white fish, which is low in fish oil content. The observed higher stroke risk could, therefore, be due to an unfavorable risk—benefit ratio, with (1) relatively little benefit because of the low fish oil content and (2) potentially harmful effects from possible contaminants in the fish (eg, mercury) or from transfatty acids and lipid oxidation products in the fried fats and oils, particularly partially hydrogenated fats and oils used repeatedly for frying.15 Fried fish/fish sandwich consumption may also be a marker for some other factor that increases cardiovascular risk; however, the observed relationships were present after adjustment for a variety of demographic, clinical, and lifestyle characteristics. Further research is necessary to confirm these observations, to determine if they are specific for certain kinds of fish or frying oils, and to examine potential mechanisms.

	Several characteristics of our study design enhance the validity of our findings. The prospective design as well as the exclusion of those with known cerebrovascular disease at baseline reduce potential biases from recall differences or dietary changes due to known disease. Standardized assessment of a wide variety of subject characteristics increased the ability to adjust for confounding factors. Close follow-up and centralized adjudication reduced the potential for missed or misclassified outcomes. The population-based recruitment strategy enhanced generalizability.

	Potential limitations are also present. Usual fish intake was assessed at the beginning of the study and may have changed over time. Additionally, the food frequency questionnaire assessed categories of fish intake, rather than precise frequencies or quantities. These factors would produce error (misclassification) in the measurement of fish intake, which would bias results toward the null. For fried fish intake, we could not separately evaluate the type of fish versus the preparation method. Although we adjusted for a variety of participant characteristics, residual confounding by unmeasured or imprecisely measured factors cannot be excluded.

	The proportion of older adults in the United States and most other nations is rising. Because cardiovascular disease risk increases dramatically with increasing age, determining which factors are related to healthy aging is of critical importance. We assessed the relationship between dietary habits and stroke risk late in life, with an average baseline age of 73 years and 12 years of follow-up. While the associations we observed may reflect dietary habits at earlier ages, our findings suggest that diet may influence stroke

	risk later in life. Our results also indicate that the fish oil content or preparation method may be important when considering the effects of fish intake on stroke risk. Continued investigation of these relationships, including potential mechanisms of benefit and risk, is indicated.

 Fish consumption and stroke risk

	As a result of evidence that HMG-CoA reductase inhibitors (statins) may have direct actions against diffuse coronary artery damage in addition to a cholesterol-lowering effect, much research is being focused on the potential pleiotropic effects of statins. Clinical studies with positron emission tomography (PET) that can quantify myocardial blood flow (MBF)1 have shown that the myocardial vasodilatation index (MVI) can be reduced in patients without evidence of coronary artery disease (CAD).2-7 Cholesterol-lowering drugs, including statins, have been reported to improve the MVI.8-11 Studies of the effects of statins on impaired MVI in hyperlipidemic patients, however, have been inconsistent.8-12

	The objective of the present randomized study was to evaluate the effect of simvastatin (Zocor) and pravastatin (Pravachol) therapy on impaired MVI in patients with increased cholesterol levels.

	We compared nondiabetic hypercholesterolemic patients without hyperten-

	sion and without evidence of CAD who had not previously taken lipid-lowering drugs (n = 44) with normal control subjects (n = 22). Patients were randomly assigned to pravastatin (10—20 mg/day; n = 22) or simvastatin therapy (5–10 mg/day; n = 22). Baseline MBF and MBF during hyperemic stress with dipyridamole loading (MBF-dipyridamole) were measured with [13N]ammonia and PET before treatment and 8 to 12 months after treatment. The MVI was computed by dividing MBF-dipyridamole by the baseline MBF. The mean length of time for treatment in the pravastatin and simvastatin groups was 10.2 ± 2.1 and 10.1 ± 1.9 months, respectively.

	Patients in the pravastatin and simvastatin groups were similar with regard to general characteristics (Table 1). Baseline total cholesterol and low-density lipoprotein (LDL) cholesterol levels were also similar, and both total cholesterol and LDL cholesterol levels were markedly higher than those in the control group (Table 2). For both treatment groups, the total cholesterol level was markedly decreased at the end of therapy, and the LDL cholesterol level fell to the same level as the control group (Table 2). There was no significant difference in percent change in total cholesterol and LDL cholesterol between the two treatment groups.

