Untreated or uncontrolled hypertension is one of the most powerful and prevalent risk factors for heart disease and stroke in the United States.

 In African Americans, hypertension arises prematurely and its onset is often more severe, with higher levels of uncontrolled hypertension despite patient awareness levels similar to those found in non-Hispanic whites. One of the difficulties in managing hypertension in all populations is its relatively asymptomatic nature early in the disease process. Factors that have been noted to contribute to the high level of uncontrolled hypertension in the United States include issues with access to care, failure of providers to initiate or intensify treatment, and cultural beliefs regarding the adverse effects of medication. Clearly, adherence to treatment impacts control rates, and cognitive and behavioral interventions may show promise in improving blood pressure in the future.

Getting patients to adhere to antihypertensive medication regimens is difficult, especially African Americans. Although patient compliance issues can lead to suboptimal blood pressure control, objective data remain elusive, yet the benefits of specific approaches have been confirmed. During the 2008 Scientific Sessions of the American Heart Association, Lisa M. Lewis, PhD, RN, assistant professor of nursing at the University of Pennsylvania, discussed current epidemiologic data and various approaches to recognizing African American belief systems that can impact adherence. Dr Lewis conducted a qualitative study that explored community-dwelling hypertensive African American beliefs and their effect on adherence to antihypertensive medications. The model used was a community/academic partnership with 3 focus groups consisting of 40 participants at 2 community centers in a northeastern urban environment. Each of the focus groups was asked to comment on medication adherence, and their responses were recorded and transcribed verbatim. The data were assessed using thematic analysis. The

sample consisted mostly of female subjects (n = 27) with a mean age of 57 years. Only 14 high school graduates were noted in the group, and the unemployment status was more than 65% (n = 27).

The study recognized the impact of socioeconomic considerations in chronic disease management, and approximately 50% of the sample (n = 18) was noted to earn an annual income of $20,000 or less. In addition, hypertension had been diagnosed at least 8 years earlier in most of the participants, with a majority reporting adherence to medication (n = 26). The quality of the results confirmed that the most salient belief associated with adherence was “it’s a matter of life and death,” which multiple study participants articulated. Nevertheless, there were 3 social factors that made achieving long-term patient compliance challenging. These included difficulties in obtaining care with limited resources, maintaining a positive health outcome in neighborhoods riddled with violence, and negotiating feelings of physician mistrust.

One of the shortcomings of Dr Lewis’s provocative study was its qualitative nature. Also, as Dr Lewis noted, the results were garnered from a small cohort and cannot be generalized, but they may provide significant insight into the contextual factors associated with the often complex and difficult lives of some community-dwelling, hypertensive African American patients.

Interestingly, studies have shown that blacks are actually as likely to be aware of having hypertension and to receive pharmacologic treatment as whites. Nevertheless, from 1988 to 1994 and 1999 to 2002, the disparity in effectiveness of therapy increased between whites and blacks.

 The keys to treating African Americans include a focus on prevention, assessment of patients at high risk, and early intervention, usually with combination therapy. Compared with 35.4% of whites in NHANES (National Health and Nutrition Examination Survey) 2003-2004, only 28.9% of African Americans were controlled (

 Furthermore, in hypertensive African Americans, approximately 30% and 20% of all deaths in men and women, respectively, may have been attributable to uncontrolled blood pressure.

Clinical trials have demonstrated that with effective therapy, African Americans can have improved outcomes. It has been found that the high rates of severe and uncontrolled hypertension in this population can be at least partially curtailed with increased physical activity and a decrease in psychological stress; however, although lifestyle is the bedrock of antihypertensive care, most patients will need at least 2 or more medications to achieve control, especially those who are middle-aged and older.

Lack of adherence to blood pressure medications predicts poor control and is one of the underlying factors for the serious health disparities regarding morbidity and mortality observed in African Americans. Because of patient compliance issues, target organ damage, including heart failure, end-stage renal disease, fatal and nonfatal stroke, and coronary heart disease mortality continue to be disproportionately high in this population. NHANES 1999-2000 reported that only 53% of people being treated for hypertension had their blood pressure controlled to less than 140/90 mm Hg, with rates lower in women than in men.

 Unfortunately, for African Americans, the rates of control are worse than in the general population, and only a minority of all African Americans with hypertension have controlled blood pressures. Adherence to a scheduled regimen of taking prescribed medications greatly impacts care, yet this is difficult to accomplish. Data have consistently shown that many adults do not remain adherent to antihypertensive therapy after 1 year.

As Dr Lewis’s study demonstrates, socioeconomic standards influence poorer outcomes and lower quality of care. Although some studies suggest genetic factors may contribute to increased rates of hypertension in African Americans, including greater severity and complications, patient-related barriers and clinician-associated inertia probably explain most of the disparities in morbidity and mortality.

While patient awareness issues must be considered, many patients, even with appropriate awareness, do not adhere to taking their prescribed medications. Community screening, health-related education, and simply making the patient aware of the condition are inadequate to decrease the excessive morbidity and mortality observed in African Americans in the United States. Unfortunately, research remains qualitative and is limited in providing clear-cut methods to increase adherence and blood pressure control in this difficult-to-treat population. Interventions that take cognition and cultural beliefs into account may actually contribute extensively to understanding and curtailing medication nonadherence; thus, findings from studies like those conducted by Dr Lewis may be important if they can be used to tailor interventions to increase medication adherence in high-risk patients. 

Articles

Lipids

Community-dwelling African American beliefs may affect adherence to antihypertensive medications

Type 2 diabetes mellitus has been increasing in prevalence over the past few decades, nearing epidemic proportions, and the number of persons with this disease is projected to double by 2030. It is also well known that many individuals remain undiagnosed. Diabetes is considered a coronary heart disease risk equivalent, especially in patients with long-standing dysglycemia. Two major risk factors associated with type 2 diabetes are elevated blood pressure and hyperlipidemia. In managing type 2 diabetes, control of these comorbid conditions is considered as important as controlling blood glucose levels. Despite the availability of numerous therapeutic options, glycemic control and blood pressure and lipid targets remain suboptimal in many individuals. While traditional oral therapies may be effective at decreasing hyperglycemia, the need for new agents and formulations is apparent. At the American Heart Association 2008 abstract presentations, an interesting report noted the possible benefit of exenatide (Byetta) in controlling multiple cardiovascular risk factors, including blood pressure and lipids, potentially reducing morbidity and mortality in patients with type 2 diabetes. The report was presented by Richard M. Bergenstal, MD, executive director, International Diabetes Center at Park Nicollet, Minneapolis, MN, and supported by a grant from Amylin Pharmaceuticals, Inc, of San Diego, CA.

Previous studies indicated that exenatide may be beneficial in reducing hemoglobin A1C (HgbA

) levels when administered twice daily, demonstrating a decrease in body weight and subsequent improvements in blood pressure and lipid profiles. The trial reported by Dr Bergenstal evaluated a once weekly formulation of exenatide, which was administered to 120 patients with type 2 diabetes for 52 weeks (1 year). Baseline variables included an HgbA

 of 8.3 ± 1.0%, weight of 103 ± 19 kg, and a body mass index of 35.2 ± 5.0 kg/m

. After 1 year of treatment, there was an improvement in HgbA

 levels (-2.0 ± 0.1%) and in weight loss (-4.1 ±0.6 kg). Interestingly, significant improvements in both systolic and diastolic blood pressure were observed (-6.2 ± 1.2 mm Hg and -2.8 ± 0.8 mm Hg, respectively). These blood pressure changes occurred from an average baseline of 128/78 mm Hg and were statistically significant (

 <.05). Additionally, subjects (n = 65) with higher systolic blood pressure (≥130 mm Hg at baseline) showed even greater improvements. These subjects had a mean blood pressure of 139/81 mm Hg at baseline and their systolic blood pressure decreased between 11.4 ± 1.9 mm Hg (

 <.05) and their diastolic blood pressure decreased between 3.6 ± 1.2 mm Hg (

In addition to controlling blood pressure, dyslipidemia must be curtailed in patients with diabetes for optimal cardiac risk reduction. Bergenstal and colleagues noted favorable improvements in serum lipids. The mean baseline total cholesterol level was 170 mg/dL, which decreased by 7.9 ± 2.3 mg/dL. The mean baseline low-density lipoprotein cholesterol level was 89 mg/dL and was decreased by 2.2 ± 2.4 mg/dL. High-density lipoprotein (HDL) cholesterol levels did not significantly increase. In fact, HDL cholesterol levels at the end of the trial decreased 0.3 ± 0.8 from a baseline of 44 mg/dL. Triglycerides, on the other hand, improved remarkably from the baseline of 179 mg/dL, decreasing by 40.1 ± 111.5.

