	Many noninvasive methods exist for cardiac imaging, such as echocardiography and magnetic resonance imaging (MRI), but only cardiac MR (CMR) can provide high-resolution volumetric imaging of the heart in correct three-dimensional spatial and temporal resolution without ionizing radiation or nephrotoxic contrast. This enables CMR to furnish a detailed interpretation of cardiac function and anatomy. Furthermore, by using MRI contrast agents, CMR can provide valuable information about regional myocardial perfusion and myocardial viability. This viability technique, known as delayed enhancement (DE) imaging, is able to distinguish reversible myocardial dysfunction from acute or chronic myocardial infarction.1-6 Hence, by combining these features, CMR can provide valuable information of unparalleled quality that cannot be provided by any other single imaging method.

	CMR images are created using a variety of signal acquisition strategies or “sequences.” Volumetric imaging of cardiac structure and function, including regional myocardial function, is provided by cine imaging using an electrocardiogram-gated steady-state free precession (SSFP) sequence. Compared with traditional two-dimensional imaging, CMR is able to provide a superior, more reliable interpretation of ventricular anatomy and function. The accuracy and reproducibility of measurements, as well as the spatial and temporal resolution exhibited by CMR, have led to its currently being considered the gold standard for quantification of ventricular volume, function, and mass.7-11

	Evaluation of left ventricular function and mass provides essential data for continued management of the cardiac patient. Clinical implications range from medication choices to the placement of automated internal cardiac defibrillators. These measurements, therefore, require accurate, reliable, and reproducible values. Although echocardiography is accepted as the initial test of choice for this evaluation, CMR is now considered the preferred method. Furthermore, left ventricular mass is known to be an important marker of subsequent cardiovascular morbidity and mortality.7-15 Compared with left ventricular mass evaluation by CMR, two-dimensional echocardiography is relatively unreliable, partly because of interobserver variation.7 These attributes, provided by a single study, along with limited patient and operator interference, make CMR a desirable alternative to other imaging methods.

	The precision and clarity of the images generated by CMR have also led to its firm establishment as a method for evaluation of various cardiac disorders, such as congenital heart disease and cardiac masses, as well as aortic and pericardial diseases.14 Congenital heart disease has been particularly revolutionized by the use of CMR. CMR imaging relies on two separate techniques. The morphologic evaluation is completed by spin-echo and MR angiographic techniques, whereas the functional and flow information is provided by the previously described fast cine-SSFP and velocity-encoded sequences.16-20 Partly because of this technology, CMR appears to be widely accepted as the imaging method of choice for evaluating anomalies involving the aorta and central pulmonary arteries and for postoperative follow-up of patients with congenital heart disease. The combination of such specific functional and morphologic assessment generates an unrivaled description of complicated anatomy that is essential for successful surgical correction.16-20

	Another well-established area of CMR imaging excellence involves the investigation of cardiac masses. Until recently, the evaluation of a cardiac mass relied predominantly on echocardiography with subsequent biopsy. In addition to the aforementioned accuracy of spatial and temporal detail, using contrast techniques as well as noncontrast signal intensity and anatomical-topographical features allows CMR to distinguish the presence of perfusion, infarction, inflammation, and fibrosis within masses. Through this combination of detail, CMR can be used to discriminate thrombi, myxomas, and malignant tumors.21-27 It can therefore provide an accurate noninvasive method of evaluation and identification of a large variety of cardiac masses with less risk to the patient.

	The combination of volumetric and flow velocity imaging has broadened the utility of CMR to encompass valvular imaging and quantitation of the severity of valvular stenosis or regurgitation. By using CMR, valvulopathy can be assessed with such exactitude that some authors suggest that there is less need for invasive evaluation.14 Although echocardiography remains the currently accepted initial mode of evaluation for valvular disease, CMR has much to offer selected patients. For example, patients who are being assessed for possible surgical intervention require exact valvular measurements, as well as accurate estimation of overall cardiac function. Although this can be provided by echocardiography, the windows can often be limited by concomitant valvulopathies, which can lead to overestimation or underestimation of the severity of the valve disease, and inaccurate ejection fractions and body habitus interference, which can lead to poor imaging.28-30

	CMR, however, can provide measurements of peak velocity and flow that are at least as accurate as echocardiography. Additionally, the severity of val-vular disease can be measured through several different methods using CMR, which improves the accuracy of the findings. One of the techniques includes the use of cine gradient echo MR imaging, which allows measurement of the area of the signal void corresponding to the abnormal flow jet. Alternatively, this method can be used to obtain ventricular volumetric measurements, which are then used to calculate the regurgitant fraction. A third method involves the use of velocity-encoded cine MR imaging, which actually quantifies regurgitant blood flow.

	There are also several methods available to evaluate stenoses, including flow jet evaluation and calculation of transvalvular pressure gradients and valve area, again attainable by a single imaging study.28,30-32 These imaging options also allow measurements to be adjusted for existing valvulopathies. This means that errors associated with estimation are reduced with CMR while extremely accurate and reproducible values are provided. With respect to limitations resulting from body habitus, CMR provides unequalled imaging, in part, because of negligible interference from surrounding tissue. These values are often critical factors in determining when surgical intervention is indicated.

	Another recent advancement in CMR is the ability to distinguish areas of infarction from ischemia. Infarct imaging is performed using an inversion recovery turboflash sequence. To distinguish viable myocardium, the contrast agent gadolinium chelate (Gd) is required with subsequent DE imaging. The Gd migrates into the cardiac cells, and the rate of washout from the cells can determine functionality. Cells with expanded extracellular space, such as those seen in areas of infarction, have a slower washout of Gd compared with areas of reversible ischemia. Thus, these areas of DE can be distinguished as nonviable myocardium, presumably secondary to acute infarction and necrosis or old scarring.1,4,33,34 In fact, as the transmural extent of DE increases, the prognosis for functional recovery of that myocardial segment worsens.1,4,33 Because of the precise spatial detail and established accuracy of DE imaging, many investigators have confirmed the utility of CMR DE imaging as the gold standard for detection of infarcts and quantitation of infarct size and shape.

	The diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy (so-called ARVD/C), is another useful application of CMR. This electrophysiologic abnormality is characterized by fibro-fatty replacement of the right ventricle, leading to arrhythmias, right ventricular failure, and sudden death.35,36 Until recently, analysis of these fibro-fatty changes required a myocardial biopsy for diagnosis. Noninvasive detection by CMR has an excellent correlation with histopathology and can predict inducible ventricular tachycardia. Because of this specificity, cardiac MR imaging is developing into the method of choice for the evaluation of patients who are suspected of having ARVD/C.35,36

	Although limitations of CMR exist, such as certain physical limitations, availability, and patient tolerance, the many applications for the use of CMR are still being determined. With improving cost effectiveness and more advanced techniques, it is likely that CMR imaging will become a routine procedure for the evaluation of multiple areas of heart disease.

Articles

Cardiology Review Online

Cardiac magnetic resonance imaging

	The article by Shai and colleagues (page 37) is a complex, elegant analysis of the data linking lipid parameters to future coronary artery disease (CAD) in the Nurses’ Health Study, summarizing and commenting on an article originally published in Circulation.1 The authors analyzed 234 CAD cases and 449 controls from blood samples collected from 32,826 women. They conclude that because of the powerful association of low high-density lipoprotein cholesterol (HDL-C) levels with CAD among women, HDL-C—related ratios, simply the total cholesterol/HDL-C ratio, should be considered as the primary target tool in measures to prevent CAD.

	I went to the National Cholesterol Education Program (NCEP) literature to investigate that panel’s rationale for the most recent Adult Treatment Panel III (ATP III) guidelines,2 revised in 2004 after the publication of five major clinical trials. The executive summary of the original NCEP ATP III guidelines can be found in JAMA.3 It is simply stated that current documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C. Recent lipid-lowering drug trials provide no new evidence in this regard, but new drugs that raise HDL are currently under development.

	The ATP III authors acknowledge that post hoc analysis of clinical trials with fibrates, drugs that modestly raise HDL-C, indicates that fibrates reduce the risk for CAD events in patients with high triglycerides and low HDL-C, especially when patients have diabetes or characteristics of the metabolic syndrome. Fibrates may have an adjunctive role in patients with high triglycerides and low HDL, especially in combination with HMG-CoA reductase inhibitors (statins). Earlier concerns about myopathy when statins and fibrates are mixed are lessened by fenofibrate, which does not substantially increase the risk for clinical myopathy in patients treated with moderate doses of statins. Nicotinic acid is another attractive alternative (when tolerated), which can be used alone or in combination with statins to produce a marked reduction in low-density lipoprotein cholesterol (LDL-C) and a rise in HDL-C.

	The other side of the coin, not uncommonly encountered in practice, is the woman with both a high LDL-C and HDL-C. It has been my observation that many physicians already use the HDL-C—based ratio to reassure these women that LDL-C lowering is not necessary. In the NCEP report,3 an HDL-C higher than 60 subtracts one point from the Framingham risk score calculation. Thus, under the current guidelines, a high HDL-C will only occasionally alter the recommendation for LDL-C lowering in women at risk for CAD. Further guidance on this point from prospective clinical trials would be useful.