	The three groups were similar at baseline with regard to MBF. Baseline MBF in the two treatment groups did not change throughout the study (Figure 1). The MBF-dipyridamole, however, was significantly lower in both treatment groups than in the control group before treatment, although there was no difference in MBF-dipyridamole before therapy between the two treatment groups. Simvastatin significantly increased MBF-dipyridamole to the control level, whereas pravastatin did not (Figure 2).

	Baseline MVI in the two treatment groups was similar before therapy and was significantly lower than in the control group. After treatment, however, simvastatin significantly increased MVI to the level of the control group, whereas pravastatin did not (Figure 3).

	The two treatment groups had no significant change in baseline MBF after treatment. Furthermore, MBF-dipyridamole in the simvastatin group before therapy was not significantly different from that of the pravastatin group. Percent change for MVI in the simvastatin group, however, was significantly higher than that in the pravastatin group. Percent change for MVI in the simvastatin group showed weak but significant negative correlations with percent change in total cholesterol and LDL cholesterol levels.

	Studies of the effects of statins on impaired MVI in hyperlipidemic patients have produced varying results, namely, a significant improvement from simvastatin or fluvastatin treatment7-11 and no significant improvement from pravastatin.12 The effect of statins on MVI, however, has not been compared directly.

	In this study, MBF-dipyridamole and MVI were significantly reduced in hypercholesterolemic patients, and both were reversed by simvastatin but not by pravastatin. Because study patients had little likelihood of developing CAD, reduced MVI can be credited to diffuse injury to the coronary arteries. Simvastatin, therefore, had a direct effect on improvement of myocardial vasodilatory function via improvement of the injury to the coronary arteries, whereas pravastatin did not, despite the fact that the improvement in lipid fractions for both simvastatin and pravastatin was comparable.

	Our results indicate a difference in the effects of simvastatin and prava-statin on the impaired MVI in hyper-cholesterolemic patients. Furthermore, improvement of MVI is not attributed to the improvement of plasma lipid fractions but to some other mechanism. Improvement in lipid profiles is not the only advantage of statins. These drugs also favorably affect blood vessels, and differences in pleiotropic effects between pravastatin, which is hydrophilic, and simvastatin, which is lipophilic, have been reported. Simvastatin has also been shown to induce apoptosis of vascular smooth muscle cells, as well as to inhibit the abnormal proliferation and migration of smooth muscle cells, whereas pravastatin has not. Improvement of MVI is most likely the result of the direct vascular effects of statins, and differences in such effects explain our results, which showed that only simvastatin improved MVI. The mechanisms involved in the improvement of MVI remain uncertain; this suggests that statins may affect coronary circulation not through the reduction of lipid levels but through other actions, which may vary among statins. With simvastatin treatment, improvement of MVI correlated weakly but significantly with lipid fractions. This may possibly be because the improvement of MVI and the lipid-lowering effects depend partially on a common factor, such as the drug’s bioavailability.

	In patients with high cholesterol levels, studies have shown that pra-

	vastatin beneficially affects endothelial function, but not MVI, which indicates that increasing endothelial function is not related directly to improvement of MVI. Simvastatin’s beneficial effects on MVI may be attributed to an improvement in diffuse coronary damage.

	Statins have direct beneficial effects on blood vessels in addition to their cholesterol-lowering properties, and the extent of these novel pleiotropic effects differs according to the individual statin. Simvastatin improves impaired myocardial vasodilatation function through some mechanism other than its cholesterol-lowering action.

Myocardial vasodilatation with simvastatin versus pravastatin in patients with hypercholesterolemia

	A 61-year-old woman with hyperlipidemia but no history of heart disease or chronic diseases was admitted to our hospital. She had no symptoms or signs of coronary artery disease (CAD), including negative results on exercise stress testing. She agreed to participate in our study using positron emission tomography (PET) and [13N]-ammonia to assess the myocardial vasodilatation index (MVI) in response to dipyridamole loading. The patient was treated with simvastatin (Zocor; 10 mg/day) for 10 months. The plasma total cholesterol concentration decreased after simvastatin treatment, from 307 mg/dL before therapy to 212 mg/dL after therapy, as did the plasma low-density lipoprotein (LDL) cholesterol level (from 222 mg/dL before to 134 mg/dL after) and plasma triglycerides (165 mg/dL before to 143 mg/dL after). Plasma high-density lipoprotein (HDL) cholesterol concentration was similar before (52 mg/dL) and after (49 mg/dL) therapy. A dynamic PET perfusion study showed that baseline myocardial blood flow (MBF; mL/min/100 g heart weight) before simvastatin therapy (66.0 mL/min/100 g) was comparable with MBF after therapy (75.7 mL/min/100 g). MBF during dipyridamole administration before therapy (145.4 mL/min/100 g) improved after simvastatin therapy (376.0 mL/min/100 g). MVI as determined by a ratio of MBF during dipyridamole administration to baseline MBF before therapy (2.20) significantly increased after therapy (4.97). Static PET myocardial perfusion images at rest and during dipyridamole loading did not show any regional perfusion abnormality.