Exenatide is a synthetic peptide with incretin-mimetic actions. This novel diabetic medication, which was originally identified in the Gila monster lizard (Heloderma suspectum), enhances glucose-dependent insulin secretion by the pancreatic beta cells by preventing inappropriate glucagon secretion and slowing gastric emptying, increasing satiety and promoting weight loss. Currently, exenatide is indicated as adjunctive therapy to improve glycemic control in type 2 diabetes patients who have not achieved adequate glycemic control using metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione.

Exenatide differs in chemical structure and action from conventional diabetic medications, such as insulin, sulfonylureas (including Dphenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, and alpha-glycosidase inhibitors. Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide mimics the enhancement of glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins. The amino acid sequence of exenatide partially overlaps with human GLP-1 and has been shown to bind and activate the known human GLP-1 receptor. The mechanism of action consists of an increase in glucose-dependent synthesis of insulin and in vivo secretion of insulin from pancreatic beta cells involving cyclic AMP and/or other intracellular signaling pathways.

Exenatide promotes insulin release only when there are elevated glucose concentrations and improves glycemic control by reducing fasting and postprandial glucose levels. The insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Exenatide also moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia, resulting in decreased hepatic glucose output and decreased insulin demand. This novel agent does not impair the normal glucagon response to hypoglycemia.

Exenatide is administered as a subcutaneous injection because oral administration is ineffective. This GLP-1 analogue provides resistance to the rapid degradation seen with GLP-1 by DPP-IV. Unlike with DPP-IV inhibitors, there appears to be longer action. In addition to significant reductions in HgbA

 of 0.8% to 1.7%, this treatment is associated with an additional weight loss of 1.75 to 3.8 kg. The weight loss mechanism appears to be primarily through promotion of satiety, leading to reduced fluid intake and regulation of the gastric emptying rate, limiting postprandial glucose excursions. These beneficial metabolic responses are also accompanied by an increase in insulin secretion from pancreatic beta cells in a glucose-dependent manner with little or no associated hypoglycemia. There appears to be suppression of glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, which in turn suppresses hepatic glucose output.

Previous studies have indicated that the most common adverse events with exenatide are gastrointestinal complications, particularly nausea. The cumulative incidence of nausea, which was predominately mild in intensity, occurred in 29% of the patients over the 52 weeks of therapy. Concern over the cardiovascular benefit of at least 1 recent antidiabetic agent (ie, rosiglitazone resulting in an increased risk of cardiovascular morbidity and potentially mortality) has suggested the need for close monitoring of the cardiovascular effects of antidiabetic agents, especially those with which we have limited long-term clinical experience. Newer type 2 diabetes treatments include GLP-1 based approaches with DPP-IV inhibitors, such as oral sitagliptin, and GLP-1 analogs, which must be given by injection.

Control of blood pressure is one of the most significant components of cardiovascular risk reduction in patients with type 2 diabetes. In Dr Bergenstal’s study, systolic blood pressure was reduced below 130 mm Hg in 71% of patients. Although exenatide’s ability to stimulate weight loss may have contributed to the reduction in blood pressure, an analysis of systolic blood pressure changes at 52 weeks revealed that patients treated with once weekly exenatide had reduced systolic blood pressure irrespective of whether or not they lost weight. It should be noted that changes in concomitant antihypertensive medicines were allowed only if deemed necessary by the investigators. Hopefully, future analyses of these data will determine to what extent antihypertensive medication contributed to the blood pressure control noted with exenatide.

The most common side effect of exenatide therapy was nausea, and a drawback is the need for the medication to be administered through subcutaneous injections; however, a once weekly formulation may make this option feasible for more patients in the future. Dr Bergenstal’s study indicates that treatment with exenatide on a once weekly basis is a generally well tolerated therapy that may offer numerous benefits, including significant improvements in glycemia, body weight, blood pressure, and lipid levels. 

Exenatide once weekly improves blood pressure and lipid profile in patients with type 2 diabetes

There has been a paradigm shift in electrophysiology because of advances in catheter ablation technology. Advanced imaging techniques are required to evaluate accuracy of catheter tip placement, measure lesion size, and determine location before radiofrequency ablation, improving guidance during technically difficult procedures (eg, transseptal puncture and coronary sinus access), and reducing fluoroscopic exposure to patients and medical personnel. Conventional ablation, such as used for accessory pathways, atrioventricular nodal tachycardia, and typical flutter, has depended on electrophysiologic data alone; however, ablation of new anatomic targets (eg, pulmonary veins) requires electrograms and precise target anatomic information. This is because a misdirected ablation can lead to an unsuccessful procedure or serious complications, including esophageal fistula, pulmonary vein stenosis, or cardiac tamponade from atrial wall perforation. To prevent such mishaps, computed tomography (CT) and magnetic resonance imaging (MRI) have been used before the procedure to define atrial and pulmonary vein anatomy. More recently, fusion imaging has been used. With this modality, MRI and CT images acquired before the procedure and echocardiographic images obtained during the procedure are merged with an electroanatomical map acquired during the procedure.

Preprocedure images do not show anatomic alterations in chamber size and changes in location of pulmonary vein ostia resulting from hemodynamic alterations secondary to changes in heart rate, volume, and blood pressure status; thus, live anatomic imaging during ablation is highly desirable. Live imaging also allows evaluation of anatomy during and following ablation and its correlation with conduction block or lack thereof. Progress has been made in the area of live MRI, live CT, and live 2D and 3D echocardiographic imaging. This article focuses on echocardiography and CT imaging.

The most widely used imaging method during ablation is intracardiac echocardiography. Two catheters in clinical use include the Ultra ICE™ (Boston Scientific) and AcuNav™ (Acuson, Siemens).

Ultra ICE is a single-element, mechanical transducer housed in a 9 Fr catheter that provides a 360° radial image at 9-MHz frequency. It does not have Doppler capabilities. As early as 2004, an external motor was used, allowing controlled withdrawal of the catheter at 0.5-mm increments and feeding 2D images at each depth to an external Tom Tec workstation to generate 3D volume data. In a study including 20 patients undergoing caval-tricuspid isthmus ablation for typical atrial flutter, 3D data were acquired,

 and investigators found 2 types of isthmus anatomy: (1) a prominent Eustachian ridge, which appeared like a curtain arising posterior to the coronary sinus and extending to the anterior wall of the inferior vena cava; and (2) a smooth isthmus with a small inconspicuous vertical Eustachian ridge. Subjects with a prominent Eustachian ridge required far more burns (25 burns) to achieve complete isthmus block compared with those who had a smooth isthmus (8 burns). In addition, unlike 2D images, which show a dense white area reflecting edema in the area of ablation, 3D image reconstruction provided precise visualization of the entire area of ablation, from the tricuspid valve to the inferior vena cava.

The AcuNav catheter is a 10 Fr, 64-element, phased array transducer, which provides a 90° sector image at operating frequencies of 5.5 to 10 MHz. An external motor has also been used with the AcuNav catheter, allowing rotation of the catheter along its axis at 2° to 5° increments and converting the 2D images to electrocardiogram- and respiration-gated data on an external Tom Tec workstation. This method was used to obtain data in animal models (5 sheep) and in 6 patients undergoing ablation for atrial fibrillation.

 All anatomical structures and instruments of interest could be visualized with the catheter tip seated in the mid right atrium, including the ablation catheter in the left atrium, mitral valve, left atrial appendage, all 4 pulmonary veins, thrombus on catheters, right ventricular and left ventricular endocardium, catheter in right ventricle, and interatrial septal anatomy. Acquisition time with this method varies between 1 to 3 minutes based on heart rate. The reconstruction time is 2 to 4 minutes, and this method does not yield live 3D imaging.

Transducer arrays have been mounted on catheters adapted to be used with volumetric scanners that acquire pyramidal volume data from 2 axes perpendicular to the array and B scans parallel to the array. Live 3D data were acquired in an open chest sheep model, whereby the imaging catheter was introduced into the left atrium surgically from the left atrial roof. The catheter was able to visualize pulmonary vein ostia in 3D as well as the mapping catheter introduced from the left ventricular apex, with images mimicking real anatomy and far superior to 2D images used to guide ablation.

Live intracardiac 3D imaging using an intracardiac catheter is being introduced by General Electric, but live 3D transesophageal echocardiography (TEE) is the most recent clinically available development. Although it has the limitation of requiring general anesthesia for prolonged procedures, 3D TEE provides unparalleled live images that are already being used to perform ablation of complex arrhythmias.

Another recent development has been the merging of intracardiac echocardiography with electroanatomical mapping and CT imaging using the CartoSound (Biosense Webster) image integration model. The intracardiac catheter is tipped with a biosensor that enables tracking of the catheter in space. The contour of the left atrium and pulmonary veins is traced in each 2D image and assigned a map on a map reader. A 3D shell is then created from the contour. A comprehensive 3D shell of the left atrium and pulmonary veins is made from multiple images. This 3D echo shell is then merged with the CT image.