	Thus, the study by Shai and colleagues adds to a body of epidemiologic data and post hoc clinical analyses strongly suggesting the importance of HDL-C as a therapeutic target, a hypothesis that will surely be tested with great vigor in upcoming clinical trials of HDL-C—active drugs.

Linking lipid parameters to coronary artery disease in women

	Although the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program recommends obtaining a full fasting lipoprotein profile, including total cholesterol, low-density-lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels,1 the most significant measurement is considered to be LDL cholesterol, and the reduction of LDL cholesterol is the chief goal of treatment to reduce the risk of coronary artery disease (CAD).

	It is recognized that increased LDL cholesterol levels lead to the development of atherosclerosis1; however, the use of LDL cholesterol levels to predict the risk of CAD is controversial.2 LDL particles can be heterogeneous in size and number,3 and smaller LDL particles may be more atherogenic.4 The use of another measurement has been proposed as a predictor of CAD risk—total apolipoprotein B100 (apoB100).5

	Over the past decades, lipid measurements have been significantly improved and standardized, and the primary predictor in clinical guidelines may be reconsidered. Because they provide assessment of protective lipid fractions and atherogenic factors, better determination of risk may be made using such ratios as apoB100/apoA-I ratio, LDL cholesterol/HDL cholesterol, or total cholesterol/HDL cholesterol. For patients with increased triglyceride levels, non-HDL cholesterol levels were put forth by ATP III as an alternative predictor to LDL cholesterol1; in clinical practice, however, lipid indexes were not suggested as a favored measurement tool.

	We assessed the usefulness of various lipid measurements in predicting CAD events in a nested case-control study among participants in the Nurses’ Health Study (NHS).

	Blood samples were taken from 32,826 female nurses enrolled in the NHS from 1989 to 1990. Incident fatal CAD and nonfatal myocardial infarction (MI) between the time of blood collection and May 31, 1998, was the end point. Physicians established the diagnosis of MI using criteria proposed by the World Health Organization.6 Determination of fatal MI was made by autopsy or hospital records. Subjects with a previous report of cancer or CAD before the blood collection were excluded. Each case was matched by age and smoking history to two controls who were free of CAD at the time of the case diagnosis. The lipid analyses were performed in a certified laboratory.

	A total of 449 control subjects and 234 CAD cases (35 with fatal CAD and 199 with nonfatal CAD) participated in the study. Lower HDL cholesterol levels, higher levels of all other lipid measurements, higher body mass index (BMI), parental MI, hypertension, and diabetes occurred more commonly in the cases compared with the control subjects (data not shown).

	Following are the relative risks (RRs) associated with an increase of approximately 1 standard deviation (SD; mg/dL) after adjustment for homocysteine, BMI, family history, hypertension, diabetes, C-reactive protein, postmenopausal hormone use, physical activity, alcohol intake, and blood draw parameters in multivariate models: triglycerides, RR = 1.3 (1.0—

	1.5), SD = 80; LDL cholesterol, RR = 1.4 (1.1—1.7), SD = 36; apoB100, RR = 1.7 (1.4–2.1), SD = 32; HDL cholesterol, RR = 0.6 (0.5–0.8), SD = 171; and total cholesterol, RR = 1.4 (1.1–

	1.6), SD = 40. The RRs for the lipid indexes were as follows: total cholesterol/HDL cholesterol, RR = 1.6 (1.3—

	1.9), SD = 1.3; non-HDL cholesterol, RR = 1.6 (1.3—1.9), SD = 42 mg/dL; apoB100/HDL cholesterol, RR = 1.7 (1.4–2.1), SD = 1.0; and LDL cholesterol/HDL cholesterol, RR = 1.5 (1.3–

	In the Figure, A shows that HDL cholesterol was the principal contributor to the prediction model, increasing the receiver operating characteristic (ROC) to 0.63 from 0.51 in the stepwise model, which was adjusted for smoking status and age only. ApoB100 was the second contributor, raising the ROC to 0.66. The regression was performed again with a multivariable model, as shown in B of the Figure. HDL cholesterol was still the principal contributor to prediction of the model, increasing the ROC to 0.70 from 0.69. LDL cholesterol was brought into the second step, and the ROC increased to 0.72. In the Figure, D shows that additional information was not provided by triglyceride or apoB100 levels over that provided by LDL and HDL cholesterol levels. Also in the Figure, C shows that apoB100 levels did not provide additional information for a model in which we forced the other clinical parameters, whereas HDL levels did. Significant additional information was provided to the multivariate intercept by all of the lipid indexes. The ROC was increased to 0.72 from 0.69 by the ratios containing HDL cholesterol: apoB100/HDL cholesterol, LDL cholesterol/HDL cholesterol, and total cholesterol/HDL cholesterol. E through G in the Figure show that there were no other lipid biomarkers that contributed significantly; H shows that the ROC was increased to 0.71 by non-HDL cholesterol, and the model was additionally improved when HDL cholesterol was added.

	Over a period of 8 years, taking into consideration a number of lipid and nonlipid risk factors for CAD, we assessed the usefulness of a number of plasma lipid parameters in predicting future CAD in women. The principal lipid predictor for postmenopausal women was HDL cholesterol, using a multivariate model that was adjusted for various lipids. The total cholesterol/HDL cholesterol ratio is a single measurement that can predict CAD risk apart from other proven risk factors, supplying a strong predictive model that can be used in clinical practice.

	We showed that HDL cholesterol rather than LDL cholesterol was the primary discriminator among the women in the study, but both values are needed to predict CAD in a multivariate model. Although HDL cholesterol level is a defined risk factor in the ATP III algorithm for primary prevention,1 with an HDL cholesterol below 40 mg/dL counted as a risk factor and an HDL cholesterol above or equal to 60 mg/dL counted as a protective factor, the superiority of HDL cholesterol level as a major predictor among women is not well established. The reasons might be historical, driven by unstandardized HDL cholesterol measurements in the past and the lack of established HDL-raising drugs.

	ApoB100 was the lipid fraction that was most significantly related to CAD risk. The liver synthesizes apoB100, which is secreted with very-low-density lipoprotein (VLDL). Because there is one apoB100 molecule per lipoprotein particle, total apoB100 reflects the total particle numbers in LDL, VLDL, and intermediate-density lipoprotein (IDL).7 Because the half-life of LDL cholesterol particles is nine times the half-life of IDL and VLDL particles,8 the number of LDL particles can be approximated by the apoB100 concentration. Our results are consistent with previous epidemiologic studies,9,10 and the Canadian Cardiovascular Society has targeted levels of apoB100 below 90 mg/dL for patients at high risk for CAD.11 Although apoB100 remained the superior lipid-biomarker predictor in a multivariate model, its association was appreciably attenuated by other CAD risk factors.

	For patients with triglyceride levels above or equal to 200 mg/dL, a secondary aim of therapy is treatment of non-HDL cholesterol, which includes cholesterol in triglyceride-rich and LDL-rich lipoproteins.1 It has been suggested that non-HDL cholesterol is a less expensive and more practical par-ameter for CAD risk assessment that is already available from the lipid panel.12 However, among lipid indexes, non-HDL cholesterol provided the exclusive unsaturated model, for which HDL cholesterol was needed to provide additional information (H in the Figure). These measurements reflect different biological elements, in spite of the fact that there is a high association between non-HDL cholesterol and apoB100. Animal models have shown that the atherogenicity of cholesterol

	in VLDL is weaker than that of cholesterol in LDL.13 Non-HDL cholesterol, therefore, may not be a good replacement for apoB100.

	All the HDL-cholesterol—related ratios, which reflect the proportion of atherogenic to antiatherogenic lipid fractions, showed superior predictive value. Ratios of lipids or apolipoproteins, or both, have been better predictors of CAD risk than have levels of any lipid fraction.14 By taking into account the triglyceride-rich lipoproteins, the total cholesterol/HDL cholesterol ratio appears to be a better predictor15 of CAD than LDL cholesterol/HDL cholesterol. In our study, the apoB100/HDL cholesterol ratio showed the strongest and most linear association with MI. However, clinical usefulness of this ratio must be judged against the cost of its measurement, the present lack of a direct therapeutic option, and the very small gain in overall predictive value compared with that of the available total cholesterol/HDL cholesterol ratio.

	Because of the powerful association of low HDL cholesterol levels with CAD among women, HDL-cholesterol—related ratios, such as the total cholesterol/HDL ratio, should be considered as the primary target tool in measures to prevent CAD.

Lipid parameters as predictors of  coronary artery disease in women

	What should we emphasize most in our patients with type 2 diabetes—blood sugar management or cardiovascular risk reduction? That is the question posed by Langenfeld and colleagues (Pfützner, page 30).1

	In their study, they point out that most patients with type 2 diabetes die of cardiovascular disease; furthermore, many patients with type 2 diabetes present with cardiovascular disease before their blood sugar is elevated. Supporting their argument is the finding by Haffner and colleagues2 that type 2 diabetic patients at presentation are equivalent in cardiovascular risk to nondiabetic patients who have already had a myocardial infarction.