	A 49-year-old man with hyperlipidemia but no history

	of heart disease or chronic diseases was admitted to our hospital for treatment of hyperlipidemia. He had no symptoms or signs of CAD, including negative results on exercise stress testing. He agreed to participate in our study. After treat-ment with 20 mg/day of pravastatin (Pravachol) for 10 months, the plasma total cholesterol (266 mg/dL before

	therapy versus 222 mg/dL after therapy), plasma LDL cholesterol (168 mg/dL before versus 118 mg/dL after) and

	plasma triglyceride (206 mg/dL before versus 160 mg/dL after) levels improved. Plasma HDL cholesterol concentration also improved (57 mg/dL before versus 74 mg/dL after). However, a dynamic PET myocardial perfusion study with [13N]-ammonia and a two-compartment tracer kinetic model1* showed that baseline MBF before pravastatin therapy (63.0 mL/min/100 g) was comparable with that after the therapy (61.0 mL/min/100 g). MBF during dipyridamole administration also did not change (100.0 mL/min/100 g before therapy versus 106.0 mL/min/100 g after therapy), nor did MVI (1.59 before versus 1.63.0 after). Static PET myocardial perfusion images at rest and during dipyridamole loading did not show any regional perfusion abnormality.

	It has been well recognized that hyperlipidemia can reduce MVI in patients without symptoms and signs of heart disease.2-7 It has also been reported that lipid-lowering therapy can improve MVI in hyperlipidemic patients.8-11 However, studies have been inconsistent. For example, it has been reported that pravastatin cannot improve MVI in hyperlipidemic patients,12 whereas fluvastatin (Lescol)9 and simva-statin can.10,11 Apart from reducing cholesterol, the secondary effects of statins appear to differ between simvastatin and pravastatin. Our results suggest that simvastatin but not pravastatin can improve impaired MVI in patients with hyperlipidemia.

Myocardial vasodilatation index  after statin treatment

	Results of two studies presented at the American Society of Hypertension An-nual Scientific Meeting found that olmesartan medoxomil (Benicar) and olmesartan medoxomil/hydrochlorothiazide (Benicar HCT) can effectively treat patients with Stage 1 and Stage 2 hypertension to achieve blood pressure goals.

	The Benicar Efficacy in Systolic Hypertension Trial (BEST) was a 16-week, prospective, open-label, multicenter study that included 176 patients with Stage 2 hypertension (mean blood pressure 171/95 mm Hg). After a 3- to 4-week, pla-cebo run-in period, the patients (mean age 60 years) were given a 20-mg dose of olmesartan medoxomil once daily. Doses were up-titrated at 3-week intervals if blood pressure remained at 120/80 mm Hg or higher, to 40 mg olmesartan medoxomil daily, then 40/12.5 mg daily of olmesartan medoxomil/hydrochlorothiazide, and then to 40/25 mg daily of olmesartan medoxomil/hydrochlorothiazide. The primary end point was mean change in baseline systolic blood pressure at 12 weeks. The secondary end points assessed blood pressure changes from baseline after each titration period as well as the number of patients who achieved the blood pressure goal of 140/90 mm Hg or lower or normalization of blood pressure to below 120/80 mm Hg. Results showed that the 40/25-mg dose of olmesartan medoxomil/hydrochlorothiazide helped 70% of patients with a mean blood pressure of 171/95 mm Hg to reach the goal of below 140/90 mm Hg. This treatment lowered systolic blood pressure by an average of approximately 35 mm Hg.

