CDU Contributing Editor

NEW ORLEANS Early identification of individuals at risk for cardiovascular disease, including myocardial infarction, stroke and peripheral vascular disease, has become increasingly important within the past decade as advances in therapy, including drug treatment as well as minimally invasive revascularization therapies, have enabled physicians to alter the course of disease and achieve significant improvements in patient outcome. As discussed by presenters at the 2004 scientific sessions of the American Heart Association (AHA, Dallas), held here last November, about 140 million Americans over age 35 have some degree of elevated risk for cardiovascular disease; 70.6% exhibit one or more defined risk factors; and 64.4 million people in the U.S. have some form of cardiovascular disease. A range of methods have been developed to screen patients for the presence of cardiovascular disease, including blood pressure monitors, blood tests including point-of-care (POC) tests for risk markers such as blood lipid levels, noninvasive imaging modalities and electrocardiograms used to check for heart rhythm disorders. Between 50 million and 60 million of those at risk can be identified as having cardiovascular disease using home or office-based screening, such as POC biomarkers and blood pressure measurement.

The next level of testing, which identifies between 40 million and 50 million of the at-risk individuals, employs office-based testing technologies such as the ECG, lipid testing and imaging methods including electron beam computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound and, most recently, noninvasive angiography using high-resolution multislice CT scanners. A much smaller number of individuals, numbering between 2 million and 3 million in the U.S., have a sufficiently high risk based on the results of home and office-based testing to qualify for invasive diagnosis using conventional angiography.

However, improved screening technologies still are needed, according to experts presenting at the AHA sessions, because up to 60% of acute myocardial infarctions and sudden cardiac deaths occur with no prior warning symptoms, and more than 60% of patients who suffer an acute coronary event are later not found to have had an arterial stenosis of 50% or greater. As a result, researchers are evaluating additional techniques that can help to identify vulnerable plaques that, while not creating a flow-limiting stenosis, are nevertheless believed to be capable of rupturing, resulting in an acute blockage of the artery. Recently, attention has focused on methods for assessment of endothelial function, based on evidence that factors such as inflammation of the arteries and lack of adequate mechanical compliance of the vessel wall may also be significant risk factors. Noninvasive methods, including at least one introduced only within the past few months, are now available to help physicians assess the state of the vascular endothelium. Molecular imaging technologies also promise to improve the specificity and sensitivity of diagnostic imaging for cardiovascular disease, employing targeted injectable agents designed to identify specific properties of a blood vessel, such as lipid-rich plaque, that are believed to pre-dispose an individual to an acute event.

Advances in disease risk assessment

Table 1 describes some novel and emerging technologies that are now available or under development to enhance the ability to identify individuals with cardiovascular disease. The technologies described in the table can be used in conjunction with established screening modalities to improve the ability to detect disease at an early stage, and may prove valuable in allowing detection of at-risk patients who do not exhibit conventional risk factors. For example, arterial pulse wave augmentation analysis, a technology developed by Omron (Kyoto, Japan), the leading supplier of blood pressure products for consumer use, is a new method that shows promise for assessment of endothelial dysfunction. The technique provides an assessment of arterial stiffness using tonometry of the radial artery. The Omron analyzer measures peaks in the systolic pressure waveform to compute an Augmentation Index (AI). As discussed by Junichiro Hashimoto, MD, PhD, of the Tohoku University Graduate School of Pharmaceutical Sciences (Sendai, Japan), at an Omron-sponsored symposium held during the AHA conference, an increase in AI has been shown to correlate with age, short stature, smoking, blood pressure and hyperlipidemia, while a drop in AI is correlated with a high heart rate. In addition, an increase in AI of about 10% is associated with a two-fold increase in risk of left ventricular hypertrophy. Population studies show that AI levels are correlated with the presence of coronary artery disease. Gary Mitchell, MD, president of Cardiovascular Engineering (Holliston, Massachusetts), a firm involved in the development of the technology, said AI is particularly valuable for assessment of patients with hypertension, since it allows substratification of risk within groups stratified by blood pressure alone. Importantly, AI detects effects of antihypertensive drug therapy that are not detected using brachial artery pressure measurements. The parameter may help to explain some anomalous results of clinical trials wherein certain drugs (e.g., ACE inhibitors) fail to show clinical benefit in spite of a drop in brachial artery pressure.