	Langenfeld and co-workers1 have measured carotid intima-media thickness (IMT) in patients with type 2 diabetes and compared two blood-sugar—lowering agents: glimepiride (Amaryl) of the sulfonylurea class and pioglitazone (Actos), which is a peroxisome proliferator-activated receptor (PPAR gamma) agonist. While the sulfonylurea lowers blood sugar by stimulating insulin secretion, PPAR gamma agents affect adipose metabolism by shifting active adipose tissue to less metabolic fat. This process indirectly affects blood sugar by increasing its uptake in muscle tissue. They found that both medications had a similar effect on blood sugar at 24 weeks—glycosylated hemoglobin (A1C) –0.8 ± 0.09% with pioglitazone versus –0.6 ± 0.8% with glimepiride. Carotid IMT was reduced significantly at 12 and 24 weeks only with pioglitazone.

	PPAR gamma agents such as pioglitazone affect blood sugar lowering and are also anti-atherogenic. They have several diverse effects including lowering many markers of inflammation, such as cytokines in monocytes, apoptosis in macrophages, and adhesion molecules in endothelial cells. Measurement of carotid IMT is evolving as a surrogate marker of cardiovascular risk. In addition, proinsulin, which is usually elevated in patients with type 2 diabetes, can also be measured as a marker of insulin resistance in clinical practice. It is likely that these two markers will be increasingly utilized to follow cardiovascular risk assessment in patients with type 2 diabetes.

	The study of Langenfeld et al1 emphasizes that type 2 diabetes is a clinical syndrome. In some patients who tend to be thin, insulin deficiency is the major problem, and these patients will respond to sulfonylureas and insulin if necessary. More commonly in patients with type 2 diabetes, central obesity and insulin resistance are the major culprits. Treatment of these patients should emphasize better health habits, including strategies to encourage weight loss, blood pressure management, blood sugar reduction with glitazones or metformin (Glucophage, Glumetza), and appropriate lipid therapy. The available glitazones, though, have some disagreeable adverse effects, such as significant weight gain and, often, edema that is resistant to diuretic treatment.

	We are at a turning point in the care of type 2 diabetes. Much recent data has shown that most patients with type 2 diabetes have an insulin-resistant state that markedly enhances cardiovascular risk. Some of these patients will develop increased blood sugar early in their course as insulin secretion is inadequate, while others may develop increased blood sugar very late. In fact, some patients will never be diagnosed with type 2 diabetes because we utilize elevated blood sugar as the defining marker of type 2 diabetes and their blood sugar is not elevated. Regardless of whether blood sugar is elevated, therefore, we need to treat our patients with insulin resistance as early and as aggressively as possible.

Blood sugar management or  cardiovascular risk reduction in  type 2 diabetes? That is the question 

	A 71-year-old woman presented to our unit with a “new” manifestation of type 2 diabetes mellitus after having changed primary care physicians. Her screening blood glucose level was 320 mg/dL. The other laboratory values were as follows: body mass index (BMI), 28.4 kg/m2; glycosylated hemoglobin (A1C), 11.4%; fasting blood glucose, 298 mg/dL; triglycerides, 3.21 mmol/L; low-density lipoprotein (LDL) cholesterol, 6.43 mmol/L; high-density lipoprotein (HDL) cholesterol, 1.04 mmol/L; high-sensitivity C-reactive protein (hsCRP), 5.4 mg/L (high cardiovascular risk, > 3 mg/L); intact proinsulin, 17.6 pmol/L (elevation indicating advanced-stage beta-cell dysfunction); and adiponectin, 6.4 mg/L (suppression indicating insulin resistance and increased cardiovascular risk). The patient had cardiac arrhythmia in her youth but showed no signs or symptoms of cardiovascular deterioration. Given the degree of A1C elevation, it was suspected that the disease was already prevalent and had been undetected for several years.

	Treatment was initiated with diet and exercise recommendations, metformin (1,000 mg), and pioglitazone (beginning with 30 mg after 14 days of metformin, increasing to 45 mg after 4 weeks). Laboratory tests showed the following values, which improved within the first 6 weeks and were almost normalized after 3 months: BMI, 26.8 mmol/L; A1C, 7.2%; fasting glucose, 114 mg/dL; triglycerides, 1.44 mmol/L; LDL cholesterol, 3.3 mmol/L; HDL cholesterol, 1.44 mmol/L; hsCRP, 1.64 mg/dL (intermediate risk, 1—3 mg/L); intact proinsulin, 6.5 pmol/L (normal levels, < 11 pmol/L), and adiponectin, 44.2 mg/L (elevation leading to vasoprotective and anti-inflammatory effects). This case shows the degree of cardiovascular biomarker response that can be expected within the first 3 months of treatment when effective insulin-resistance–oriented antidiabetic therapy is used.

Response to insulin-resistance%u2013 oriented treatment

	About 75% of patients with type 2 diabetes die from macrovascular complications; however, only 35% of patients with type 1 diabetes do so. This significant difference is linked to the underlying disorders of type 2 diabetes: insulin resistance and beta-cell dysfunction. Insulin action at the metabolically active cell level increases glucose uptake, but activation of insulin receptors at the inner layer of the arteries induces the production of nitric oxide (NO) and mediates a variety of vasoprotective and anti-inflammatory effects at the endothelial level (Figure 1). Therefore, insulin resistance leads to hyperglycemia but also to impairment of vasoprotection and substantial endothelial dysfunction, with increased secretion of adhesion molecules and increased monocyte activation and migration into the vascular wall.1

	At the same time, beta-cell dysfunction is followed by increased secretion of the insulin precursor, proinsulin, which is considered to be an instigator of adipogenesis and a cardiovascular risk factor by stimulating plasminogen activator inhibitor (PAI)-1 expression and by blocking fibrinolysis.2,3 In fact, intact proinsulin secretion forced by increasing insulin resistance can be regarded as the independent contribution of beta-cell dysfunction to the overall increased cardiovascular risk in patients with type 2 diabetes.4 An increased level of fasting intact proinsulin is a specific indirect indicator of insulin resistance that is suitable for diagnosis of insulin resistance in daily practice.5,6 Based on this background, it is to be expected that drugs addressing the underlying pathophysiology of type 2 diabetes should also induce improvements in vascular function and the macrovascular risk profile.

	We performed the PIOglitazoNe: study for the Evaluation of the Efficacy in cardiovascular Risk reduction (PIONEER) study, a prospective, parallel, 6-month investigation of the effect of two oral antidiabetic treatment approaches—peroxisome proliferator-activated receptor-gamma (PPARg) activation with pioglitazone (Actos) and stimulation of beta-cell secretion with glimepiride (Amaryl)

	—on glucose metabolism, cardiovascular risk, insulin resistance, and beta-cell dysfunction in orally treated patients with type 2 diabetes. Patients received either 45 mg of pioglitazone or 1 to 6 mg of glimepiride adjusted to optimize glucose control. The study was completed by 173 patients (66 women, 107 men), with a mean age (± SD) of 63 ± 8 years. The mean duration of disease was 7.2 ± 7.2 years, and the mean glycosylated hemoglobin (A1C) was 7.5 ± 0.9%. Observation parameters at baseline and the end point were A1C, glucose, insulin, intact proinsulin, lipids, adiponectin, high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1 levels, and intima-media thickness (IMT). The latter measurement was performed by one single investigator and a blinded independent analyst to minimize the variability of the method.

	A1C was equally improved in both treatment arms (—0.6 ± 0.8% in the glimepiride group and –0.8 ± 0.9% in the pioglitazone group; P < .001) compared with baseline. There was no significant difference between the two groups at baseline and end point. Marked improvements, however, were seen only in the pioglitazone group for the cardiovascular risk profile (a reduction in IMT, hsCRP, MMP-9, and MCP-1 levels and an increase in adiponectin and high-density lipoprotein levels), beta-cell dysfunction (reduction of fasting insulin and proinsulin), and insulin resistance (reduction of homeostasis model of insulin resistance [HOMA-IR] and intact proinsulin), as shown in Figure 2.7-9

	Insulin receptors exist on multiple cell types in the human body. In the majority of the cells, insulin induces glucose uptake. This is not the case in the endothelial cell, however, where insulin receptor activation stimulates NO-synthetase. NO induces a variety of vasoprotective actions, including but not limited to reduction of adhesion molecule secretion, improvement of erythrocyte deformability, and reduction of monocyte/macrophage activation.10 The endothelial cell layer provides the barrier between the inner cells and the bloodstream. It is directly exposed to those molecules in the blood that produce oxidative stress and toxic effects (eg, glucose in concentrations above 180 mg/dL). As a result, deterioration of insulin action by development of insulin resistance leads to an impairment of endothelial function, and the organism is less protected against systemic arteriosclerosis.

	PPARg activation by pioglitazone, for example, improves the intracellular insulin signal transduction process and decreases overall insulin resistance. This effect is, of course, not limited to metabolic insulin resistance, but is also effective at the vascular level in the endothelial cells. As shown in our study, the response to effective insulin resistance treatment by thiazolidinediones is an overall reduction of IMT and vascular inflammation. The additionally observed improvement in beta-cell dysfunction leads to a beneficial reduction of intact proinsulin secretion and an increase in adiponectin levels. These findings support our current understanding of the connection between beta-cell dysfunction insulin resistance and the metabolic syndrome, as shown in Figure 2. It is noteworthy that adipogenesis seems to be the driver for hypertension, dyslipidemia, and inflammatory activity. In contrast to drugs targeting blood glucose levels only, pioglitazone addresses insulin resistance, which breaks the lethal cycle of insulin resistance and adipogenesis and may consequently reduce further symptoms of the metabolic syndrome (Figure 3).