	Results of another study presented at the meeting, Treatment of Stage 1 and Stage 2 Hypertension Utilizing an Olmesartan Medoxomil-based Treatment Algorithm, also demonstrated the efficacy of olmesartan medoxomil/hydrochlorothiazide,

	as well as olmesartan medoxomil. This study, a 24-week, multicenter, open-label trial, included 79 patients with Stage 1 hypertension and 100 patients with Stage 2 hypertension. Patients were started on olmesartan medoxomil, 20 mg daily, after a placebo run-in phase of up to 4

	weeks. If the goal of 130/85 mm Hg or lower was not achieved, the dose was increased at 4-week intervals according to the study algorithm, using the same doses as in the BEST study for each in-

	5 to 10 mg daily, thereafter if needed. Of the eligible patients with Stage 1 hypertension who were taking olmesartan medoxomil or olmesartan medoxomil/

	hydrochlorothiazide, 89% reached the aggressive goal of 130/85 mm Hg or lower, and of the total patients with Stage 1 hypertension, 56% reached goal on olmesartan medoxomil monotherapy alone. More than one half of the patients with Stage 2 hypertension reached goal taking olmesartan medoxomil or olmesartan medoxomil/hydrochlorothiazide.

	Joseph Izzo, Jr., MD, professor of medicine and pharmacology, State University of New York at Buffalo, and a member of the executive committee of the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) commented on the results of the studies, stressing the importance of meeting goals outlined in JNC 7. The two studies demonstrate that tools are available for helping patients reach these goals, he said.

Olmesartan medoxomil-based treatments effectively  lower blood pressure 

	San Francisco—Primary results of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial presented last year showed that treatment with the angiotensin receptor blocker (ARB) valsartan (Diovan) or the calcium channel blocker (CCB) amlodipine (Norvasc) had similar effects in patients with hypertension and a high risk of cardiac disease. For one of the other end points, however&mdash;new-onset diabetes&mdash;there was a 23% lower risk of developing diabetes in the valsartan group compared with the amlodipine group.

	According to information presented at the 20th Annual Meeting of the American Society of Hypertension by Kenneth A. Jamerson, MD, professor of internal medicine at the University of Michigan (UM),

	a new analysis of the diabetes end point in VALUE has reconfirmed the positive effect of valsartan on glucose metabolism. The new analysis of data showed that the difference in risk of diabetes onset appears to be attributable to valsartan and not to other underlying risk factors.

	The original VALUE trial enrolled 15,313 patients in the United States and Europe, 9,995 of whom did not have diabetes at the start of the study. All patients were over age 50 and had hypertension and a high risk for having a cardiac event. At the end of 4 or more years of follow-up, 11.5% of patients taking valsartan had developed diabetes versus 14.5% of those taking amlodipine.

	Commented Dr. Jamerson, “Since we know from other studies that other hypertension medications, such as diuretics, come with a higher risk of diabetes, this result is especially interesting.” His

	UM colleague and VALUE trial chairman, Stevo Julius, MD, ScD, stated, “This analysis looked in great detail at which factors might predict new onset of diabetes in this population, and found that the difference in risk of onset must be due to an active effect of valsartan. Whether this is due to increased insulin sensitivity, prevention of oxidative stress, or some other mechanism is still to be determined.”

	Prevention of new-onset diabetes was not a primary goal of the VALUE study, so more research will be needed to confirm these findings.

	Patients with diabetes before randomization were excluded from the VALUE trial, and all cases of new-onset diabetes were identified according to three criteria: (1) reports in adverse events databases, (2) patient study forms showing a new diagnosis of diabetes or new use of antidiabetic medications, or (3) blood tests at the end of the study that showed serum glucose greater than 7.8 mmol/L.

	Using this definition and a mean follow-up of 4.2 years, the patients in the highest-risk group were found to be six times more likely than those in the lowest-risk group

	to develop diabetes, but those in the highest- and second-highest-risk groups who were taking valsartan were significantly less likely to develop diabetes. According to the authors, this suggests that valsartan has some effect on glucose metabolism beyond blood pressure lowering, but the mechanism remains unclear.

	in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. The NAVIGATOR trial is attempting to determine if long-term administration of either drug will delay or reduce the development of type 2 diabetes and cardiovascular disease in patients with impaired glucose tolerance and at high cardiovascular risk.