Another new risk assessment tool described at the AHA sessions with applications in the detection of endothelial dysfunction is ADMA, a novel laboratory test for an endogenous inhibitor of nitric oxide. Nitric oxide plays a key role in maintaining normal function of the vascular endothelium, and the detection of elevated levels of ADMA is correlated with the presence of hypercholesterolemia, hypertension, chronic heart failure, chronic renal failure, erectile dysfunction, and elevated levels are also found in pregnant women who subsequently develop pre-eclampsia. DLD Diagnostika (Hamburg, Germany) has developed the ADMA test, which is available for research use in Europe. The test may not only provide a broad-spectrum indication of the presence of endothelial dysfunction, but also has a potential role in therapy, since the higher cardiovascular morbidity and mortality associated with elevated ADMA can be counteracted by administering L-arginine, a common amino acid.

Zargis Medical (Princeton, New Jersey) has just initiated shipment of a new software-based product for analysis of heart sounds, the Cardioscan, which the company believes can help primary care physicians, and in particular pediatricians, improve detection of heart murmurs while also reducing the number of patients referred unnecessarily for echocardiography exams. The Zargis Acoustic Cardioscan (ZAC), which was developed jointly by Zargis and Siemens Medical Solutions (Erlangen, Germany), acquires, records and analyzes the acoustic signals of the heart and provides a visual presentation for interpretation by a physician. The product consists of an electronic stethoscope, a laptop computer and a printer, along with proprietary signal analysis software. Users pay a $250 initial fee for a six-month evaluation of the software, and an annual license fee of $1,000 thereafter. The product is designed to augment the auscultation skills of primary care physicians. Zargis believes that 60% to 80% of echocardiography referrals by pediatricians and primary care physicians for assessment of heart murmurs may be unnecessary and that the Cardioscan can help reduce such referrals. At present, there is no separate reimbursement for the added cost of the exam, but the company is performing studies to demonstrate that added reimbursement is justified. The Cardioscan was cleared by the FDA in mid-2004, and initial shipments of the product have begun in the U.S.

Another emerging trend within cardiology is a focus on sleep apnea as a syndrome that can serve as a key warning sign of the development of cardiovascular disease. Not only is there a strong independent association between sleep apnea and an increased risk of hypertension, heart failure, stroke and atrial fibrillation, but in addition abnormalities associated with obstructive sleep apnea may contribute to the initiation and progression of cardiac and vascular disease. Sleep apnea results in extreme cycles of hypoxia and reoxygenation, hypercapnia and intrathoracic pressure changes. Consequences of those recurring events include endothelial dysfunction, vasoconstriction and vascular oxidative stress, coagulopathy, increased leptin and insulin resistance, and sympathetic activation, resulting in increased risk for a range of cardiovascular syndromes. A large percentage of individuals with sleep apnea are undiagnosed, driving a need for improved technologies for sleep apnea testing.

Respironics (Murrysville, Pennsylvania) introduced a new product in the $2 billion worldwide market for sleep apnea diagnostic and therapeutic products at the AHA conference, the Alice 5 Polysomnography System. The new system collects data from sensors placed on the patient, and includes the Stardust portable recorder that can be used to detect sleep apnea. A recent trend in the market, according to Respironics, is for cardiologists to set up sleep labs, as awareness increases in the cardiology community of the link between sleep apnea and cardiovascular disorders.

Another recent development in the market is the introduction of the LifeShirt from VivoMetrics (Ventura, California). The LifeShirt System consists of a suite of products and services that collects data continuously from patients in any location. It includes an 8-ounce, machine-washable shirt with embedded sensors for measurement of respiratory function, ECG, posture and activity level. Optional peripheral devices measure blood pressure, oxygen saturation and end tidal CO₂. Data is stored on the LifeShirt Recorder and VivoLog Digital Patient Diary, an integrated PDA that continuously stores data on a flash memory card. VivoMetrics also operates a data center that provides data analysis services for users of the LifeShirt. The LifeShirt System is used for home diagnosis of sleep apnea, monitoring of patients in clinical trials and in academic research.