 The technology is feasible and enables delivery of ablation to precise anatomic targets. The technique may obviate the need for CT images acquired before ablation.

CT imaging and segmentation technical considerations

Most medical images are made up of an array of small squares or rectangular elements called pixels.

 Each pixel has an associated image intensity. This provides the coordinate system of the image, and an element in the image can be assessed by its 2D position within this array. A typical CT slice is formed of 512 x 512 pixels, each corresponding to a portion of the cut through the patient and measuring about 0.5 x 0.5 mm

 The matrix and the pixel size are related to the display field of view (FOV). For example, if the FOV is 25 cm, each pixel will be 0.48 mm

 (FOV/matrix size; 25/512). This dimension determines the limiting in-plane spatial resolution of the image. The 2D axial slices are then stacked together to form a 3D volume. Each pixel corresponds to a small volume element, which is called the voxel. The height of the voxel is determined by the slice thickness. Using the above example, if the axial slice thickness is 1.5 mm, the voxel size would be 0.35, determined using the following equation: 0.48 x 0.48 x 1.5 mm

In a CT imaging system configuration, an x-ray projects a fan-shaped beam that is collimated to lie within an X-Y plane of a Cartesian coordinate system; this is generally referred to as the imaging plane.

 Therefore, during CT imaging, the anatomy of interest passes through this imaging plane and the image data are acquired and reconstructed. Acquisition is typically accomplished by obtaining different views as the x-ray source and detectors rotate around the anatomy or volume. Reconstruction of these data generates a 2D array of quantized gray-scale values or pixels. Pixel values are a measure of the x-ray attenuation in Hounsfield units (HU), where the HU = 1000 — (4μ/μw-1), with μ being the average linear attenuation coefficient of the volume element represented by the pixel and μw being the linear coefficient of water for the effective energy at the beam exiting the patient. Therefore, water has an HU number of 0 and a region with a CT number of 100. HU has a linear attenuation coefficient that is 1% greater than the linear attenuation coefficient of water.

In the most commonly used ECG-gated helical CT acquisition, the x-ray tube (and detector array) rotates continuously around the patient collecting data, while the patient table (and the patient) is moved at a constant speed through the imaging plane. The helical CT thus collects a continuous sequence of consecutive axial images from a volume of the patient’s anatomy. Faster scanning, as is currently done with 64-slice CT scanners, allows a large volume of data to be collected in short (<10 seconds) periods of time. The factors selected in scanning a patient include slice width, FOV, gantry rotation speed, volume of coverage, and basic contrast injection protocols. Scan time is calculated from the scan volume (total distance traveled by the table) divided by the table speed. The “pitch,” which is defined as ratio of distance the table moves per 360º rotation, is also important. A pitch of 1.0 means the patient table moves a distance of 1 slice. Similarly, a pitch of 0.2 means the gantry rotates 5 times as the table moves a distance equal to the collimator width.

Cardiac motion, due to heartbeat, respiration, and patient movement while lying on the table, can produce artifacts that appear as blurring in the reconstructed image. Such blurring effects may complicate the diagnosis. Employing a short scan time, as can be done with current scanners, may prevent or minimize these artifacts due to the speed of the acquisition. To avoid respiration artifacts, scanning is performed with the patient holding their breath after inspiration or expiration. The acquired data are synchronized with the collection of the ECG (QRS) signal. The ECG signal is recorded in parallel with the CT through a noninvasive monitoring device connected to the patient. The data acquired during consecutive cardiac time intervals can be combined to produce an image of the heart at the same phase of the cardiac cycle. Retrospective gating allows alignment of images during any phase of the cardiac cycle due to the continuous helical acquisition.

Once the image is acquired, it is stored in a proprietary format. The data then can be exported from the scanner. Because images obtained by scanners made by one manufacturer may need to be imported to that of another manufacturer or to a different viewing screen, a medical image standard known as DICOM (Digital Information and Communications in Medicine) has been devised and is widely used. This format allows data to be exchanged between scanners and viewing consoles. The American Radiological convention is to display axial images with the right side of the patient appearing at the left and the posterior side at the bottom of the computer workstation screen.

The process of dividing images into different regions to visualize areas of interest is called segmentation.

 Image segmentation methods can be grouped into thresholding, boundary detection, and region identification.

Thresholding is the simplest but most effective segmentation method. During thresholding, pixels with intensities below a threshold value are assigned one class and the remaining pixels a different class. Regions are then formed by connecting adjacent pixels of the same class; thus, boundary extraction methods use information about intensity differences between adjacent regions to separate the regions from each other. Region identification techniques then form regions by combining pixels of similar properties. The simplest region identifying technique could start with at least 1 seed (a starting point) per region. Neighbors of the seed are visited and the neighbors that satisfy the predicate (a simple predicate compares the intensity values of the pixel to the average intensity value of the region) are added to the region. Segmentation, as relevant to ablation for atrial fibrillation, for example, can be used to identify the anatomy of the left atrium and its vasculature, allowing it to be viewed separately from the remaining chambers of the heart and the surrounding anatomy, such as the lungs.

The advent of 3D imaging has allowed ablation for complex arrhythmias to become more efficient, safe, and effective. It has also shortened procedure and fluoroscopic time by providing imaging that is more intuitive to the electrophysiologist. Developments in live 3D imaging are ongoing. Live 3D TEE imaging is clinically available, and live 3D intracardiac imaging is on the cusp of availability. 

Emerging imaging technologies in ablation

Isolated diastolic heart failure is a common form of heart failure, especially in the elderly, and is now a recognized cause of increased morbidity and mortality. In a focused session on echocardiography and diastolic function, existing predictors of outcome in diastolic dysfunction were evaluated in large patient data sets and newer parameters were investigated in select patient cohorts.

Prognostic role of known mortality predictors

In 47,701 patients without severe valvular heart disease and preserved LV systolic function, relative wall thickness and LV mass index were independent predictors of mortality over a mean 1.7 years of follow-up in all age groups (<50, 50-70, and >70 years). *Three categories of LV geometry were evaluated: normal, eccentric hypertrophy (evaluated by LV mass index), and concentric hypertrophy (evaluated by relative wall thickness).

 Both LV mass index and relative wall thickness were independently associated with increased mortality in all groups.

Relative wall thickness was by far the strongest independent predictor of all-cause mortality, especially in younger patients. The mean hazard ratio for increased relative wall thickness was 34 for those younger than age 50; 10 for those between 50 and 70 years; and 5.5 for those older than age 70. Baseline demographics of the study population were not discussed, including prevalence of hypertension, diabetes, and coronary artery disease (CAD), use of medications, or the independent influence of these risk factors on mortality.

In the same cohort of patients (47,865), LA volume index was an independent predictor of mortality in all 4 geometric groups: normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Mean ± 1 standard deviation of LA volume index was 32. There was a 15% versus 6% mortality in those with increased LA volume index compared with those who had a normal index.

 A more recent study has shown that an increased LA volume index has the same prognostic significance as a low ejection fraction in patients with CAD.

 The presented study shows the prognostic power of LA volume index over the pattern of LV hypertrophy in subjects with normal LV systolic function.

Other investigators examined the predictive value of a combined evaluation of LA function and geometry in patients presenting with dyspnea (mean age, 63 years). In 163 patients, LA volume index/A’ (annular A’ velocity averaged over medial and lateral annulus) had a similar predictive value as B-type natriuretic peptide (BNP) and E/E’ (ratio of mitral peak velocity of early filling [E] to early diastolic mitral annular velocity [E’]) in determining diastolic dysfunction grade (area under the curve = 0.91, 0.90, and 0.93, respectively; 

 The best cut off value of LA volume index/A’ was 4. In the 68 patients with LA volume index/A’ of 4 or more, BNP was much higher (1207 vs 176 pg/mL) and pulmonary atrial reversal duration was greater than mitral inflow A duration (25 vs -3). At 13-month follow-up, this parameter was an independent predictor of a combined outcome of death and rehospitalization for heart failure (odds ratio [OR] = 3.9) in those 65 years or older (OR = 3.8) with an ejection fraction less than 50% (OR = 4.8).

One group used left atrial diameter along with LA systolic force (derived from mitral valve orifice area and peak A velocity with a cutoff point of 14.33 Kdynes) as a surrogate of LA function in 2808 subjects with a mean age of 59 years in the Strong Heart study. Of these subjects, 43% had hypertension, 47% had diabetes, and 54% were obese. There was a 2.7% incidence of heart failure over an 8-year follow-up. When adjusting for age, sex, hypertension, diabetes, obesity, LV mass, ejection fraction, and E/A ratio (ratio of early [E] to late atrial [A] mitral Doppler peak flow velocity), the presence of LA enlargement or increased LA force was not associated with a higher risk of heart failure, but when combined there was a higher risk of heart failure (OR = 1.9).