 Blood pressure drug reduces risk of new-onset diabetes

	A s documented in several large population-based clinical trials, the widespread use of HMG-CoA reductase inhibitors (statins) has the potential to dramatically reduce the incidence of cardiovascular disease.1-5 Statins work by inhibiting the rate-limiting step of cholesterol synthesis, HMG-CoA reductase-dependent cholesterol biosynthesis. This inhibition results in a decrease in hepatocellular cholesterol, which causes an upregulation of hepatic low-density lipoprotein (LDL) cholesterol receptors, with the result that more LDL is removed from

	the circulation and serum LDL levels are lowered. This cholesterol-lowering effect has been assumed to underlie the clinical efficacy of

	the class of drugs; however, other pleiotropic

	effects are increasingly being acknowledged.6 These effects include improvement of en-

	dothelial dysfunction, increased nitric oxide bioavailability, antioxidant effects, antiinflammatory properties, and stabilization of atherosclerotic plaques, all of which have obvious relevance in patients with subclinical coronary artery disease.

	The present study by Yokoyama and colleagues (page 13) indirectly investigated the statin effect on endothelial dysfunction. The study was designed to test whether there are differences in myocardial blood flow (MBF) and myocardial vasodilatation index (MVI) in patients with presumed subclinical coronary disease, and whether these indices can be selectively influenced by treatment with statins. MBF was determined by [13N]ammonia positron emission tomography (PET) scanning in 44 asymptomatic patients with hypercholesterolemia before and after lipid-lowering treatment and contrasted with 22 normal controls. An equal number of hypercholesterolemic patients were randomly assigned to low doses of pravastatin (Pravachol) and simvastatin (Zocor) and were treated for 10 months, yielding equivalent cholesterol lowering. Both groups and controls underwent myocardial perfusion scanning by [13N] PET at rest and with dipyridamole before and after treatment with their respective statins. MBF and MVI were decreased significantly before treatment as compared with controls in both hypercholesterolemic groups. Only the simvastatin group showed a statistically significant improvement in these measures after treatment.

	The data suggest that simvastatin, not pravastatin, asserts pleiotropic effects that improved MVI since cholesterol and LDL lowering were similar in both groups. It is certainly possible that these results are mediated by innate differences in the statins. Pravastatin is a hydrophilic statin, while simvastatin is lipophilic, and in vitro studies have suggested that lipophilic and not hydrophilic agents are more effective in activating inducible nitric oxide synthase.7 In rat blood vessels, acute vasodilatation was achieved in a dose-dependent fashion with lipophilic statins but not hydrophilic statins.8 Any extrapolation from in vitro studies, however, should be tempered by the fact that the drug levels required to bring about pleiotropic effects are far greater than those that can be achieved in vivo. Given this, the distinction between simvastatin and pravastatin may be a reflection of relative drug potency (very low levels of statins were employed in this study) and not innate biologic differences, a conclusion that is supported by the fact that more potent hydrophilic statins such as ro-suvastatin have also shown similar pleiotropic effects as compared with lipophilic statins.9,10

	While this study suggests that myocardial vasodilatation, which is a marker of endothelial dysfunction, is selectively improved with simvastatin, the results should be viewed with caution. In clinical trials, both simvastatin and pravastatin have been shown to decrease cardiovascular events, a fact that would seem to cede more bio-

	logic importance to the primary lipid lowering class effect than the pleiotropic effect. It is also possible that the differences in the treatment groups in this small study were not related to drug effects but to differences in the patients studied. Although the authors made a good-faith effort to randomize the patients appropriately (and in fact baseline lipoprotein profiles were similar), there may well have been varying levels of endothelial dysfunction or inflammation (as well as age and sex differences) in the two treatment groups that were not appreciated. In fact, there was improvement in MVI in eight of the 22 patients treated with pravastatin and no improvement in six of the patients treated with simvastatin. This could possibly have been acknowledged had the authors chosen a more complex double-blind crossover design.  

	While it appears likely (albeit as yet not conclusively demonstrated) that all statins are not the same, the more compelling question, perhaps, is which of the several pleiotropic effects associated with this class of drugs (if any) are clinically important. Addressing this question is critically important and not at all straightforward.

Are all statins alike? How important is pleiotropy?

	San Francisco—A new definition of hypertension that incorporates additional risk factors for cardiovascular disease has been proposed by a writing group for the American Society of Hypertension (ASH). The proposal was announced at the 20th Annual Scientific Meeting of ASH in San Francisco.

	Defining hypertension solely by numbers “doesn’t suffice because blood pressure is a continuous variable,” said Thomas Giles, MD, president of ASH and professor of medicine at Louisiana State University, New Orleans.

	“In the past, there was a heavy reliance on blood pressure numbers…

	limiting the ability to calculate risk in an individual. Hypertension is more than just an elevated number,” he said.

