CDU Contributing Editor

BARCELONA — Cardiovascular diseases are the major cause of death throughout Europe, accounting formore than 4 million deaths annually in the region and also causing a high level of morbidity and reduced quality of life. As shown in Table 1, about 17% of the population of the European region has a known predisposition to cardiovascular disease, over 7% have preclinical disease, and 1.5%-2% have symptomatic disease. Hospital discharge rates for ischemic heart disease are increasing steadily in the European region, driven mainly by a rapid rise in discharge rates in the Commonwealth of Independent States (CIS), which are 12 out of 15 countries of the former Soviet Union, as well as a sharp rise over the past five years in the 10 countries that joined the European Union since May 2004, which includes countries such as Poland, Hungary, the Czech Republic, Estonia, Slovakia, and Slovenia. In spite of the increasing rate of hospitalization, however, crude rates for cardiovascular mortality have remained relatively stable, due mainly to improved treatments.

Focus on earlier detection

As discussed here at the World Congress of Cardiology (WCC), a joint meeting of the World Heart Federation (Geneva, Switzerland) and the European Society of Cardiology (Sophia Antipolis, France), experts in cardiology say that mortality rates can be improved even further through appropriate application of existing and emerging technologies, particularly those technologies that enable early detection of cardiovascular disease. Imaging systems, both noninvasive and invasive, are among the key technologies expected to play a role here, along with advanced tools in the areas of genetic profiling, biomarkers, targeted therapy, remote patient monitoring, and informatics.

Advances in the application of computed tomography (CT) scanning, MRI, positron emission tomography (PET) and ultrasound imaging in cardiology are having a major impact on mortality, and invasive imaging methods such as intravascular ultrasound are also becoming increasingly important.

An important emerging area is vulnerable plaque detection, with the goal of identifying localized regions of the coronary arteries that are likely to cause an acute event and implementing preventive treatments. Based on clinical studies, up to 86% of heart attacks and 88% of strokes may be caused by rupture or erosion of vulnerable plaque. Longer-term advances in biotechnology-based therapies hold promise for reversing some forms of cardiovascular disease, leading to additional improvements in survival.

Advances in non-invasive imaging

A wide range of non-invasive imaging modalities are being used for diagnosis and monitoring of cardiovascular disease, including CT scans, MRI, ultrasound, PET and nuclear imaging. As shown in Table 2, the combined global market for equipment in these segments approached $15 billion in 2005. And growth is projected to range from 5% to in excess of 14% on a compound annual basis through 2009, depending on the segment, with the highest growth predicted in the PET, CT and MRI segments.

The estimates shown in Table 2 represent sales of equipment for all applications, including cardiovascular imaging. However, due to the high incidence and prevalence of cardiovascular disease worldwide, imaging of cardiovascular disease comprises one of the highest-volume applications for such equipment.

Leading suppliers of imaging equipment for cardiovascular applications include GE Healthcare (Chalfont St. Giles, UK) — which reported 2005 worldwide sales of $15.2 billion (+12.6%); Siemens Medical (Erlangen, Germany); Philips Medical Systems (Eindhoven, the Netherlands); Toshiba Medical Systems (Tokyo); and Sonosite (Bothell, Washington) and Esaote S.p.A. (Firenze, Italy), both in cardiac ultrasound.

In the CT imaging segment, key advances were described at the WCC in the areas of non-invasive angiography, as well as in the use of CT to detect vulnerable plaque. Replacement of invasive angiography with noninvasive imaging modalities has been a goal of imaging companies since multi-slice technologies emerged. As discussed by Stephan Achenbach, MD, of Erlangen, Germany, at a WCC symposium sponsored by Siemens Medical, the development of 64-slice CT has for the first time allowed non-invasive imaging of the coronary arteries to be performed, at least under some circumstances, with resolution that is essentially equivalent to that for invasive angiography. Sensitivity for disease detection with 64-slice CT compared to invasive angiography ranges from 86% to 99% depending on the study, and specificity ranges from 95% to 98%.

The limitation of CT, however, is that heart rate must be less than 65 beats per minute (bpm), since motion artifacts occur at higher rates that are not always obvious. While drugs such as oral beta blockers are effective in reducing heart rate to under 60 bpm in some patients, those with atrial fibrillation may not respond satisfactorily. In addition, irregular heart beats can produce image artifacts. In the future, such limitations are likely to be reduced as high-speed image acquisition components become available. Even with existing 64-slice systems, however, studies discussed by Wolfgang Rutsch, MD, of Charite Medical School (Berlin), have recently demonstrated that invasive angiography can be avoided in 34% of cases using non-invasive CT imaging.

The main drawback to using multi-slice CT for routine coronary imaging is the relatively high radiation dose to the patient. The dose is typically three to four times higher than for invasive angiography, resulting in an estimated four additional cases of cancer per 10,000 patients imaged. Most physicians consider that dosage level to be too high for routine use, limiting the widespread application of CT in coronary imaging.