E/E’ and LA volume index in heart failure

E/E’ (septal) has been shown to correlate with pulmonary capillary wedge pressure. One group evaluated the predictive power of E/E’ and LA volume index for first heart failure.

 Of 917 patients with a mean age of 73 years and no history of heart failure, atrial arrhythmia, or valvular disease, and who were followed for a mean of 3.5 years, E/E’ above 14 predicted first heart failure with a sensitivity and specificity of 54% and 83%, respectively. The prediction of first heart failure was more accurate when both LA volume index and E/E’ were included (C-statistic for the multivariate model including both factors was 0.76 versus 0.70 for LA volume index alone).

Infarct related artery coronary flow reserve and LV diastolic function after a first acute myocardial infarction (MI)

Studies have shown the prognostic value of diastolic dysfunction in patients who have experienced a first acute MI.

 A study from Japan evaluated a combination of coronary flow velocity and LV diastolic function in 201 patients who had a first left anterior descending infarct and underwent successful primary percutaneous coronary intervention (PCI).

 After stenting, coronary flow velocity was measured distal to the lesion by an intracoronary Doppler wire. Three days following the acute MI, conventional echo Doppler was performed. Three categories of patients were evaluated: those with nonrestrictive mitral inflow (deceleration time ≥130 ms), those with normal coronary velocity (D wave deceleration time >600 ms and no systolic flow reversal), and those with restrictive inflow, microvascular dysfunction, or both. Diastolic function was measured by mitral inflow E wave deceleration time. At 6 months, repeat LV grams were performed and LV remodeling was defined as an LV end-diastolic volume index of 20% or more. The incidence of LV remodeling at 6 months was 6% in those with nonrestrictive mitral inflow; 37% in those with normal coronary velocity, but restrictive mitral inflow; and 83% in those with restrictive inflow, microvascular dysfunction, or both (

 <.001). Those with LV remodeling also had a higher prevalence of thrombolysis in MI grade II flow and abnormal blush grade after PCI.

Isovolumic relaxation velocity by 2D speckle tracking in nonischemic cardiomyopathy

In 52 patients with nonischemic cardiomyopathy and a mean age of 57 years, 2D speckle tracking was used in the 18 apical segments to determine relaxation velocity in the global isovolumic relation period by strain rate.

 During a follow-up of 22 months, 15 patients developed cardiac events (sudden cardiac death, hospitalization for congestive heart failure (CHF) or refractory CHF (class III or IV). On multivariate analysis, including age, ejection fraction, end-systolic volume index, diastolic strain rate-isovolumetric relaxation (SR-IVR), and systolic dyssynchrony index, SR-IVR was the only independent echocardiographic predictor of cardiac events. In 8 of 15 patients with cardiac events, the SR-IVR value was negative.

The prognostic significance of an L’ wave in patients with triphasic mitral inflow, marked by the presence of an L wave, was evaluated in 185 patients over a mean follow-up of 36 months.

 Those with an L’ wave on mitral annular Doppler (57% of those with mitral inflow L wave) had higher BNP levels, LV mass index, LA volume index, E/E’, and mitral inflow L wave velocity. These patients also had a higher incidence of all-cause death and rehospitalization for heart failure than those without (12.4% vs 10.8%). In the multivariate model including age, Killip class, renal insufficiency, and moderate-to-severe mitral regurgitation, the presence of an L’ wave was the most independent predictor of adverse outcome in these patients. The cutoff velocity when L or L’ is abnormal on mitral inflow or mitral annular Doppler was not discussed.

A study from Korea evaluated a new parameter, namely, LV diastolic function reserve index, which was calculated as E’ base x ΔE’ (ΔE’ was the change of E’ from baseline to exercise).

 This study included 227 diabetic patients with a mean ejection fraction of 0.68. Over 34 months of follow-up, the primary end point, which was a composite of all-cause death and rehospitalization for heart failure, occurred in 14 patients (6.1%). When examining age, CAD history, renal insufficiency, LV mass index, LA volume index, and ejection fraction, LV diastolic function reserve was the most independent predictor of adverse outcomes. After patients were classified by the median value of LV diastolic function reserve index at 50 W of exercise, patients with an index below 13.5 showed poorer clinical outcomes compared with those with an index of 13.5 or above (

Studies have extended the role of LV hypertrophy pattern, LA volume index, and E/E’ as prognostic variables in asymptomatic CAD and acute MI patients. New parameters, including coronary microvascular functional reserve and LV diastolic flow reserve, were evaluated in patients presenting with a first acute MI treated with acute PCI and in diabetic patients with normal systolic function. The findings of prognostic significance of microvascular dysfunction after acute MI could add significantly to the clinical care of patients with acute MI if Doppler flow reserve could be measured by transthoracic echocardiography. Other parameters evaluated included triphasic mitral inflow pattern and LV diastolic functional reserve on stress testing. The cutoff velocity when L or L’ is abnormal on mitral inflow or mitral annular Doppler was not discussed. 

*Increased relative wall thickness with normal ventricular mass (‘concentric remodeling’), increased mass with normal relative wall thickness (eccentric hypertrophy), and concentric hypertrophy (increase in both variables). Normal LV mass is considered <125 g/m

. Concentric remodeling is defined by the thickness of the septum or posterior wall divided by the LV radius at end-diastole ≥0.45.

New insights on echocardiographic evaluation of diastolic function

A post hoc analysis of the ATHENA (A Placebo-controlled, Double-blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter) trial presented at the 2008 American Heart Association Scientific Sessions found that dronedarone (Multaq) significantly reduced the occurrence of hospitalization and the length of hospital stays in patients with atrial fibrillation (AF). Compared with placebo, dronedarone reduced the total amount of hospital days by 28% (9995 vs 13,986 days) and decreased the amount of time spent in the hospital for heart-related conditions by 35% (5875 vs 9073 days). It also showed that dronedarone reduced the occurrence of AF-related hospitalization by 37%, while reducing initial non-AF cardiovascular hospitalization by 14%. Statistical analyses revealed that patients with normal heart rhythm at the start of the ATHENA trial had their time to a first recurrence of AF reduced by 25% when compared with placebo.

Multaq, which is to be marketed by sanofi-aventis, is currently being reviewed by health regulators in the United States and Europe. If approved, researchers say that it could be a safer option than amiodarone, which is commonly used for irregular heartbeats but associated with lung and thyroid gland toxicities. “Why would I consider prescribing amiodarone if I can give a drug like [dronedarone] that is effective, but does not have amiodarone’s toxicities?” said Richard Page, MD, a lead investigator of the study and head of the division of cardiology at the University of Washington School of Medicine. Dr Page noted, however, that a head-to-head trial directly comparing amiodarone with dronedarone has not yet been undertaken.

According to Christian Torp-Pederson, MD, from the Gentofte University Hospital in Copenhagen, and a member of the study’s steering committee, the incidence of AF-related hospital stays is increasing rapidly “and therapeutic solutions to reduce this burden are needed…These new data showed that, for the first time, an antiarrhythmic drug significantly and consistently reduced hospitalization incidence and duration, which led to a substantial reduction in total hospitalization burden in this patient population.”

When asked what he thought about this study, Suneet Mittal, MD, from St. Luke’s-Roosevelt Hospital Center in New York, and a member of the 

 editorial board, commented that “Dronedarone represents a potentially important addition to the armamentarium of anti-arrhythmic medications. Impressively, when used in elderly patients at moderate to high risk of developing AF, dronedarone reduced the likelihood of developing AF as compared with placebo.” Dr Mittal also noted that a major advantage of dronedarone is that it reduces cardiovascular hospitalizations and death. “However, more data are needed with respect to its safety in patients with underlying left ventricular dysfunction and congestive heart failure,” he cautioned.

The ATHENA trial is the largest, antiarrhythmic, morbidity-mortality study ever conducted in AF. The trial was done at more than 550 sites in 37 countries and consisted of 4628 patients who were either 75 years or older (with or without cardiovascular risk) or younger than 75 years and with at least 1 cardiovascular risk factor. It did not include individuals with decompensated heart failure. The patients were randomized to receive either dronedarone 400 mg twice daily or placebo, and they were then followed-up for a maximum of 30 months. 