	“Our new definition incorporates the presence or absence of risk factors, early disease markers, and target-organ damage, and more accurately represents the different physiological abnormalities in the cardiovascular system and other organs caused by hypertension.”

	The new definition is needed, he said, because more than 80% of patients with hypertension have additional comorbidities, such as obesity or glucose or lipid abnormalities. “For any level of blood pressure, the risk adjustment depends on a huge number of factors that need treatment as well,” he said.

	Current blood pressure classifications use arbitrary cutpoints to define hypertension at its various stages, without assessing the patient’s actual risk based on other factors such as left ventricular hypertrophy, microalbuminuria, or lipid levels. This system may be misleading because an individual patient’s blood pressure can fall a few millimeters of mercury below a defining cutpoint yet the patient can have a significant number of other cardiovascular risk factors or target-organ damage.

	“Hypertension is a progressive car-diovascular syndrome arising from complex and interrelated etiologies. Early markers of the syndrome are often

	present before blood pressure elevation is sustained; therefore, hypertension

	cannot be classified solely by discrete blood pressure thresholds. Progression

	and structural cardiac and vascular abnormalities that damage the heart,

	kidneys, brain, vasculature and other organs and lead to premature morbidity and death.”

	An expanded classification scheme has also been proposed to reflect the new thinking. For example, Stage 1 hypertension would be defined by early signs of functional and structural changes in the heart and small arteries, “and could be reflected in, for example, microalbuminuria, just to indicate one,” he said. This stage would also include individuals with multiple cardiovascular risk factors and early disease who do not yet show evidence of target-organ damage.

	The new definition does not contain the “prehypertension” category that was created by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of

	High Blood Pressure (JNC 7). “We believed that the term was a transitional one,” said Dr. Giles. “It painted 40 million people with the same brush but within this group there are some at low risk and some at high risk.” Under the proposed new definition, individuals with low blood pressure levels and no signs of vascular abnormalities are classified simply as normal, thus averting any stigma.

	The goal of the new definition is to assist practitioners in identifying individuals at risk for cardiovascular disease at an earlier point in the disease process, he continued. This may mean a risk assessment strategy that incorporates an electrocardiographic measure of left ventricular size, screening for microalbuminuria, a lipid profile, a measure of glucose metabolism, and potentially a determination of systemic inflammation and plasma renin levels.

	In the new definition, treatment of hypertension may change to include HMG-CoA reductase inhibitors (statins) and thiazolidinediones. “We’ll need a thinking physician and a thinking patient to come up with the best regimen for every individual,” said Dr. Giles.

	of medicine, State University of New York in Brooklyn, “clinical heterogeneity is really a major key for understanding hy-pertension and having to consider a new definition.”

 ASH proposes new definition of hypertension

	San Francisco—More than three fourths of patients with difficult-to-control hypertension can achieve their systolic blood pressure (SBP) goal by use of a fixed-dose combination of irbesartan/hydrochlorothiazide (Avalide), according to data presented at the 20th Annual Scientific Meeting of the American Society of Hypertension.

	Only one third of patients with hypertension have their blood pressure controlled to levels recommended in national guidelines, and 5 out of 10 treated hypertensive patients are not at goal blood pressure, said Elijah Saunders, MD, lead author of a study known as Irbesartan/HCTZ Blood Pressure Reduction in Diverse Patient Populations (INCLUSIVE). The blood pressure goal is less than 140/90 mm Hg, and less than 130/80 mm Hg for hypertensive patients with diabetes or chronic kidney disease, according to current national guidelines.

	The study was conducted at 119 centers across the United States and included 1,005 patients with SBP uncontrolled on monotherapy. At least 100 patients were enrolled in each of several predefined subgroups, including African Americans, Hispanics/Latinos, those with metabolic syndrome, those with type 2 diabetes, or those 65 years or older.

	“This was the first large-scale hypertension study to include such a broad range of patient groups,” said Dr. Saunders, professor of medicine, cardiology, and hypertension, University of Maryland, Baltimore.

	After a placebo washout period, patients received hydrochlorothiazide, 12.5 mg/day, alone for 2 weeks, followed by

	8 weeks of irbesartan/hydrochlorothiazide, 150/12.5 mg/day, and then 8 weeks of irbesartan/hydrochlorothiazide, 300/25 mg/day.