Imaging technologies play expanded role

Diagnostic imaging technologies are also becoming increasingly important modalities for risk assessment in cardiovascular disease, as well as for diagnosis and monitoring of therapy. MRI, for example, is showing considerable promise for use as a screening tool for the detection of coronary artery disease. MRI is noninvasive, uses no ionizing radiation, is not operator-dependent, and allows rapid scanning. For example, a scan covering the region from the subclavian artery to the aorta can be performed in about two and one-half minutes, and an entire MRI exam including patient preparation can be completed in 15 minutes. The spatial resolution of MRI has improved rapidly over the past few years, and the technique can now be used to measure carotid medial thickness and aortic wall thickness, and to assess coronary perfusion, the latter application employing gadolinium contrast agents. One emerging application, tied to the growing interest in using electrical stimulation therapy such as ICDs for the treatment of ischemic cardiomyopathy, is the use of contrast-enhanced MRI to identify scar tissue that is susceptible to arrhythmia. Based on the degree of heterogeneity of cardiac tissue when viewed using MRI contrast imaging, physicians can predict if an arrhythmia is inducible, indicating risk for sudden cardiac death.

As discussed by Manesh Patel, MD, of Duke University Medical Center (Durham, North Carolina) at the AHA sessions, another new application of MRI in cardiology is the detection of cardiac involvement in patients with sarcoidosis. Although sarcoidosis typically afflicts the lymph nodes, liver, spleen, lungs, skin and eyes, with cardiac involvement of only 5% based on published guidelines, the actual prevalence of cardiac sarcoidosis may be as high as 25% to 30% in the U.S., according to Patel, and up to 60% in Japan, making it the leading cause of sudden cardiac death in that country. Using a technique called delayed-enhancement MRI, which elucidates scar tissue in the heart, Patel has demonstrated the ability to identify patients who are likely to suffer subsequent cardiac events.

Yet another new MRI technique, steady-state free precession or SSFP, has been shown to allow mapping of oxygen saturation levels in the heart. As discussed by Rohan Dharmakumar, MD, of the University of Toronto, who is collaborating with GE Healthcare Technologies (Waukesha, Wisconsin) in development of the technique, SSFP-based MRI oximetry can accurately track oxygen saturation changes, exhibiting a 2% to 3% change in signal per 1% change in saturation when imaged at 3 Tesla. Dharmakumar showed images demonstrating the ability to assess the oxygenation status of the microcirculation in the heart, potentially allowing a highly detailed mapping of cardiac ischemia to be performed noninvasively.

Advances in MRI contrast agents are opening up a number of new applications for MRI in cardiology, based on the emerging field of molecular imaging. For example, Feridex, an iron oxide nanoparticle-based MRI agent from Berlex (Montville, New Jersey), a unit of Schering AG (Berlin, Germany), is being used in concert with antibody targeting to detect activation of endothelial cells. A targeted nanoparticle-antibody agent that binds specifically to VCAM-1, a known marker of endothelial activation, is being used to perform magnetic resonance immunohistochemistry (MRIhc) by researchers including Szilard Voros at the University of Virginia (Charlottesville, Virginia). Such techniques represent a next-generation modality that may eliminate the need for invasive biopsy in order to perform tissue pathology exams. Voros described in vitro experiments with a 1.5 Tesla MRI scanner in which selective imaging of cells expressing VCAM-1 was observed, and no non-specific binding to other cells was detected. It was possible to obtain semi-quantitative information on the level of VCAM-1 expression. Voros is planning in vivo experiments with various sizes of nanoparticles.

Another nanoparticle-based MRI agent is being developed by Theseus Imaging, a unit of North American Scientific (Chatsworth, California). The agent consists of an antibody to Annexin-V, a marker of cellular apoptosis and necrosis, labeled with 300 nm magnetic nanoparticles. Theseus also has developed a radiolabeled version of Annexin-V, which is used in SPECT imaging. In MRI studies in mice performed by David Sosnovik of Massachusetts General Hospital (Boston), the Theseus agent detected apoptosis in infracted myocardium with high specificity, showing no evidence of non-specific binding. Although it is necessary to wait until about six hours following reperfusion post-infarct to perform the imaging study, the agent could detect both apoptotic and necrotic cardiac tissue. The radiolabeled version of Annexin-5 has been used in clinical studies aimed at detection and imaging of unstable plaque. In patients who had suffered a recent transient ischemic attack (TIA) associated with a demonstrated carotid stenosis, the agent has been shown to localize to affected vessels. Furthermore, uptake of the agent is correlated with the presence of unstable plaque as determined via ex vivo analysis of excised tissue.