Home INR monitoring is alternative to monthly clinic visits

Home monitoring of international normalized ratio (INR) values is a feasible alternative to monthly clinic visits in patients on chronic warfarin therapy, said David Matchar, MD, director of the Duke Center for Clinical Health Policy Research, Durham, NC. Patients who may find home INR testing attractive are those who are disabled or live far from clinics, making access to routine care difficult. “In typical clinical practice, warfarin is underutilized, with fewer than half of patients in some settings receiving anticoagulation,” said Dr Matchar. “The quality of management can be poor, with patients in the therapeutic range less than half the time.”

In the study conducted by Dr Matchar, which was funded by the US Department of Veterans Affairs, weekly patient self-testing was compared with monthly clinic testing of INR in 2922 patients who were on chronic warfarin therapy with indications for mechanical heart valves or atrial fibrillation (AF). Patients randomized to home testing were trained in its use. “The training took about a half hour. The patients were given the devices to take home, used them for 2 to 4 weeks, and then were retested [for competency],” Dr Matchar said.

With an average of 3 years of follow-up, there was no significant difference between the 2 groups on the primary composite end point of stroke, major bleeds, or death; this end point occurred in 7.9% of patients assigned to home INR monitoring and 8.9% of the clinically tested patients.

Home INR testing did show significant superiority to high-quality clinic monitoring on the secondary end point, which was time that INR was in the therapeutic range. The cumulative amount of time in the therapeutic range exceeded 60% in both groups; the time in the target range was improved by about 7% in the home INR monitoring group, said Dr Matchar. By the end of the study, the time in the target range was nearly 70% in the home INR monitoring group and about 60% in the monthly monitoring group. Furthermore, satisfaction scales revealed higher satisfaction with home INR monitoring.

Anticoagulation clinics “require patients to come to a centralized location, which limits the potential to perform high-frequency testing, and, in some cases, may limit access to anticoagulation treatment because of difficulties with travel for testing and management,” he said. Although this study showed no difference in clinical outcomes between the 2 strategies, a previous study of more than 13,000 patients with AF demonstrated that as time in the therapeutic INR range increased, the number of thromboembolic events prevented also increased and the number of intracranial hemorrhages decreased, noted Alan Go, MD, from Kaiser Permanente of Northern California.

Dr Go said that “regardless of the approach, high-quality management of anticoagulation leads to low rates of ischemic stroke and intracranial hemorrhage in patients with AF or mechanical heart valves.” He noted, however, that the resource utilization and cost implications of home INR monitoring should be assessed. 

Microalbuminuria linked with coronary calcium

In asymptomatic persons, microalbuminuria predicts the presence of coronary artery calcium and its progression, said Andrew P. DeFilippis, MD, Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, MD. This finding comes from a subset of the MESA (Multi-Ethnic Study of Atherosclerosis) study, a project initiated in 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease in a population-based sample of 6500 middle-aged and older adults. MESA included white, black, Chinese American, and Hispanic ethnicities.

Data on urinary albumin:creatinine ratio (UACR) were available for 5666 of the subjects. The association between microalbuminuria, defined as UACR of 30 to 300 mg/g, and incident coronary artery calcium and progression of coronary artery calcium was assessed. Of the subjects with microalbuminuria, 62% had coronary artery calcium at baseline compared with 48% without microalbuminuria (

 <.001). At a median follow-up of 2.4 years, microalbuminuria increased the odds of developing coronary artery calcium over the course of the study by 76% (

 = .005). As a continuous variable, the presence of microalbuminuria remained significant as a predictor of the development of coronary artery calcium (

 = .016). Among those with coronary artery calcium at baseline, the risk of progression of the disease was 9-fold higher among those with microalbuminuria (

 = .009). When microalbuminuria was examined as a continuous variable, those with microalbuminuria were 3 times as likely to have progression of their coronary calcium (

Americans’ LDL cholesterol is falling but triglycerides are up; obesity is the culprit

A new 30-year analysis of the National Health and Nutrition Examination Surveys (NHANES) shows a favorable downward trend in levels of low-density lipoprotein (LDL) cholesterol in the US population, but an increase in nonoptimal levels of triglycerides, reports Jerome D. Cohen, MD, of the National Lipid Association, and professor emeritus, St. Louis University. The increase in triglyceride levels strongly correlates with obesity over the 3 surveys, he noted.

Lipid values in adults aged 20 to 74 years were compared between NHANES conducted between 1976 and 1980 (NHANES II), 1988 and 1994 (NHANES III), and NHANES 1999-2006 (NHANES). The presence of abnormal LDL cholesterol as a single abnormality fell from 43.48% to 40.13% from NHANES II to the most recent NHANES. At the same time, the presence of abnormal triglycerides as a single abnormality increased from 2.42% to 5.53%, and the prevalence of abnormal triglycerides plus abnormal high-density lipoprotein (HDL) cholesterol doubled from 2.1% to 4.0%.

“It’s a good news, bad news, situation,” said Dr Cohen. “We are achieving the Healthy People Initiative 2010 goal of a total cholesterol less than 200 mg/dL. The average cholesterol in the latest survey was about 200 mg/dL. What’s driving this reduction is a lowering of LDL. As more people are taking statins, the average cholesterol has come down. The increase in triglycerides is the bad news, and this increase was not surprising given the increase in body mass index (BMI) and the growing prevalence of obesity,” he noted. In the most recent survey, about one third of subjects qualified as obese based on their BMI (>30 kg/m

), compared with only 15% in the earliest survey.

The study also revealed a strong increase in elevated triglyceride levels among people older than 60 years, with the likelihood of having unhealthy triglycerides increasing nearly 5-fold from 1.8% in 1976-1980 to 8.7% in 1999-2006. Researchers involved with the study concluded that patients’ triglyceride levels require more vigilant monitoring in an effort to improve preventive care.

Lifestyle changes (ie, weight loss through healthier eating and exercise) should be encouraged in patients with elevated triglycerides, including those with metabolic syndrome and type 2 diabetes, who often exhibit high triglycerides in addition to low levels of HDL cholesterol, said Dr Cohen.

Patients and physicians need to understand the importance and role of all 3 lipids in cardiovascular risk. Motivating patients to make lifestyle changes may require education and the use of dieticians in practice; patients often aren’t motivated to make such changes until they experience chest pain and require angiography, noted Dr Cohen. Pharmacologic options, such as fish oil, niacin, and fibrates (fenofibrate and clofibrate) are useful in reducing triglyceride levels as an option beyond diet and exercise, he said. There may be some resistance to niacin because of flushing, although a long-acting formulation reduces this problem.

Fibrates can reduce triglyceride levels by approximately 50%. Some fibrates interact with statins to increase the risk of myopathy. In using a fibrate and statin together, “I’ll start with a nonmaximal dose of a statin and see how the patient tolerates it before increasing the dose,” said Dr Cohen. 

Patients misperceive reasons for elective PCI

Patients misperceive the benefits of elective percutaneous coronary intervention (PCI), said John H. Lee, MD, fellow in preventive cardiology at the Mid America Heart Institute, Kansas City, MO.

About 1 million PCIs are performed annually in the United States, with the majority being elective. When performed for acute coronary syndromes, PCI has been shown to reduce the incidence of death, myocardial infarction (MI), and hospitalization. “In the elective setting, the benefits are less clear,” said Dr Lee, pointing to the results of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) study, in which medical therapy was equivalent to PCI on the end point of ischemic events in patients with stable coronary artery disease. The only definitive benefit to PCI in the elective setting is relief of angina and improvement in quality of life, he said.

To assess patients’ perceptions of the benefits of elective PCI, 498 consecutive patients who received an elective PCI between January 2006 and October 2007 were mailed 1-page questionnaires, of which 350 responded. The questionnaires sought to elicit the patients’ beliefs about the benefits from their elective PCI in the preceding year. The mean age of the respondents was 67.8 years and 76% were men.

The respondents’ beliefs were as follows:

71% said that they thought the PCI would prevent a future MI

42% indicated that it was done to improve an abnormality on their stress test

31% responded that PCI was performed for angina relief

According to the patients, 18% were offered medical therapy, 13% were offered coronary artery bypass graft surgery, and 68% were offered no alternative. The results were not significantly different when comparing responses before and after the release of the COURAGE study in 2007. Better education of patients is needed prior to elective PCI to facilitate informed consent, said Dr Lee. 

ATHENA trial post hoc analysis shows dronedarone significantly reduced hospitalization incidence and duration

Global Pulse: News from the American Heart Association Scientific Sessions 2008, November 8-12, 2008

A 78-year-old woman with a history of hypertension and dyslipidemia presented to her primary care physician with exertional chest pain that started a few months earlier. Her cardiac examination and electrocardiogram were abnormal. Her cardiac troponin was negative. A stress test was performed, which showed evidence of anteroapical and inferior mild ischemia. To better evaluate her coronary anatomy, 64-slice computed tomography (CT) angiography was performed, as the patient was reluctant to have an invasive coronary angiogram. CT angiography revealed coronary artery disease as well as an incidental diagnosis (

Can you identify the incidental diagnosis?