	The mean change in SBP from baseline to week 18, the primary end point of the study, was —21.5 mm Hg, from 154.4 to 132.9 mm Hg. Seventy-seven percent of patients achieved their SBP goal. Diastolic blood pressure (DBP) was reduced by a mean of 10.4 mm Hg, from 91.3 to 80.9 mm Hg, and 83% of patients achieved their DBP goal.

	at their SBP goal 10 weeks into the study, when they had been treated with the lower dosage of irbesartan/hydrochlorothiazide.

	SBP control rates were greater than 50% in each subgroup examined, and ranged from 56% in patients with type

	2 diabetes to 82% in women. All other subgroups assessed (elderly, African American, Hispanic/Latino, metabolic syndrome, men) had SBP control rates in excess of 70%. DBP control rates ranged from 63% to 96%, with all subgroups except those with type 2 diabetes experiencing DBP control rates in excess of 70%.

	“We showed that a more aggressive approach can take us from one third of patients controlled to 75% being controlled,” said study coauthor Joel Neutel, MD, associate clinical professor of medicine, University of California-Irvine. “The use of combination therapy earlier on in the management of hypertension will get more patients to goal. Using complementary drugs in combination makes it much easier to treat all subgroups of patients.”

	The study was unique for three reasons, said Dr. Saunders. It was conducted in a general practice setting, it focused on SBP control, and it enrolled patients who were already receiving treatment but whose blood pressure was not controlled.

 Combination Rx achieves SBP goal in difficult-to-treat patients

	San Francisco—Elasticity of the small arteries is improved more with coadministration of amlodipine (Norvasc) and atorvastatin (Lipitor) compared with either treatment alone, said Jay N. Cohn, MD, at the 20th Annual Scientific Meeting of the American Society of Hypertension. The improvement may explain the better cardiovascular outcomes associated with the combination compared with either drug alone.

	Reduced arterial compliance is characteristic of hypertension and dyslipidemia. Small artery compliance is reduced in the presence of endothelial dysfunction, said Dr. Cohn, a professor of medicine in the cardiovascular division at the University of Minnesota Medical School. “We know that endothelial dysfunction is a very important contributor to morbid events occurring,” he said.

	Premature loss of arterial elasticity predicts the risk of developing cardiovascular disease.

	The additive effect of amlodipine and atorvastatin on small artery compliance may account for their superiority in reducing the incidence of vascular events in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), said Dr. Cohn. In ASCOT, which was conducted in 19,257 patients with hypertension, the treatment arm that was assigned to both amlodi-pine and atorvastatin experienced fewer cardiovascular events than the arm assigned to amlodipine alone. Amlodipine had a more favorable effect on cardiovascular events than a comparator beta blocker antihypertensive regimen.

	In the Atorvastatin and Amlodipine in Patients With Elevated Lipids and Hypertension (AVALON) Arterial Wall Compliance (AWC) trial (a substudy of ASCOT), 667 patients with hypertension and low-density lipoprotein (LDL) cholesterol of 100 to 250 mg/dL had measurements of vascular compliance at baseline, 8 weeks, and 28 weeks in response to 8 weeks of double-blind treatment with placebo; amlodi-pine, 5 mg/day; atorvastatin, 10 mg/day; or the two drugs coadministered. The mean age of the patients was 56 years.

	Small artery elasticity improved by 2.2% from baseline to 8 weeks with atorvastatin alone, by 11.6% with amlodipine alone, and by 19.6% with the combination. Patients who were assigned to placebo had a 2.1% decline in small artery compliance.

	“When you put together a calcium antagonist and a statin, you get a dramatic improvement in endothelial function, which in fact may account for why these drugs have a favorable effect on outcomes,” he said. “Since they are more than additive…the effect on endothelial function appears to be a direct consequence of these drugs and their working through separate mechanisms.”

	Coadministration of amlodipine and atorvastatin produced sustained improvement in small artery elasticity through 28 weeks, said Dr. Cohn.

	Small artery compliance is an assessment of nitric oxide release and its bioactivity while the patient is at rest. Arterial stiffness with age is partly the result of less nitric oxide release.

	The arterial elasticity test is completed in 5 minutes; it uses a blood pressure cuff placed on the patient’s upper left arm and an arterial pulse wave sensor on the right wrist overlying the radial artery. Interpretation of the results takes less than 1 minute. (The device was invented by Dr. Cohn.)

July 2005

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