	Our findings, however, also induce another critical thought that is linked to the current understanding of type 2 diabetes diagnosis and treatment. Di-agnosis of type 2 diabetes is solely based on deteriorated blood glucose levels, and the deleterious effects of insulin resistance at the vascular level are not considered. The exclusive definition of type 2 diabetes as a fasting blood glucose level above 127 mg/dL or 2-hour values above 200 mg/dL after a glucose challenge11 is the reason many patients with type 2 diabetes suffer from macrovascular disease at the time of “official” diabetes diagnosis. It is expected that different phenotypes of type 2 diabetes exist. They are associated with different degrees of vascular and metabolic insulin resistance, which finally defines the clinical picture. Although a myocardial infarction or arteriosclerosis may be the first symptom of the disease in some patients, other patients may predominantly manifest with major blood glucose deterioration.

	Effective treatment of insulin resistance with appropriate methods (diet, exercise, and sensitizing drugs) may be a much more efficient treatment approach than solely performing “blood glucose cosmetics,” for example, using sulfonylurea drugs. Further substantial information regarding the effect of thiazolidinedione treatment on cardiovascular mortality can be expected from ongoing large outcome studies. The results of the most advanced trial, the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive),12 were published recently.13 As expected from our findings, it showed a significant decrease by 16% of the combined hard end points of all-cause mortality (—9%), myocardial infarction (–22%), and stroke (–18%) after just 3 years of observation in comparison to placebo treatment. Thus, it proved the beneficial effect of pioglitazone treatment on cardiovascular outcome in patients with type 2 diabetes.

Pioglitazone decreases carotid intima-media thickness in  diabetes mellitus

	The treatment of heart failure (HF) has undergone a revolution over the past

	20 years with the recognition of the importance of neurohormonal activation in the development and progression of HF. This has led to the use of angiotensin-converting en-

	zyme (ACE) inhibitors and beta-blocking agents as the cornerstone of therapy for HF associated with systolic dysfunction (ie, reduced ejection fraction). Because ACE inhibitor treatment for HF was the first neurohormonal therapy studied and demonstrated to have

	a benefit, ACE inhibitors are initiated first in the treatment of HF, and beta blockers, which were studied later, are subsequently added to the patient’s regimen. The important study of Sliwa (page 24) suggests that we may have it backwards.1

	Between 1987 and 1992, the Cooperative North Scandinavian Enalapril Survival Study, Studies of Left Ventricular Dysfunction, and the Vasodilator Heart Failure Trial demonstrated that ACE inhibitor therapy was beneficial in patients with left ventricular systolic dysfunction of all symptomatic classes.2-5 Based on the compelling data demonstrating the benefit of ACE inhibitors in these patients, there has been a concerted effort to implement this evidence-based medicine.6 Everyone has been encouraged to “get with the guidelines.” This has culminated in each hospital’s quality of care being graded by the percentage of patients with decreased ejection fraction who are discharged on an ACE inhibitor. Each hospital’s score can be found at www.hospitalcompare.hhs.gov. The average for all reporting hospitals is 74%.

	After the landmark ACE inhibitor trials, the next advancement in the treatment of HF was the recognition that beta blockade had a powerful added effect in patients with systolic HF. These studies demonstrated that beta blockade, begun at a low dose and subsequently titrated up, improved survival, decreased hospitalization, and produced favorable remodeling in patients with systolic HF.7-10 Most of these patients were already on an ACE inhibitor when they entered the trials. It is notable that these studies demonstrated that the addition of a beta blocker in patients with systolic dysfunction has a greater effect on left ventricular remodeling than an ACE inhibitor.

	Sliwa performed a single-center, prospective, open-label study in 78 patients with HF due to a dilated cardiomyopathy who were randomly assigned to therapy with a beta blocker (carvedilol, Coreg) or an ACE inhibitor (perindopril, Aceon).1 Only patients with presumed idiopathic dilated cardiomyopathy were studied; patients with ischemic cardiomyopathy were excluded. The second agent was added after 6 months. After 12 months, patients in the group that received carvedilol as the initial therapy were tolerating a higher dose of beta blocker, were using a lower dose of diuretic, had greater improvement in symptoms and ejection fraction, and had a lower plasma N-terminal pro-brain natriuretic peptide concentration.

	The provocative implication of this study is that beta adrenergic blockade should be the initial therapy in patients with systolic HF. As with all clinical studies, there are some limitations to this important investigation. First, only 78 patients were enrolled from a single center in South Africa. Second, the study was not blinded. Third, there was a 6-month delay before adding the second agent to the patient’s regimen.

	Despite these limitations, this study suggests, but does not prove, the hypothesis that beta blockade should be the initial therapy (before adding ACE inhibition) in patients with systolic HF. The ultimate evaluation of this hypothesis will depend upon a much larger, multicenter, blinded study. Fortunately, such a study has been conducted, and the results should be available soon.11

	In the interim, how should we initiate treatment in a patient with HF? Should the patient initially diagnosed with systolic HF be discharged on a beta blocker and not on an ACE inhibitor? This, of course, would lead to a poor score for your hospital on the Web site and expose the clinician to the charge of not practicing evidence-based medicine in compliance with current guidelines. Despite these concerns, the initial use of a beta blocker before an ACE inhibitor may be the optimal method of management for certain individual patients with HF (for example, those with evidence of a hyperadrenergic state).6 An alternate approach is to initiate therapy with an ACE inhibitor, but begin beta blockade soon thereafter. Certainly, the study of Sliwa indicates that one should not wait 6 months before initiating a beta blocker.1

	In conclusion, the provocative study of Sliwa suggests that we may move beyond recapitulating the evolution of our therapeutic knowledge, as we initiate the treatment of patients with HF.

Initiating therapy for heart failure: Must ontogeny recapitulate phylogeny?

	In the treatment of congestive heart failure with left ventricular (LV) dysfunction, beta-blocking agents are traditionally administered after optimal therapy with angiotensin-converting enzyme (ACE) inhibitors has been achieved. This is done because clinical trials demonstrating the therapeutic benefits of beta blockers were conducted in patients receiving ACE inhibitors as background therapy.1-3 In congestive heart failure, however, sympathetic activation precedes that of the renin-angiotensin system.4 With the introduction and proven benefits of beta blockers in heart failure, do ACE inhibitors still deserve their role as a primary component of standard background therapy? Will more substantial benefits be realized when maximal doses of beta blockers are achieved before initiating ACE inhibitor therapy? The present study evaluated the order of initiation of beta-blocker therapy relative to ACE inhibitor therapy on LV function, New York Heart Association (NYHA) functional class, and biochemical indexes of heart failure (plasma

	NT-pro-brain natriuretic peptide [NT-pro-BNP] concentrations) in patients with heart failure.

	This was a randomized, prospective, single-center, open-label study in 78 consecutive patients with newly diagnosed idiopathic dilated cardiomyopathy in NYHA functional class II to III heart failure. Patients were randomly assigned to receive either the ACE inhibitor perindopril (Aceon, ACE inhibitor-first group,

	n = 40) or the beta blocker (BB) carvedilol (Coreg, BB-first group, n = 38) in addition to diuretics and digoxin for 6 months. After 6 months, carvedilol was added to the regimen in those receiving the ACE inhibitor and perindopril was added to the therapeutic regimen in those receiving carvedilol. We titrated both study drugs to maximum tolerable doses (systolic blood pressure was maintained at 85 mm Hg or greater, no dizziness was reported, and orthostatic hypotension did not occur). Data are presented as mean ± standard deviation. Significance was assumed at a two-tailed probability value of less than .05.

	There were no differences in hemodynamic or cardiac function, and biochemical or demographic characteristics between patients enrolled, completing 6 months of the study, and completing 12 months of the study (data not shown). There were no differences between the groups in age (ACE inhibitor-first group = 51 ± 11 years, BB-first group = 48 ± 10 years) or percentage of men (ACE inhibitor-first group = 47%, BB-first group = 44%). During the 12-month study period, 11 patients died (six in the ACE inhibitor-first group); 10 patients were not available for follow-up (5 in the ACE inhibitor-first group).

	There was an improvement in NYHA functional class at 6 and 12 months in both study groups (Table 1). The majority of the improvement occurred in the first 6 months, with minimal additional changes noted between 6 and 12 months in both groups. Improvement in functional class was consistently greater in the BB-first group, however (Table 1).

	A significant reduction in heart rate was noted at both 6 and 12 months in the BB-first group (Table 1). In the ACE inhibitor-first group, however, a reduction in heart rate was only noted at 12 months.

	Left ventricular ejection fraction (LVEF) increased in the BB-first group after both 6 and 12 months (Figure). No significant changes were noted in the first 6 months of therapy in the ACE inhibitor-first group (Figure), but there was an increase in LVEF after 12 months.

	Concentrations of plasma NT-pro-BNP were markedly raised compared with normal values for healthy, age-matched volunteers from the same population in both groups (BB-first group: 219 ± 141 pg/mL; ACE inhibitor-first group: 222 ± 254 pg/mL; normal volunteers: 12 pg/mL, P < .001). The reduction in plasma NT-pro-BNP concentrations was greater, and final plasma NT-pro-BNP concentrations at 12 months were lower in the BB-first group versus the ACE inhibitor-first group (166 ± 142 pg/mL versus 51 ± 384 pg/mL, P = .01).