 Situs inversus totalis with dextrocardia.

Situs inversus totalis with dextrocardia is a rare congenital condition in which the major visceral organs are reversed or mirrored from their normal positions and the heart apex is to the right of the thorax. The condition is present in 0.01% of the population, with an equal incidence between the sexes and no racial predilection.

 Most patients do not have any significant cardiac defects, and their life expectancy is normal, as our patient’s case demonstrates.

After the diagnosis was made in our patient (

), she underwent triple bypass surgery to treat her coronary artery disease, including a right (and not left) internal mammary artery graft to the left anterior descending artery (

). The procedure was successful, and the patient had an uneventful postoperative recovery.

The advent of technology such as multislice coronary computed tomography (CT) angiography allows us to accurately evaluate coronary anatomy and to uncover other interesting and sometimes crucial findings, such as situs inversus totalis. Identifying such anatomical anomalies is critical to avoiding diagnostic and surgical mishaps and to ensure electrocardiograms (ECGs) are not misinterpreted. In patients with recognized situs inversus totalis with dextrocardia, misleading ECGs can be minimized by reversing the precordial leads and the right and left arm leads. The P waves, QRS complex, and T waves are all inverted in lead I.

 Comparing changes between an old and new ECG may be helpful, and paying close attention to the left and right sides of the patient and the left and right labeling of images helps prevent mistakes in diagnosis and during surgical intervention. 

IMA-LAD = internal mammary graft to the left anterior descending coronary artery; L = left; LA = left atrium; LAD = left anterior descending; Liv = liver; LV = left ventricle; R = right; RA = right atrium; RCA = right coronary artery; RI = ramus intermedius; RV = right ventricle; St = stomach; VG-ramus = venous graft to the ramus inter-medius artery.

CT angiography: Uncovering an unusual diagnosis in the eighth decade

Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy, was initially described in Japanese patients in 1991.

 This syndrome is associated with stressful events such as the death of a loved one, domestic abuse, catastrophic medical diagnoses, postoperative stress, devastating financial losses, natural disasters, and termination of long-standing relationships. Such stressful situations are associated with increased output of catecholamine by the sympathetic nervous system, suggesting surges in this chemical compound may have a critical role in the genesis of stress-induced cardiomyopathy.

Apical segments of the left ventricle are depressed in patients with takotsubo cardiomyopathy, which results in compensatory hyperkinesis of the basal segments and ballooning of the apex during systole. The syndrome frequently mimics acute coronary syndrome (ACS) and is often accompanied by reversible left ventricular apical ballooning in the absence of clinically significant coronary artery disease. Although most patients regain left ventricular function and make a full recovery, some do not, and a case of death from myocardial rupture has been reported.

 A rare complication of takotsubo cardiomyopathy is left ventricular thrombus, with only 5 such cases having been reported in the literature.

 We report an additional case of this complication in a postmenopausal woman who was successfully treated with anticoagulation therapy.

A 67-year-old woman with a history of hypertension and mild asthma presented to our institution for further evaluation after receiving a diagnosis of takotsubo cardiomyopathy. The syndrome began while she was attending a sporting event, during which she developed nausea and chest discomfort. Her symptoms continued throughout the night, and she experienced shortness of breath, jaw fullness, and right arm numbness and tingling the following morning.

The patient presented to the emergency department, where a 12-lead echocardiogram showed ST-segment elevation in leads V

, with inverted T waves in leads II, III, and aVF. Her cardiac troponin T peaked at 2.3 ng/mL (normal, 0-0.10 ng/mL). Cardiac catheterization showed normal coronary arteries, but she experienced a spasm of the left circumflex artery that resolved upon administration of intracoronary nitroglycerin and nicardipine (Cardene). Left ventricle angiography was consistent with takotsubo syndrome. Her hospital course was unremarkable, and she was discharged with the following once-daily oral medications: lisinopril (Prinivil), 2.5 mg; carvedilol (Coreg), 6.25 mg; triamterene and hydrochlorothiazide (Maxzide, Dyazide), 37.5 mg; and aspirin, 325 mg.

Eight days after the initial event, the patient was asymptomatic, but she presented to our institution for a second opinion. An echocardiogram showed an apical aneurysm and a 0.75 x 0.96-cm pedunculated left ventricular thrombus (

). She was admitted to the hospital and anticoagulation therapy with heparin and warfarin (Coumadin) was initiated. The patient was dismissed on hospital day 5 with the following oral medications: carvedilol, 6.25 mg (administered twice daily); lisinopril, 2.5 mg (administered twice daily); triamterene and hydrochlorothiazide, 37.5 mg (administered once daily); and warfarin (dosage was adjusted to maintain an international normalized ratio between 2.5 and 3.5). An echocardiogram performed at 1-month followup showed complete resolution of the thrombus and a normal ejection fraction (

More than 80% of takotsubo cardiomyopathy cases occur in postmenopausal women (mean age, 65—72 years).

 Some institutions estimate the syndrome to occur in approximatey 1 of 30 patients undergoing catheterization.

 In 2006, Pillière and associates reported a prevalence of 0.7% in a large urban area.

 The authors estimated that roughly 12,250 patients in the United States could present with takotsubo syndrome annually. Dhar and colleagues reported a prevalence of less than 2%.

 The best estimates suggest that 0.7% to 2.2% of patients presenting with suspected ACS have symptoms and ECG findings consistent with stress-induced cardiomyopathy.

Patients with takotsubo cardiomyopathy generally have a good prognosis, with most making a complete recovery several weeks after receiving conservative treatment.

 The mortality rate is estimated to be 1%, and the recurrence rate is estimated to be 8% or less.

 Complications include mitral regurgitation, ventricular tachycardia, ventricular fibrillation, ventricular free wall rupture, and left ventricular mural thrombus.

Our literature search identified 5 case reports of left ventricular mural thrombus formation occurring as a complication of takotsubo syndrome.

 Of the 5 reports, 4 were written in English, and all reported complete resolution of the thrombus with warfarin therapy. The mechanism for the thrombus formation may be blood stasis in the region of the akinetic segment of the left ventricle.

Management of takotsubo cardiomyopathy is based on the patient’s overall condition. No controlled studies have provided data that define optimal medical management, but reasonable treatment includes standard therapy for left ventricular dysfunction, including antiplatelet agents, angiotensin-converting enzyme inhibitors, and beta blockers to prevent excessive sympathetic activity.

 Anticoagulant medications may be considered to prevent apical thrombus formation.

Increased awareness of takotsubo cardiomyopathy will result in more frequent diagnosis. A better understanding of this disorder would be beneficial to optimize treatment in these patients. Prospective studies are needed to determine the incidence of this syndrome more accurately, to ascertain the long-term prognosis on the basis of the clinical features and echocardiographic and angiographic findings, and to elucidate the specific pathophysiologic mechanisms responsible for the syndrome’s development. 

Takotsubo cardiomyopathy resulting in left ventricle thrombus

On November 8, 2008, the ABC held its 21st Annual Dr Walter M. Booker Sr. Memorial Symposium, which was titled “Present Status and Future Considerations for High Risk Populations: Imaging, Prevention, and Intervention.” Co-chairs were Paul L. Douglass, MD, senior member and past president of the ABC, and chief of the division of cardiology, Atlanta Medical Center, Atlanta, GA, and Kevin L. Thomas, MD, an emerging ABC leader, and staff member of the division of cardiovascular disease, clinical cardiac electrophysiology, Duke University Medical Center, Durham, NC. Drs Douglass and Thomas developed an excellent scientific program focusing specifically on clinical research and practice related to cardiovascular risk reduction through prevention, modern diagnostic approaches, and imaging.

The first section of this continuing medical education event focused on multimodal cardiac imaging and featured speaker Ola A. Akinboboye, MD, MPH, MBA, director of cardiac imaging, New York Hospital Queens, Flushing, NY. Dr Akinboboye discussed computed tomography angiography (CTA) versus calcium scoring for diagnosing coronary heart disease, noting that calcium scoring has increasingly been incorporated into clinical pathways for the expert diagnosis of subclinical coronary artery disease. He also indicated that as modern techniques improve, CTA may prove even more useful than other modalities in assessing the extent of coronary stenoses in symptomatic patients and in determining which patients presenting to the emergency department with apparent acute cardiac symptoms may be safely discharged to home. A second component of the section on multimodal cardiac imaging was led by Jennifer H. Mieres, MD, associate professor of medicine and director of nuclear cardiology, division of cardiology, New York University School of Medicine, New York, NY. Dr Mieres detailed the useful incorporation of myocardial perfusion stress imaging in the diagnosis of patients with apparent chest pain related to ischemic heart disease.