Another new MRI contrast agent is being developed by Epix Pharmaceuticals (Cambridge, Massachusetts) that has applications in cardiovascular imaging. The Epix agent, EP-2104R, is a magnetic resonance contrast agent that targets fibrin. Fibrin is present in all thrombus, and in all stages of clot formation. The Epix agent has been shown to detect in-stent thrombosis in a pig model. A study described at the AHA sessions by Andrea Wiethoff of Epix assessed the ability of EP-2104R to detect human thrombi in vivo, and showed that MRI using EP-2104R could detect some small thromboembolic particles that were not detectable by CT scans. Chronic thrombi collected from thrombectomies show higher signal levels than fresh thrombi, probably because the fibrin is more organized and accessible in chronic thrombi. A delay of about 30 minutes is needed after administration of the agent before the thrombi can be visualized on the MRI. Epix also is developing MS-325, another MRI contrast agent that binds albumin in the bloodstream, and may offer an alternative to X-ray angiography, potentially addressing a very large market. Epix estimates that, by 2010, MRI angiography will comprise more than half of the 12 million-plus angiograms performed annually in the U.S., excluding cerebral and carotid angiograms.

An even more rapidly growing segment of the diagnostic imaging market, however, and one which also has important applications in the diagnosis of cardiovascular disease, is positron emission tomography (PET) imaging, including PET combined with CT scans. Suppliers of PET and PET/CT scanning systems include CTI Molecular Imaging (Knoxville, Tennessee), GE Healthcare, Philips Medical Systems, a unit of Royal Philips Electronics (Amsterdam, the Netherlands), Positron Corp. (Houston) and Siemens Medical Solutions. While PET scanners have been available clinically for well over a decade, the market has recently entered a rapid growth phase, reaching $770 million worldwide in 2003 according to data from GE Healthcare, with a compound annual growth rate of more than 30%, as shown in Table 2, significantly outpacing growth in the MRI segment.

Positron, a leading supplier of PET systems for cardiac imaging, reported a doubling in revenues between 2001 and 2003, to $5.1 million in 2003. The company's mPower PET scanner is priced at $1.3 million, vs. about $2 million for combination PET/CT systems that are increasingly being touted by other suppliers as the optimal modality for cardiac imaging. PET can prove highly profitable for imaging centers, with a cost per scan of around $1,200 vs. a reimbursement level of $2,000 to $3,000. At present, PET scans for the assessment of myocardial viability are covered (by Medicare) for primary or initial diagnosis prior to revascularization, or following an inconclusive SPECT exam. Cardiac imaging centers have experienced a significant increase in PET scan procedure volume, consistent with the market growth data shown in Table 2, in part because the use of PET has been shown to drive reductions in the cost of management of coronary artery disease, including reduced costs for coronary angiography due to lower utilization.

SPECT is another important imaging modality for use in cardiac diagnosis, mainly for performing myocardial perfusion studies. Siemens Medical Solutions exhibited the Symbia TruePoint SPECT-CT system, first introduced in July 2004, which combines SPECT imaging with multi-slice CT. A Symbia system with dualslice CT is priced at under $600,000, while a six-slice CT-SPECT system is priced at about $900,000. Since introduction of the Symbia in the U.S., one system has been installed, at the University of Michigan (Ann Arbor). GE Healthcare and Toshiba Medical Systems (Tokyo) both have introduced volume CT scanners, which provide the capability to perform CT angiography and reduce the amount of contrast agent needed to obtain angiographic data. The GE LightSpeed VCT system provides 64-slice resolution, and can acquire a complete image in five seconds. The Toshiba Aquilion 64 also offers 64-slice volumetric CT imaging with the capability to capture 64 slices at 0.5mm resolution in 0.4 seconds, and is priced at $1.4 million.