	In the BB-first group the mean dose of furosemide was lower (Table 2). Compared with those in the ACE inhibitor-first group, patients in the BB-first group were able to tolerate a higher dose of carvedilol at 12 months (Table 2). There were no differences between groups in the dose of perindopril achieved (Table 2).

	We have shown in this study that left ventricular function and symptoms, as well as laboratory responses, were substantially better if beta blockade preceded, rather than followed therapy with an ACE inhibitor in the initial sequence of treatment of patients with newly diagnosed conges-tive cardiac failure. Patients who were given carvedilol first were able to tolerate a higher dose of carvedilol and needed lower doses of diuretic agents at 1 year after initiating therapy. Starting with beta blockade first produced more favorable responses, including better functional class, higher achievable dose of beta blocker, lower dose of furosemide, and more marked changes in LV systolic (left ventricular ejection fraction) and diastolic function and a biochemical index of raised filling pressures (plasma NT-pro-BNP concentrations).

	There are a number of possible theoretical and scientific reasons that could explain our findings. Patients who were prescribed carvedilol as initial therapy were able to tolerate a higher dose of carvedilol after 1 year of therapy. This higher dose of the beta-adrenoreceptor blocker achieved in the group receiving carvedilol first could partly explain the differences in hemodynamic and symptomatic improvement between the two groups. This is consistent with data that demonstrate a better outcome following the use of higher doses of both ACE inhibitors and beta-adrenoreceptor blockers in heart failure.5,6

	Beta-adrenoreceptor blocker therapy could simply be more effective than ACE inhibitor therapy in newly diagnosed heart failure. Sympathetic activation precedes the activation of the renin-angiotensin-aldosterone system in heart failure, as demonstrated by measurements of plasma neurohormonal levels in the Studies of Left Ventricular Dysfunction trial.4 Therefore, prevention of the deleterious effects of beta-adrenergic stimulation should be achieved as early as possible  LV if dysfunction is present. This hypothesis is supported by the marked differences in changes in measures of LV systolic function and functional class between the two groups that were noted after 6 months of therapy.

	Reverse remodeling is regarded as one of the important determinants of long-term outcome in the treatment of heart failure. Although ACE inhibitors slow the remodeling process, no reverse remodeling has been observed with this class of agents.7 However, studies with carvedilol administered to patients with heart failure reversed LV remodeling.8 In our study, LV diastolic chamber dimensions were reduced in the group of patients in whom carvedilol was initiated first, whereas in those patients receiving the ACE inhibitor as initial therapy, only a trend for a reduction was noted.

	The present study had several limitations that include the lack of mortality data, an outcome that cannot be adequately assessed in a single-center study. It was an open-label rather than a double-blind study. However, in the present study, assessments of hemodynamic function were conducted by investigators and laboratory technicians unaware of medication received by patients.

	In conclusion, this study provides the first proof that initiating therapy with carvedilol before an ACE inhibitor results in higher tolerable doses of carvedilol and better improvement in functional class and LV function, opposed to the conventional sequence of drug use in the treatment of heart failure. These results are encouraging and suggest an alternative therapeutic approach in patients with newly diagnosed heart failure.

Carvedilol before angiotensin-converting enzyme inhibitor therapy in heart failure

	Atrial fibrillation has been and remains the most common arrhythmia; however, optimal management strategies are still the subject of much discussion and

	controversy. It has been assumed previously that rhythm control is preferable to rate control for a variety of reasons, including better relief of symptoms, lower risk of thromboembolic events, and lower incidence of congestive heart failure. In addition, there is a “cosmetic” advantage to maintaining sinus rhythm, at least for the practitioner. In the last few years, a

	number of studies have compared a strategy of rate control and anticoagulation with one of rhythm control, the largest being the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial.1-3 The findings of these studies challenge the belief that maintaining sinus rhythm is preferable in the majority of patients.

	The study by Kaufman and colleagues (page 18) assessed the risk of proarrhythmic events in the rhythm control arm of the AFFIRM trial. Indeed, this is an important study, given the trend in this trial toward increased all-cause mortality, as well as the greater number of hospitalizations among patients taking antiarrhythmic drugs. The issue of proarrhythmia has been extensively studied; for example, the Cardiac Arrhythmia Suppression Trial demonstrated increased mortality with the use of class IC antiarrhythmic drugs in patients with ischemic heart disease.4 Other trials have shown increased mortality in patients with atrial fi-brillation who were treated with Class I antiarrhythmic drugs.5-7 It is important to note that although these drugs can be hazardous in certain subsets of patients with structural heart disease, they can be quite safe in others. Moreover, the method of administering these drugs was varied in these studies, and over the years, certain unofficial guidelines have emerged in an effort to avoid proarrhythmia and possible syncope or death.8,9

	The incidence of arrhythmic events at 5 years was surprisingly low in this study (5%) and accounts for a small portion of the total mortality of the rhythm control arm (27%). The incidence of torsades de pointes was slightly higher in the rhythm-control arm; however, the incidence was lower than that previously reported and occurred late, largely owing to the development of hypokalemia, hypomagnesemia, bradycardia, or worsening renal function.

	Discontinuation of a drug due to pulmonary events occurred in 7.3% of patients in the rhythm-control arm versus 1.7% in the rate- control arm (P < .001), and nearly two thirds of the patients had been exposed to amiodarone (Cordarone, Pacerone). Whether this was related in any way to mortality is not known. In a recently published analysis of cause-specific modes of death in the AFFIRM trial, it was found that there was no difference in death due to cardiac cause (9% in the rhythm-control arm versus 10% in the rate-control arm). A significantly higher proportion of deaths in the rhythm-control arm were due to noncardiac causes (P = .008) and were pulmonary and cancer-related deaths.10

	As the authors of this study point out, the AFFIRM investigators imposed strict guidelines regarding the use of antiarrhythmic drugs. For example, Class IC drugs could only be used in patients with a normal left ventricle and a normal stress test. They were contraindicated in patients with congestive heart failure, structural heart disease, myocardial disease, left ventricular hypertrophy, coronary artery disease, abnormal left ventricular function or wall motion, or a left ventricular ejection fraction below 50%. On the other hand, while Food and Drug Administration guidelines (ie, in-hospital administration, assessment of renal function, etc) were followed for the use of dofetilide (Tikosyn), no such restrictions were placed on the use of sotalol (Betapace, Sorine) or Class IA drugs. Whether or not these drugs were administered in an outpatient setting is unknown; however, because this is not common practice, it can be assumed to be minimal.

	The AFFIRM trial has challenged the notion that sinus rhythm is preferable to rate control in atrial fibrillation; however, it has raised a number of questions, and the answers are by no means simple. This analysis provides us with important information and insight that is crucial to our decision making regarding specific therapy for specific patients. In the AFFIRM trial, the trend toward increased mortality in the rhythm-control arm does not appear to be related to proarrhythmia. Nonetheless, proarrhythmia from antiarrhythmic drugs can be minimized by careful patient selection and strict adherence to dosing and monitoring requirements.

Rate control versus rhythm control  in atrial fibrillation

	Proarrhythmia has become increasingly recognized as a hazard of antiarrhythmic drug therapy.1 Certain populations are at higher risk when exposed to certain types of drugs. Women are more likely than men to develop prolonged QT intervals and torsades de pointes ventricular tachycardia.2 Patients with advanced structural heart disease are at high risk for proarrhythmia, especially when exposed to sodium channel blocking medications.3,4 Awareness that certain types of patients are at high risk when exposed to specific types of drugs has allowed clinicians to exercise caution when choosing antiarrhythmic drugs for their patients. We analyzed the risk of proarrhythmia in patients with atrial fibrillation who were enrolled in the rhythm-control arm (exposure to antiarrhythmic drugs for the maintenance of sinus rhythm) of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study to determine the risk of proarrhythmia when using today’s safety guidelines.5-7

	Details about patient selection for AFFIRM have been published previously.5-7 Patients randomized to the rhythm-control strategy form the basis of this analysis. Strategy assignment was open-label: patients received antiarrhythmic drug therapy at the choice of their physicians, provided that this choice fell within the safety guidelines specified by the AFFIRM protocol, based on standard safe clinical practice (Table). Doses were selected based on renal and hepatic function, and electrocardiograms were monitored for changes. Choices of antiarrhythmic drugs included quinidine (Cardioquin, Quinaglute), procainamide (Procan SR, Pronestyl), disopyramide (Norpace), flecainide (Tambocor), propafenone (Rythmol), moricizine (Ethmozine), sotalol (Betapace, Sorine), amiodarone (Cordarone, Pacerone), and when it became available toward the end of the study, dofetilide (Tikosyn). Some patients received ibutilide (Corvert) briefly in the hospital for attempted chemical cardioversion. If a patient failed a drug because of recurrent atrial fibrillation or intolerance, his or her clinician could choose another agent.

	Data collected at follow-up visits included clinical characteristics, antiarrhythmic drug exposures, electrocardiographic measurements, and arrhythmic events. Multivariate analysis was used to determine the effects of clinical characteristics on the risk of proarrhythmia. Some analyses were performed only on subjects exposed to the drugs thought to be most likely to cause proarrhythmia (quinidine, procainamide, disopyramide, sotalol, ibutilide, and dofetilide).