One of the highlights of the Booker Symposium was the Dr Herbert W. Nickens Memorial Lecture, which was given by Dr Thomas, who merged recent data, personal reflections, and ongoing efforts at Duke University to identify strategies to overcome health care disparities, including educating patients on the complex nature of cardiovascular diseases and on the importance of adhering to treatment regimens, as well as encouraging them to become partners in their own care. Following the Nickens lecture, Dr Douglass moderated an up-to-date discussion of noncoronary catheter-based interventions for treating valvular heart disease, patent foramen ovale, and atrial septal defects. Peter C. Block, MD, director of the clinical trials office, department of cardiology, Emory University Hospital, Atlanta, GA, discussed several newer techniques for valvular repair and replacement using catheter-based approaches. J. Kevin Harrison, MD, director of the cardiac catheterization lab, Duke University Medical Center, discussed similar techniques as a means of closing patent foramen ovale and atrial septal defects without the need for open chest surgery.

The Booker Symposium also highlighted frontiers in cardiovascular pharmacotherapy. John M. Flack, MD, MPH, professor and chair, department of internal medicine, Wayne State University, Detroit, MI, discussed some of the recent safety and efficacy data related to vasodilating beta blockade and oral renin inhibition. In addition, Kenneth A. Jamerson, MD, professor of internal medicine, University of Michigan, Ann Arbor, MI, described the importance of first-line combination therapy for many (if not most) patients with hypertension. Additionally, he noted emerging evidence that a long-acting calcium channel blocker may have benefits when added to a renin-angiotensin blocking agent, such as an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

During the symposium, the ABC distributed its academic and community service awards. Ms Tynetta Brown, former executive director of the North Carolina Cardiovascular Health Program, and former senior manager for Ally Development Cardiovascular at AstraZeneca Pharmaceuticals, was given the Dr Walter M. Booker Health Promotion Award for her work in the field of cardiovascular risk reduction and prevention. Ms Brown developed a public health stroke network in the Carolinas, where there are extraordinarily high rates of stroke death, by bringing together multiple health organizations and high-risk communities in an integrated effort to promote awareness of the importance of controlling dyslipidemia, hypertension, diabetes, and obesity. In addition, Roderic I. Pettigrew, PhD, MD, a long-time ABC member and the first director of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, was given the Dr Herbert W. Nickens Epidemiology Award. Dr Pettigrew is a recognized expert in the field of bioimaging and has been instrumental in developing methodology to examine biologic processes, disorders, and diseases through imaging. He has also been a proponent of making cutting-edge technology available to all populations, regardless of race, ethnicity, or social class. 

Insights from the 21st Annual Dr Walter M. Booker Sr. Memorial Symposium

Modifiable cardiovascular risk factors include lifestyle-based factors (eg, smoking, exercise, diet) and pathologic conditions (eg, hypertension, diabetes, obesity, dyslipidemia, metabolic syndrome). When 2 or more of these risk factors occur simultaneously, as is often the case, they interact synergistically to increase cardiovascular disease (CVD) risk. The presence of multiple risk factors in asymptomatic, otherwise apparently healthy subjects increases cardiovascular risk by as much as it does in patients with symptomatic CVD. For example, in patients with no cardiovascular history, the 8-year risk for CVD is increased 4-fold in the presence of a single risk factor (hypercholesterolemia). The 1-year cardiovascular event rate in patients with multiple sites of symptomatic arterial disease is increased 5-fold compared with patients with risk factors only (

 <.001 for trend). Consequently, it is now considered less important to differentiate between primary and secondary prevention, and more relevant to look at global cardiovascular risk to improve health outcomes. During the 2008 American Heart Association Scientific Sessions, experts convened to discuss refractory risk. They highlighted the multiplicative effect of multiple CVD risk factors and provided clinicians with helpful treatment strategies for patients with refractory risk factors.

The patient case we presented was that of a 57-year-old white woman referred for refractory hypertension. She was asymptomatic, except for daytime fatigue, somnolence, and the presence of diffuse muscle aches, particularly when trying to exercise. Her medical history was remarkable for longstanding hypertension, and she had been taking atenolol (Tenormin) 100 mg for 2 years, amlodipine (Norvasc) 5 mg, and lisinopril (Prinivil) 40 mg for 1 year. She also had a history of poorly controlled diabetes mellitus, which was managed with diet and a sulfonylurea, and dyslipidemia, which was managed with simvastatin (Zocor) 20 mg. There was no history of premature CVD in her family, but her mother and a maternal aunt had type 2 diabetes mellitus. The patient never smoked, reported an approximately 80-lb weight gain since high school, and rare leisure-time physical activity.

The physical examination was remarkable for a heart rate of 82 beats per minute, blood pressure of 158/88 mm Hg, respiratory rate of 16 breaths per minute, weight of 215 lb at a height of 5’ 7”, body mass index of 33 kg/m

, and a waist circumference of 38 inches. She was afebrile, and the remainder of her examination was within normal limits. The electrocardiogram showed normal sinus rhythm with normal axis and intervals. No left ventricular hypertrophy was identified. Fasting labs revealed a glucose of 124 mg/dL, glycosylated hemoglobin A1c (HgbA

) of 8.5, total cholesterol of 227 mg/dL, triglycerides of 330 mg/dL, high-density lipoprotein (HDL) cholesterol of 35 mg/dL, low-density lipoprotein (LDL) cholesterol of 126 mg/dL, creatinine of 1.4 mg/dL, and glomerular filtration rate of 56 mL/min/1.73 m

Global CVD risk stratification approaches

The mainstay of any evaluation includes global CVD risk stratification, and this patient is no exception. Given her multiple risk factors, including age, hypertension, dyslipidemia, diabetes, obesity, and lack of physical activity, she is at high risk for morbidity and mortality from CVD.

One approach to assessing global cardiovascular risk in the clinic is the use of risk charts, such as those jointly issued recently by the European Society of Hypertension/European Society of Cardiology (2007), the World Health Organization/International Society of Hypertension, or the National Cholesterol Education Program. The methods these assessment tools use to calculate risk differ, and, most importantly, these charts appear to be hardly used in clinical practice. In a large European survey of primary care physicians, only 13% always used risk charts to assess a patient’s likelihood of developing CVD, with between 40% and 50% of physicians in different European countries never using them. Regardless of the method used to assess global CVD risk, the underlying premise is the same: multiple risk factors increase the risk for CVD in a multiplicative way.

The Framingham study showed that the presence of 5 risk factors increases risk 60-fold compared with the presence of just 1 risk factor. More recently, INTERHEART, a large international case-control study designed to assess the importance of risk factors for coronary heart disease in 52 countries worldwide, showed that 9 risk factors (abnormal serum lipid levels, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, insufficient intake of fruits and vegetables, consumption of too much alcohol, and lack of physical activity) accounted for 90% of the risk of myocardial infarction (MI). In the case of MI, the most important risk factors were smoking and abnormal lipid levels, which together accounted for about two thirds of the increased risk; smoking alone accounted for 36%.

Dr Byron Hoogwerf discussed glucose-lowering considerations in patients at high risk for CVD. Recent data have highlighted the importance of glucose lowering, but questioned just how low to go when it comes to glucose. Concerns regarding hypoglycemia remain paramount, and recent clinical trials, such as ACCORD (Action to Control Cardiovascular Risk in Diabetes), VADT (Veterans Affairs Diabetes Trial), and ADVANCE (Action on Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), have failed to demonstrate improvement in outcomes when HgbA

 levels below 7.0 mg/dL are aggressively targeted. Overall, when one considers whether an HgbA

 target below 7.0 mg/dL is warranted, Dr Hoogwerf asserts that the answer is probably “yes,” despite there being no assurance of reduced CVD risk. With respect to glucose-lowering agents, he emphasized using those that keep the risk for hypoglycemia and weight gain low. In view of the patient’s marginal elevation in creatinine, caution with agents such as metformin is warranted, and dose adjustment with gliptins is essential. Finally, caution regarding heart failure with thiazolidinedione and metformin are necessary.

Given these data, the aggressive reduction of risk is essential to mitigating cardiovascular events. Dr George Bakris reviewed what evaluation measures and treatment steps are required for managing our patient’s blood pressure. Clearly, based on multiple clinical trials, the aggressive lowering of blood pressure in this woman is known to be associated with significant improvement in cardiovascular events, particularly stroke. She is already on a multidrug regimen, but not at optimal doses.