Advances in ultrasound imaging, a modality that has found widespread applications in cardiology, also were described at the AHA sessions. The market for ultrasound imaging products, which approached $4.3 billion worldwide in 2003 as shown in Table 3, is continuing to grow, due in part to the introduction of technologies that are expanding the capabilities of the modality. Philips, the traditional leader in cardiac ultrasound, exhibited the iE33 Intelligent Echo system, which was launched about a month prior to the AHA conference. The iE33 uses a new transducer technology, the Pure Wave crystal, as well as a new approach to stimulation of the ultrasound probe that results in improved image quality. The Pure Wave crystal is manufactured in a layered fashion, a structure that helps avoid random domain effects that degrade the performance of conventional transducers and provides improved bandwidth. As a result, a single transducer can operate over the range from 1 Mhz to 5 Mhz, whereas it was necessary to purchase two probes to cover that range with previous generation technology. A basic 2-D system is priced at $140,000, and upgrading to 3-D adds another $35,000 to the price. Another option is real-time (live) 3-D imaging, which costs an additional $75,000. Various plug-in modules are available that are useful for cardiac imaging, such as a Region of Interest plug-in that is used for contrast imaging procedures, and software packages that allow strain imaging and color kinesis imaging to be performed. The system has the on-board capability to perform quantitative measurements.

GE Healthcare exhibited the new Vivid i portable ultrasound system. The 10-pound, battery-powered device can communicate with the hospital intranet via a wireless connection, and has a full range of probes, including a transesophageal echo (TEE) probe. The $80,000 Vivid i provides the capabilities of GE's high-end Vivid 7 ultrasound system but in a portable, lightweight platform. There is a strong trend in the ultrasound imaging market toward development of portable systems that can provide high-end imaging capability in any setting.

SonoSite (Bothell, Washington), the pioneer in handheld ultrasound scanners, has increased its revenues more than eight-fold from 1999 to 2003. As shown in Table 4, handheld ultrasound systems represent a rapidly growing sub-segment of the larger ultrasound imaging products market, estimated at about $94 million in the U.S. for 2003, and forecast to expand at a 20.8% compound annual rate over the 2003-2008 interval. One emerging cardiovascular application for handheld and portable ultrasound scanners being addressed by a number of suppliers, including SonoSite, is point-of-care assessment of intima-media thickness (IMT). SonoSite has introduced an IMT assessment option for its Titan platform that utilizes a software package running on a companion PC for data analysis.

According to SonoSite, while there is not yet an approved reimbursement code for IMT measurement, some third-party payers are paying from $130 to $170 per exam. Mobile screening services have emerged in the market that offer scans for as little as $49. A major advantage of using a handheld scanner such as the SonoSite Titan to perform the exam is that it becomes easier to convince asymptomatic individuals that a problem exists that requires intervention, since they can directly view the display.

Other applications exist in sites such as the operating room. For example, Siemens has introduced the Cypress, a hand-carried, digital transesophageal echocardiography system that is being used to guide placement of biventricular pacing leads in the OR. The Cypress also has the capability to perform intracoronary echocardiography (ICE) exams, using the Siemens AccuNav catheter which has an ultrasound element built into its distal tip. ICE is becoming increasing popular because it requires less procedural and fluoroscopy time than TEE, does not require general anesthesia and is better tolerated by the patient than TEE.

A new modality for coronary imaging showing promise for the assessment of vulnerable plaque, optical coherence tomography (OCT), was discussed by a number of researchers at the AHA sessions. OCT technology is being developed by LightLab Imaging (Westford, Massachusetts), a unit of the Goodman Co. (Tokyo). In a study described by Mehmet Cilingiroglu of Baylor College of Medicine (Houston), OCT was used to analyze the thickness of vulnerable plaques in mice, and the results were compared to histopathology exams on the same tissues. The thickness as determined in vivo by OCT was consistently greater than that determined by histopathology, an effect that was attributed to the removal of water from the vessel tissue by formalin fixation. In fact, OCT could be used to track the shrinkage of the tissue due to fixation. OCT also demonstrated the ability to differentiate different types of plaque: the brightest light reflections occurred at regions containing calcium mixed with lipid.

Brian Courtney of Stanford University Medical Center (Palo Alto, California) described additional studies using OCT that employed pulsed infrared light and interferometry to produce polarization-sensitive images, with a goal of enhancing the ability of OCT to identify the components of vascular lesions. In ex vivo imaging studies, polarization-sensitive OCT was shown to allow differentiation between atherogenic lesions, calcifications and different fibrous cap thicknesses. The researchers believe that the technology could prove valuable for the detection and characterization of unstable plaques.