	Of the 2,033 patients randomized to rhythm control, the mean age was 69.7 ± 9 years; 71% had hypertension, 39% had a history of coronary artery disease, 23% had a history of heart failure, and 19% had diabetes. The ejection fraction was normal in 73%, mildly abnormal in 13%, and below 40% in 14% of patients. Patients were followed up for an average of 3.5 years. Their exposure to antiarrhythmic drugs at any time during follow-up was as follows: amiodarone, 63%; sotalol, 41%; propafenone, 14%; flecainide, 8%; procainamide, 8%; quinidine 7%; disopyramide, 4%; moricizine, 2%; dofetilide, 0.6%; and ibutilide, 0.2%.

	The cumulative incidence of arrhythmic events (cardiac arrest, torsades de pointes ventricular tachycardia, sustained ventricular tachycardia, and arrhythmic death) was 7% at 6 years. The Figure shows the time to first ventricular arrhythmic event in the 1,047 patients who were exposed to high-risk drugs, including quinidine, procainamide, disopyramide, sotalol, dofetilide, and ibutilide. At 5 years, the Kaplan-Meier estimate of the incidence of proarrhythmia was 5% in women and 5% in men. Multivariate analysis showed that heart failure increased the risk of proarrhythmia at 5 years (9.7% compared with 4.0% in those without heart failure). Mitral regurgitation and age older than 65 years were also associated with increased risk. After adjusting for significant covariates, female sex did not increase the risk of proarrhythmia. Torsades de pointes ventricular tachycardia occurred in 1.0% of women and 0.4% of men. This arrhythmia was usually associated with marked QT interval prolongation and often with bradycardia, hypokalemia, or hypomagnesemia.

	In this study, the incidence of proarrhythmia was low (5% at 5 years in the patients taking high-risk medications), representing only a small portion of the adverse outcomes (total mortality in the rhythm-control arm was 27%). The 0.6% incidence of torsades de pointes ventricular tachycardia was much lower than the 2% to 10% incidence reported in the earlier literature.8-13 Our findings likely reflect the careful drug-for-patient selection, electrocardiographic monitoring, and dose adjustments performed as part of the AFFIRM protocol.5

	One reason for the low overall number of proarrhythmic events may have been the common use of amiodarone, which is rarely associated with proarrhythmia, and the relatively infrequent use of Vaughan Williams Class I drugs.14 Sotalol, dofetilide, and the Vaughan Williams Class IA drugs have substantial risk of torsades de pointes ventricular tachycardia. Furthermore, Class I agents are associated with increased risk of mortality in patients with underlying structural heart disease.3,4,15 In the AFFIRM population, Class I agents were used in only about one third of patients, and the protocol specified which groups of patients could not receive them. For example, patients with coronary artery disease or left ventricular dysfunction were prohibited from receiving Class IC drugs, and physicians were discouraged from using any Class I drugs in patients with low ventricular ejection fractions.5

	Torsades de pointes ventricular tachycardia occurred in 7 of 771 women (1.0%) and in 5 of 1,262 men (0.4%). Importantly, 9 of these 12 events occurred late (not within 72 hours of drug initiation). This finding highlights the importance of avoiding late development of hypokalemia, hypomagnesemia, bradycardia, or metabolically

	mediated (eg, due to worsening renal function or drug interaction) increases in antiarrhythmic drug levels. Although we found no statistically significant increased risk of torsades de pointes in women, the low number of torsades events may have prevented the difference from becoming statistically significant.

	In the rhythm-control arm of the AFFIRM study, high-risk patients with atrial fibrillation were exposed to antiarrhythmic medications with proarrhythmic potential. The AFFIRM protocol specified guidelines for the safe use of these drugs, including drug selection, electrocardiographic monitoring, and dose adjustments based on hepatic and renal function. The overall risk of proarrhythmia was low. Although the risk of proarrhythmia continues to be an important cause for concern, clinicians can reduce this risk through informed, appropriate selection of the right drug for the right patient.

Proarrhythmic events in atrial  fibrillation: A multivariate analysis  of the AFFIRM study

	TThe Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial demonstrated that carvedilol (Coreg) provided the same antihypertensive efficacy as metoprolol (Lopressor, Toprol) in hypertensive patients with diabetes but without the adverse metabolic effects of the latter drug. The results, consistent with those of other studies, suggest that carvedilol is preferable to metoprolol in treating hypertension in this population. It is not known whether the demonstrated differences in metabolic parameters are predictive of a long-term difference in cardiovascular events. Nevertheless, in the absence of any other compelling reason to select metoprolol, it would seem logical to select a drug with fewer adverse metabolic effects in patients who are at considerable risk by virtue of having both diabetes and hypertension.

	Beta-blocking agents tend to reduce cardiac output and increase peripheral resistance, resulting in reduced blood flow to muscle, and hence reduced glucose uptake and increased insulin resistance. Nonselective beta blockers block both cardiac beta1 receptors and peripheral beta2 receptors, resulting in unopposed peripheral alpha-receptor—mediated vasoconstriction, further reducing muscle blood flow and glucose uptake. Carvedilol, unlike low-dose metoprolol, is a nonselective beta blocker; but it possesses an alpha-blocking effect that may be responsible for vasodilatation.

	Alpha-receptor blockers, such as doxazosin (Cardura), have been shown to be less effective than other antihypertensive agents as initial monotherapy for lowering blood pressure and preventing cardiovascular events, particularly heart failure.1 They are not bad drugs, however, and if anything have favorable metabolic effects, such as increased insulin sensitivity. When added to a beta blocker, an alpha blocker provides a potent antihypertensive effect, and can ameliorate the negative hemodynamic and metabolic effects of beta blockers. It is surprising, therefore, that carvedilol’s alpha-blocking effect is not mentioned in the GEMINI report as a possible mechanism of its better metabolic profile.

	Another contributor to the difference in metabolic effects between the two study drugs, and a potential weakness of the study, may have been the dose employed. The maximal dose of carvedilol, 25 mg twice daily, is widely used. The maximal dose of metoprolol (200 mg twice daily), on the other hand, is much higher than that which is widely used. Further, in GEMINI, increasing the metoprolol dosage from 200 to 400 mg per day had little additional antihypertensive effect while likely contributing to greater adverse metabolic effects. The greater reduction of heart rate and the higher incidence of bradycardia, fatigue, and weight gain in the metoprolol group are consistent with the likelihood of a greater degree of beta blockade in metoprolol-treated subjects, which might partially explain differences between the two drugs in metabolic outcome. Interestingly, in the Carvedilol Or Metoprolol European Trial, which compared efficacy of these two drugs, the maximal dosage of metoprolol was only 50 mg twice daily, which achieved a fall in heart rate equal to that seen with carvedilol.2

	GEMINI in terms of treating hypertensive diabetic patients?

	The most important factor in treating hypertension in patients with diabetes remains adequacy of blood pressure control. The GEMINI protocol differed from recommended approaches by combining an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) with a beta blocker. This combination has a lesser antihypertensive effect than regimens that combine an ACE inhibitor or ARB, which targets the renin-angiotensin system, with either a diuretic, which targets the volume component of hypertension, or a calcium channel blocker.

	Beta blockers are clearly effective in secondary prevention of coronary events and in treating heart failure. Their early use to treat hypertension cannot be advocated, however, particularly given growing evidence that other antihypertensive agents are more effective than beta blockers in primary prevention.3,4

	Finally, if combined alpha/beta blockade is desired, other drugs provide more reliable alpha/beta blockade than does carvedilol. Carvedilol, a lipophilic beta blocker, is subject to extensive first-pass hepatic metabolism, resulting in inadequate blood levels in many who take the drug. In fact, the bioavailability of the s-enantiomer responsible for most of carvedilol’s beta-blocking effect is only 16%.5 The combination of a nonlipophilic beta blocker along with an alpha blocker, such as doxazosin, has more consistent bioavailability. Unfortunately the long-term outcome of combined alpha/beta blockade using agents other than carvedilol has not been studied.

	In summary, carvedilol was associated with fewer adverse metabolic effects than high-dose metoprolol, and would thus appear preferable in patients with insulin resistance, such as diabetic patients. In treating the diabetic hypertensive patient, beta blockers should not be considered preferable to other drug classes as first or second-step therapy, in the absence of other specific indications for their use.

The GEMINI trial: The role of carvedilol in treating hypertensive patients with diabetes

	The recently published Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial reported that blood pressure—lowering therapy with the vasodilating beta blocking agent carvedilol (Coreg) did not adversely affect glycemic control in diabetic patients.1 Furthermore, carvedilol was significantly better than the beta blocker metoprolol (Lopressor, Toprol) in preserving glycemic control when added to a regimen of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). These findings are of particular clinical importance considering the reluctance to use beta blockers to treat hypertension in diabetic patients despite their proven ability to reduce mortality and hospitalizations in patients with coronary heart disease and heart failure, which are highly prevalent in the diabetic population. We review the GEMINI study and its results as they apply to clinical practice.