Resistant hypertension is defined as failure to achieve goal blood pressure when a patient adheres to the maximum tolerated doses of 3 antihypertensive drugs including a diuretic. Although the exact prevalence of resistant hypertension is currently unknown, indirect evidence from population studies and clinical trials suggests that it is a relatively common clinical problem. The prevalence of resistant hypertension is projected to increase, owing to the aging population and increasing trends in obesity, sleep apnea (as is likely the case in this individual), and chronic kidney disease. Management of resistant hypertension must begin with a careful evaluation of the patient to confirm the diagnosis and exclude factors associated with “pseudo-resistance,” such as improper blood pressure measurement technique, the white-coat effect, and poor patient adherence to lifestyle changes and/or antihypertensive medications. Education and reinforcement of lifestyle issues that affect blood pressure, such as sodium restriction, reduction of alcohol intake, and weight loss in obese individuals, are critical in treating resistant hypertension. Exclusion of preparations that contribute to true blood pressure treatment resistance, such as use of nonsteroidal anti-inflammatory agents, cold formulas, and certain herbs, is also important. Lastly, blood pressure control can be achieved only if an antihypertensive treatment regimen is used that focuses on the genesis of the hypertension. An example is volume overload, a common but unappreciated cause of treatment resistance. Use of the appropriate dose and type of diuretic provides a solution to overcome treatment resistance in this instance.

Beta blockers were used in our patient. These drugs can be effective antihypertensive agents in the diabetic population as part of a multidrug regimen. They also can be used in patients with diabetes and concomitant evidence of coronary artery disease, such as anginal symptoms, including anginal equivalents, or after MI. The effectiveness of beta blockers was demonstrated in the UKPDS (United Kingdom Prospective Diabetes Study Group), where atenolol was comparable with captopril in reducing CVD outcomes. Although these agents have been associated with adverse effects on glucose and lipid profiles and implicated in new-onset diabetes in obese patients, they are not absolutely contraindicated for use in diabetic patients. In fact, carvedilol, which has both alpha- and beta-receptor blocking properties, has been shown to induce vasodilatation and improve insulin sensitivity.

Thiazides have been shown to cause electrolyte imbalances, metabolic changes, and volume contraction. Nevertheless, the ALLHAT (Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial) study, which compared a thiazide (chlorthalidone) with a calcium channel blocker (amlodipine) or an angiotensin-converting enzyme (ACE) inhibitor (lisinopril), found that the thiazide was less expensive and superior to the ACE inhibitor or calcium channel blocker in lowering the incidence of CVD in hypertensive populations. Therefore, ALLHAT suggests that thiazides could be considered as a first-line therapy for many diabetic patients with hypertension, despite the fact that they may adversely affect insulin resistance and potassium balance in some individuals. Indeed, using a thiazide diuretic in the antihypertensive repertoire has consistently been shown to improve cardiovascular outcomes, even in those with diabetes. Treating volume expansion with thiazide diuretics can increase the activity of the renin-angiotensin-aldosterone system (RAAS); thus, combining a diuretic with an ACE inhibitor or an angiotensin receptor blocker can be an effective blood pressure-lowering combination.

It has been shown that nondihydropyridine (ND) calcium channel blockers, such as verapamil and diltiazem, decrease proteinuria in diabetics. While not to the degree of ACE inhibitors alone, ND calcium channel blockers used in combination with ACE inhibitors have been shown to have additive effects in reducing albuminuria. The Syst-Eur (Systolic Hypertension in Europe) trial with nitrendipine demonstrated that intensive antihypertensive therapy for older patients with type 2 diabetes and isolated systolic hypertension eliminated the additional risk for CVD events and stroke associated with diabetes. In the HOT (Hypertension Optimal Treatment) trial, there was a reduction in major CVD events with diastolic blood pressure control in patients with diabetes when felodipine was used as first-line therapy. These trials indicate that calcium channel blockers are not harmful or contraindicated in hypertensive patients with diabetes, and the combination of an ACE inhibitor and a calcium antagonist is effective for the management of hypertension in diabetic patients.

Therapy aimed at improving insulin sensitivity and RAAS blockade seems to offer survival benefits to diabetics with hypertension. Further work in identifying the mechanisms of hypertension, diabetes, and insulin resistance would shed more light on the missing link that connects these seemingly different disease processes.

Dr Evan Stein concluded the session with a review of what alternatives exist regarding the management of the patient’s dyslipidemia. A controversy in the lipid community is whether to increase the dose of a statin or add adjunctive therapy for further LDL cholesterol reduction. Proponents of increasing the statin dose indicate that keeping the regimen simple will improve adherence, be more cost-effective, and that adjunctive agents may not provide additional pleiotropic effects (eg, C-reactive protein reduction) comparable to higher statin doses. Conversely, others argue that doubling the statin dose may result in only a 6% further reduction in LDL cholesterol with increased side effect potential, whereas the addition of ezetimibe or a bile acid sequestrant (BAS) may result in an approximately 20% reduction in LDL cholesterol levels. In reality, each side of the controversy has valid points. While increasing the statin dose may be the simplest option in certain cases, statins do have dose-dependent side effects, particularly when titrated to the highest doses. For example, the incidence rates of myopathy and elevated transaminases increase 4- to 5-fold when titrating simvastatin or atorvastatin from 40 mg to 80 mg daily. In cases such as this, adding a second agent (ie, ezetimibe, colesevelam) with a different site of action will not only provide more LDL cholesterol reduction, but will also limit potential side effects.

The use of fixed-combination lipid-altering products (ie, ezetimibe/simvastatin and lovastatin/extended-release niacin) offers potential advantages, and, in certain cases, may be preferential to adding a separate second agent or titrating the statin. The attributes of these products compared with statin monotherapy include an overall improved effect on the lipid profile and the possibility of greater cost-effectiveness. These advantages may be especially true when targeting LDL cholesterol with the ezetimibe/simvastatin combination. There is less controversy surrounding additional agents for other types of dyslipidemia. Among patients with low HDL cholesterol levels, attaining the LDL cholesterol goal is the first priority followed by achieving the non-HDL cholesterol goal and maximizing therapeutic lifestyle changes. If HDL cholesterol still remains a concern, therapy with niacin or fibrates may then be considered. Although side effects can limit niacin use, when added to a statin, only moderate doses (1000 mg/day) are required to significantly raise HDL cholesterol (24%) while minimizing adverse events.

The potential for increased adverse events must be considered with the use of more aggressive lipid-altering therapies, including higher statin doses and combination therapy. The risk of additional serious adverse events appears to be extremely low when using agents with excellent safety profiles (ie, cholesterol absorption inhibitor, BAS) in combination with statins; however, cases of rhabdomyolysis with ezetimibe alone or in combination with other agents associated with muscle toxicity (eg, statins) have been reported. Additionally, fibrate monotherapy is associated with a risk for muscle toxicity similar to that of statin monotherapy. As a result, concerns regarding an increased incidence of adverse effects are valid and must be monitored appropriately when using statins in combination with other agents (ie, ezetimibe, fibrates, niacin). 

Assessing global cardiovascular risk to improve health outcomes

One of the most talked about clinical trials in the field of preventive cardiology, the JUPITER (Justification for the Use of Statins in Prevention: An International Trial Evaluating Rosuvastatin) trial, was presented at the 2008 American Heart Association (AHA) Scientific Sessions and published in the 

 The investigators enrolled apparently healthy men, who were at least age 50, and women, who were at least age 60, with a high-sensitivity C-reactive protein (hs-CRP) level of 2.0 mg/dL or above. Individuals who had a history of previous cardiovascular disease or diabetes were excluded from the study. Nearly 30% of the participants were ethnic minorities, and the trial included more women (6801 of 17,802 subjects) than any other lipid-lowering trials to date. Study participants were enrolled from 1315 sites throughout 26 countries and randomized to receive 20 mg of rosuvastatin (Crestor) or placebo.

Low-density lipoprotein (LDL) cholesterol was lower in JUPITER than in other primary prevention trials. The mean LDL cholesterol level was 104 mg/dL and the median was 108 mg/dL. In other trials, the mean LDL cholesterol ranged from about 130 to 192 mg/dL.

The primary end point was a combination of myocardial infarction (MI), stroke, unstable angina requiring hospitalization, coronary artery revascularization, and cardiovascular death. Surprisingly, the study was stopped after a median follow-up of 1.9 years because of a striking 44% relative risk reduction in the primary end point (hazard ratio for rosuvastatin as compared with placebo was 0.56; 95% confidence interval [CI], 0.46-0.69). Women had the same relative risk as men, and those with a family history of premature coronary heart disease (CHD) had an even greater relative risk reduction of about 65%.

The event rate was at least twice as high as would have been predicted by the Framingham risk estimate, according to the investigators. This supports the idea that an elevated hs-CRP helped to identify high-risk individuals; however, JUPITER did not just look at the standard hard event rate of nonfatal MI/CHD death for their primary end point or MI/CHD death/unstable angina, as were looked at in AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study), a prior large primary prevention study.

January 2009