	It has been well documented that patients with diabetes can reduce their cardiovascular risk by lowering blood pressure and achieving better glycemic control.2,3 Diabetic patients usually require a minimum of two antihypertensive drugs to achieve the recommended target blood pressure (< 130/80 mm Hg). Treatment with ACE inhibitors and ARBs protects the diabetic patient from nephropathy, neuropathy, retinopathy, and cardiovascular disease. Therefore, it should be the first choice along with a thiazide diuretic for the treatment of diabetic hypertension.4 Because at least 70% of deaths in diabetic patients are related to heart disease, the next drug should not be a vasodilator or a calcium channel blocker (CCB), but a beta blocker.5 Beta blockers have been shown to reduce mortality and morbidity in patients with diabetes even more than in patients without diabetes and should, therefore, be utilized earlier rather than later in these patients.4,6,7

	Nevertheless, there has been a general reluctance to use beta blockers in diabetic and nondiabetic patients because of their association with an increased incidence of new-onset diabetes and worsening glycemic control in established diabetes, both resulting from increases in insulin resistance8; however, a new generation of vasodilating beta blockers has been developed that does not decrease insulin sensitivity and, therefore, does not lower high-density lipoprotein cholesterol levels or raise glucose levels.9 Carvedilol is the only drug in this class to be approved for clinical use in the United States, and it has been shown to improve insulin sensitivity in both the diabetic and nondiabetic hypertensive patient and also to have a potent antioxidant effect.10,11

	Before GEMINI, there had not been a study that investigated the effect of beta blockade on glycemic control in diabetic hypertensive patients who were concurrently receiving an ACE inhibitor or an ARB, both of which are known to improve glycemic control by lowering insulin resistance. GEMINI compared the effects of carvedilol with those of metoprolol, a beta blocker known to decrease insulin sensitivity.11 The primary end point of GEMINI was change in glycosylated hemoglobin level (A1C), which in addition to reflecting average glycemic control during the previous 2- to 3-month period, is also a prognosticator of cardiovascular risk in both diabetic and nondiabetic patients.12

	GEMINI was a randomized, double-blind, clinical trial carried out in 205 sites in the United States, which included 1,235 patients with type 2 diabetes (A1C, 6.5%—8.5%) and documented stage 1 or 2 hypertension. Patients were receiving stable doses of either an ACE inhibitor or an ARB. Inclusion criteria were blood pressure between 130/80 mm Hg and 179/109 mm Hg for 2 to 4 weeks after discontinuing all antihypertensive medications with the exception of an ACE inhibitor or an ARB.

	Qualifying patients were randomly assigned to treatment with either carvedilol or metoprolol tartrate. To achieve a target blood pressure below 130/80 mm Hg, doses of each drug were initiated and uptitrated according to the manufacturer’s recommendations at 1- to 2-week intervals for 2 to 7 weeks. Carvedilol was started at 6.25 mg twice daily and was raised in two steps to a maximum of 25 mg twice daily. Metoprolol was started at 50 mg twice daily and was raised in two steps to 200 mg twice daily. Hydrochlorothiazide, 12.5 mg, and a dihydropyridine CCB were sequentially added if the target blood pressure was not reached with the maximum beta blocker dose. Participants were then entered into a 5-month maintenance period after reaching the target blood pressure.

	The primary outcome was the percent change in A1C between baseline and 5 months of maintenance therapy between the two groups. Secondary outcomes are listed in the Table and include measures of insulin resistance, lipid levels, and endothelial function.

	Patients enrolled in GEMINI had a mean baseline blood pressure of 149/87 mm Hg and an A1C level of 7.2%. Both drugs similarly controlled blood pressure to an average of 132/77 mm Hg. The mean beta blocker doses required to achieve this blood pressure were 17.5 mg of carvedilol twice daily and 128 mg of metoprolol twice daily, with both treatment groups requiring similar additional blood pressure medication. Eighty percent of the carvedilol group and 74% of the metoprolol group completed 5 months of maintenance therapy.

	Although carvedilol had a neutral effect on mean A1C levels (P = .65), metoprolol increased mean A1C by 0.15% (P < .001). Figure 1 shows the progressive rise in A1C for patients receiving metoprolol compared with those receiving carvedilol. The primary outcome showed significantly better glycemic control with carvedilol (0.12% difference in A1C from baseline) than with metoprolol (95% confidence interval, —0.20 to –0.03; P = .006). An increase in A1C of at least 1% was twice as frequent with metoprolol (14%) as it was with carvedilol (7%). More metoprolol patients (2.2%) than carvedilol patients (0.6%) withdrew because of worsening glycemic control (fasting blood glucose > 270 mg/dL). Differences in glycemic control were due to changes in insulin resistance as shown in Figure 2. Although there was a nonsignificant increase in insulin resistance with metoprolol, there was a significant decrease with carvedilol (P = .006), with a mean difference of 7.2% between the treatment groups (P = .004).

	There were also significantly different changes in blood lipids at 5 months (Figure 2). Metoprolol increased triglycerides by 13% (P < .001), whereas carvedilol had no significant effect. Carvedilol lowered total cholesterol

	(P = .001), and twice as many metoprolol patients than carvedilol patients had an HMG-CoA reductase inhibitor (statin) initiated or increased during the maintenance phase of the study (4.9% versus 2.4%; P = .04). No between-treatment differences were seen in either low- or high-density lipoprotein cholesterol levels. Endothelial function was also favorably affected by carvedilol because of decreased insulin resistance and/or oxidative stress, but not by metoprolol. Microalbuminuria, defined as a urinary albumin-to-creatinine ratio of 30 to 300 mg/g, was present in 19% of patients at baseline. Carvedilol use was associated with a significant 16% reduction in albumin-to-creatinine ratio, whereas there was a nonsignificant increase with metoprolol, resulting in a significant between-treatment difference (P = .003). In addition, fewer carvedilol than metoprolol patients with baseline albumin-to-creatinine ratios below 30 mg/g progressed to microalbuminuria (6.4% versus 10.3%; P = .04). Adverse drug effects were comparable between the two groups, although significant weight gain and bradycardia were more common with metoprolol.

	GEMINI is the first trial to study the metabolic effects of beta blockade when added to ACE inhibitor or ARB therapy in the treatment of diabetic hypertension. Patients were typical of those encountered in clinical practice, with blood pressures above recommended levels despite renin-angiotensin system blockade. Both carvedilol, a vasodilating beta blocker with antioxidant properties, and metoprolol, a beta1 selective blocker, successfully lowered blood pressure, although higher doses of metoprolol were required to do so.

	Glycemic control was significantly worsened by metoprolol but not by carvedilol because of an improvement in insulin sensitivity with carvedilol and a nonsignificant decrease in insulin sensitivity with metoprolol. The improvement in insulin resistance, endothelial function, and glycemic control seen with carvedilol in the GEMINI study translates into a decrease in cardiac risk for the diabetic patient; however, an outcome trial is needed to assess whether these decreases in cardiac risk translate into improved cardiovascular outcomes.

	The GEMINI study demonstrates that in the presence of agents that block the renin-angiotensin system, the use of a beta blocker that has been shown to reduce insulin resistance and improve endothelial function, such as carvedilol, will improve glycemic control and avoid the negative effects on metabolic factors that may compromise the reduction in cardiac risk associated with beta blockade.

Carvedilol versus metoprolol in  diabetic hypertensive patients

	Clinical trials and community programs go hand in hand, and we are extremely proud of our contribution in both areas. We conducted the first cardiovascular-related clinical trial in an entirely African American population in 1977, documenting the sexual side effects of antihypertensive medications. We also pioneered the first church-based health promotion initiative in 1979, empowering African Americans to prevent cardiovascular-related risks by training volunteers to take blood pressures, refer those with elevations, follow-up, and monitor. Obviously, recruiting study subjects for clinical trials is greatly facilitated by the success of our community-based programs.

	We unabashedly facilitate the development of new and innovative treatments for diseases that disproportionately affect African Americans. Although controversial, we helped to recruit the investigators and the 1,050 patients for the African American Heart Failure Trial (A-HeFT) to determine whether isosorbide dinitrate plus hydralazine (BiDil) would be beneficial for African Americans with heart failure (in addition to optimal background therapy). The results were dramatic—a 43% survival benefit. We were also partners in the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial that evaluated the impact

	of rosuvastatin (Crestor) in an entirely African American population. Again, very positive and very impressive results were achieved. We completed some 40 clinical trials for African American patients and will continue to promote clinical trials as a strategy to achieve higher quality outcomes at an affordable cost.

	We have a strong focus on community programs. We will use “Bible Marks” as a very inexpensive way to spread our message of “Seven Steps to Good Health,” and we encourage religious leaders to dedicate a minute for a health message at each gathering. Our CHOICES program (Changing Health Outcomes by Improving Cardiovascular Education and Screenings) stands out as a great innovation.

 Clinical Trials and Community Programs at the ABC

	Stockholm—Final results of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Blood Pressure Lowering Arm (BPLA) indicate significant reductions in all-cause mortality and other adverse cardiovascular end points with an antihypertensive regimen starting with amlodi-pine/atorvastatin (Caduet), with perindopril (Aceon) added as required, compared with a regimen of atenolol (Tenormin) with addition of a diuretic. The results were

	presented at the 2005 Congress of the European Society of Cardiology.

	With this finding, beta blocking agents should no longer be considered first-line treatment for patients with uncomplicated hypertension, especially those older than 55 years, said study coinvestigator Peter Sever, MD.

	The ASCOT-BPLA included 19,257 patients with hypertension who had at

	least three other cardiovascular risk factors. Patients were randomly assigned to either:

	• amlodipine/atorvastatin, 5 to 10 mg, with perindopril, 4 to 8 mg, as required, or

	• atenolol, 50 to 100 mg, with the addition of bendroflumethiazide (Naturetin), 1.25 to 2.5 mg, and potassium as required.

	The primary end point was the incidence of nonfatal myocardial infarction  and fatal coronary heart disease. By the end of the trial, 78% of patients were taking two or more antihypertensive agents and only 15% and 9% were receiving amlodipine and atenolol monotherapy, respectively.

	The study was stopped prematurely after a median of 5.5 years when mortality and several other secondary outcomes were determined to be worse in the patients assigned to atenolol-bendroflumethiazide compared with amlodipine-perindopril. At this time, the primary end point was lowered by a nonsignificant 10% in patients assigned to the amlodi-pine-perindopril regimen.

	There were, however, significant reductions in almost all of the secondary end points with the amlodipine-perindopril regimen, including total coronary events (13% reduction; P = .007), total cardiovascular events and procedures (16% reduction; P < .001), all-cause mortality (11% reduction; P = .0247), cardiovascular mortality (24% reduction; P = .001), and fatal and nonfatal stroke (23% reduction; P = .003). In addition, the incidence of new-onset diabetes was reduced by 30% (P < .001) in the amlodipine-perindopril arm relative to the atenolol-bendroflumethiazide arm. The incidence of new-onset renal dysfunction was also reduced by 15% (P = .02) in the amlodipine-perindopril arm. The clinical advantage with the amlodipine-perindopril strategy was observed in all prespecified subgroups.

	There was a mean blood pressure difference of 2.7/1.9 mm Hg throughout the trial in favor of the amlodipine-perindopril regimen. “Blood pressure accounted for about 15% of the coronary differences and 30% of the stroke differences,” said Neil R. Poulter, MD, coinvestigator of ASCOT. “Blood pressure differences are unlikely to be a single explanation.”

	Multivariate adjustment accounted for about half of the differences in coronary events and for about 40% of the differences in strokes between the treatment strategies, he said. Statistical analysis actually showed more coronary events in the amlodipine-based regimen during the first year of the study, even though blood pressure differences between the two regimens were greatest during this time, making it highly unlikely that blood pressure was responsible for the entire difference in outcomes between the two strategies, said Dr. Poulter, professor of preventive cardiology medicine, Imperial College, London.

	In addition, when using a technique called serial mean matching, which includes in an analysis only those patients with similar systolic blood pressures during the trial, the incidences of coronary events and strokes were still less with the amlodipine-perindopril strategy, he said. “Given the large population burden of hypertension, even modest incremental benefits of specific agents over others can translate into an important public-health impact,” commented Salim Yusuf, MBBS, PhD, professor of medicine and director of the Population Health Research Institute, McMaster University, Ontario, Canada.

Amlodipine-perindopril regimen in hypertension superior  to beta blocker-diuretic

	Stockholm—A meta-analysis revealed that an aspirin dose of less than 100 mg/day is associated with a lower risk of bleeding complications compared with higher doses, said investigators at the 2005 Congress of the European Society of Cardiology.

	Victor L. Serebruany, MD, president, HeartDrug Research Laboratories, and assistant professor of medicine, Johns Hopkins University, Baltimore, presented data from a review of 31 clinical trials of 192,036 patients who were taking aspirin for secondary prevention of cardiovascular disease. Only studies in which patients had clinical follow-up for at least 1 month and in which a detailed description of hemorrhagic complications was reported were included in the analysis.

	“Aspirin has been a mainstay of therapy to prevent acute myocardial in-

	farction and secondary stroke, and at least 30 million people worldwide take aspirin for these indications,” said Dr. Serebruany, lead investigator of the study. “However, most reports have focused on efficacy and clinical outcomes after aspirin use, and few studies have linked the dose of aspirin monotherapy with the incidence of bleeding events. We conducted this analysis in order to provide physicians with needed information that may help them to better determine appropriate doses of aspirin therapy for their patients.”

	The analysis compared the risk of bleeding for patients who took low- (< 100 mg), moderate- (100 to 200 mg), and high-dose aspirin (> 200 mg). Bleeding complications were classified into six categories—minor, major, gastrointestinal, stroke, fatal/life-threatening, or total.

	Patients who were taking the lowest dose of aspirin had the lowest average rate for total bleeding events, 3.26%, versus 11.31% for moderate-dose aspirin and 9.40% for high-dose aspirin. The findings hold special importance for groups of patients at highest risk of bleeding complications, such as the elderly, smokers, alcoholics, and hypertensive patients being treated with angiotensin receptor blockers, which are known to inhibit platelets, said Dr. Serebruany.

	The data provide confirmation of a dose-dependent relationship between aspirin and increased risk of bleeding complications, said coinvestigator Steven R. Steinhubl, MD, director of cardiovascular research and education, University of Kentucky, Lexington. “Based on the results of this and other analyses, it would be prudent for physicians and patients to consider a lower-dose aspirin as a preventive therapy,” he said. “I recommend that to get the cardioprotective effects of aspirin with the lowest bleeding risk, patients [should] take less than 100 mg day,” said Dr. Steinhubl. “More specifically, the only dose available below 100 mg in the US is 81 mg, so that’s what I recommend.”

	In describing the prevalence and severity of bleeding with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), he said that the number of people who die of NSAID-induced gastrointestinal bleeding yearly is similar to the number of people who die from AIDS. “The mere fact that so many people take aspirin means that it has a potential for a lot of side effects,” said Dr. Steinhubl. “So while the individual risk of a person having a side effect is low, a low risk percentage-wise can amount to a lot of people when you have 30 million people taking it.”

 Aspirin dose less than 100 mg associated with lowest risk of bleeding

	Stockholm—The antithrombotic fondaparinux (Arixtra) is as effective as enoxaparin (Lovenox) in preventing death, myocardial infarction (MI), and refractory ischemia while reducing the incidence

	of bleeding over the first 9 days in patients with acute coronary syndromes (ACS) without ST elevation. As a result of

	the reduction in bleeding, fondaparinux was associated with improved survival

	at 30 days and 6 months compared with enoxaparin, said investigators at the

	2005 Congress of the European Society of Cardiology.

	With these findings from the Organization to Assess Strategies for Ischaemic Syndromes (OASIS-5) trial, fondaparinux should be considered the preferred anticoagulant in patients with ACS who are already receiving aspirin and clopidogrel (Plavix), said Salim Yusuf, MBBS, PhD, lead investigator of the trial. He noted that previous studies have already shown superiority of fondaparinux over enoxaparin in preventing deep vein thrombosis in patients undergoing various orthopedic surgeries.

	OASIS-5 included 20,078 patients with ACS from 41 countries who were randomly assigned to receive fondaparinux, 2.5 mg/day, or enoxaparin, 1 mg/kg twice daily, for 2 to 8 days. The study medications were administered in addition to standard medical care including aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitors, and revascularization procedures.

	The primary objective was to evaluate whether fondaparinux was at least as effective as enoxaparin in preventing death, MI, or refractory ischemia. Secondary objectives included evaluation of safety (bleeding events) up to day 9, as well as determining if the relative effect of fondaparinux versus enoxaparin on the primary end point was sustained up to 6 months.

	At 9 days, 5.9% of fondaparinux recipients and 5.8% of enoxaparin recipients experienced the primary end point, which met the criterion for noninferiority of fondaparinux. Furthermore, fondaparinux was associated with a 47% reduction in major bleeding versus enoxaparin (2.1% and 4.0%, respectively; P < .001).

	Thirty-day mortality was 2.9% in the fondaparinux group and 3.5% in the enoxaparin group—a 17% reduction (P = .0219) in favor of fondaparinux. This reduction in mortality was maintained at 6 months (5.8% versus 6.6%; P = .037).

	The reduction in mortality at 30 days with fondaparinux was a direct result of the reduction in bleeding with this agent, said Dr. Yusuf, professor of medicine and director of the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. Patients who experience a major bleed in ACS are known to have a much higher risk of death during the immediate weeks following the event. “We know that major bleeding increases the risk of mortality independently by 400%,” he said.

	The risk of major bleeding at 6 months was 28% lower in the fondaparinux group compared with the enoxapain group

	(P < .001). Accordingly, the composite of death, MI, refractory ischemia, and bleeding at 6 months was 13% lower with

	fondaparinux compared with enoxaparin (P < .001). Eighty-five percent of the difference in mortality between the treatment groups at 6 months was owing to the difference in the incidence of major bleeding.

	The benefit of fondaparinux was apparent in hospitals with or without catheterization labs and whether or not patients received unfractionated heparin. “Put in context, our results showed that if you took 1,000 people with ACS and treated them with fondaparinux instead of enoxaparin, you would prevent 10 deaths from MI, 4 from stroke, and 25 major bleeds,” said Dr. Yusuf.

October 2005

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Amlodipine-perindopril regimen in hypertension superior to beta blocker-diuretic

Amlodipine-perindopril regimen in hypertension superior to beta blocker-diuretic

Aspirin dose less than 100 mg associated with lowest risk of bleeding

Fondaparinux safer than standard antithrombotic therapy in ACS

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