However, newer systems now under development will provide equivalent imaging capabilities with 25% of the current dose, making the risk equivalent to that for invasive angiography. At that point, it may become practical to use CT as the first line of a patient exam, avoiding exposing patients to the risk of complications associated with invasive angiography, and proceeding with angiography only in the approximately 50% of patients who now have a percutaneous intervention following an angiographic exam.

CT, ICE under evaluation

Multi-slice CT is also being evaluated for detection of vulnerable plaque. As with applications in angiography, excessive radiation dose remains an important issue at present limiting utilization. However, when lower-dose systems become available, CT promises to provide a viable method for measurement of overall plaque burden. New techniques described by Achenbach at the congress are now being studied that employ dual energy beams (at 80 kV and 140 kV) and show promise for identifying plaque type. Ultimately, 256-slice CT systems, such as the 2nd Spec 256-Multislice CT scanner now under development by Toshiba Medical, capable of acquiring an iso-phasic image of the entire heart in a single 1.5 second breath-hold scan, promise not only to eliminate limitations on heart rate for cardiovascular CT imaging, but also to allow an integrated view of the coronary arteries.

Another emerging application for CT imaging in cardiology is procedure guidance. One technique being evaluated for guidance of node ablation is intra-coronary echocardiography (ICE), which employs a catheter transducer for guidance of the ablation catheter, and simultaneously allows detection of intra-coronary thrombus during the procedure, helping to avoid procedural complications. GE Healthcare in partnership with St. Jude Medical (St. Paul, Minnesota) will develop the CardioICE imaging module that will be incorporated into St. Jude's existing electrophysiology ablation system to provide integrated guidance/ablation capability.

Ultrasound and VVI

Cardiac ultrasound imaging, a segment that includes technologies such as ICE, is exhibiting rapid growth in Europe and worldwide. The cardiology segment represented about 25% of the $3.8 billion global ultrasound imaging products market in 2005. Based on data provided by GE Healthcare from Klein Biomedical (New York), the cardiology segment of the U.S. ultrasound market grew 15% in 2005. GE claims the leading position in the market, with $1.36 billion in sales in 2005, up 15% vs. 2004. One application driving market expansion, at least until recently, is cardiac dyssynchrony imaging, which can be used to identify the approximately 30% of heart failure patients who will not respond to cardiac rhythm therapy employing an ICD.

Doppler ultrasound imaging techniques are used to detect and characterize mechanical dyssynchrony in heart motion. Precise measurement methods are required, since even normal patients can exhibit some degree of dyssynchrony. According to Garcia Fernandez, MD, of Madrid, Spain, who discussed cardiac dyssynchrony imaging at a symposium during the conference, some commonly used techniques, particularly time-to-peak velocity, are difficult to implement reliably in routine practice. Fernandez advocates the use of a displacement technique to obtain more consistent results in routine clinical practice.

Another advanced cardiac ultrasound imaging
technique that can be used to optimize CRT-ICD device settings for heart failure therapy is Axius Velocity Vector Imaging (VVI), developed by Siemens Medical for use on systems such as the Acuson Sequoia C512, of which over 12,000 units are installed worldwide. As discussed by Gianni Tonti, MD, of Sulmona, Italy, at a Siemens-sponsored WCC symposium, VVI provides automatic tracking of the endocardial border and measurement of segmental ejection fractions, as well as automatic calculation of cavity volume. As opposed to two-dimensional strain imaging, a method conventionally used to analyze heart motion, VVI provides information on movement in three dimensions, an advantage that could allow the percentage of non-responders to bi-ventricular pacing to be reduced.

The next advance in 3-D ultrasound imaging will utilize a matrix array detector to allow capture of a complete set of data simultaneously, rather than point-by-point as is done now, to provide true real-time images. Existing systems from Siemens must acquire four separate frames to generate a real-time 3-D image. Siemens has already developed a prototype matrix array detector for use in 3-D ultrasound imaging.

Ultrasound as hand-held modality

One of the most rapidly growing segments of the ultrasound imaging market is hand-carried or portable ultrasound instruments. Sonosite, the pioneer in that segment, reported 2005 sales of $147.5 million, up 27% vs. $115.8 million in 2004. GE, the overall market leader in ultrasound, has introduced its Compact Series of ultrasound products, including the Vivid i and the newer Vivid e (a smaller system priced at half the cost of the Vivid i) designed for cardiovascular applications. GE's compact ultrasound sales grew 45% in the first half of 2006 vs. the like period of 2005.

Worldwide, the market for hand-carried/ portable ultrasound products was estimated at $300 million for 2005, up over 54% vs. $195 million in 2004. As in the fixed-base ultrasound systems segment, cardiovascular applications comprise one of the most important sub-segments of the portable ultrasound market. A growing area of the market is systems for performing carotid intima-media thickness (IMT) measurement for cardiovascular disease screening including screening for stroke risk, an exam often performed in the physician's office and other primary care settings. Sonosite estimates that the potential market for portable ultrasound products for the physician's office and alternate sites could be as large as $3 billion in the U.S. alone.

The company has developed the SonoCalc software package to automate IMT measurement, eliminating the need for manual measurements that impedes adoption in primary care settings. A dedicated sales force for the physician's office market is being established by Sonosite in the U.S.

MRI making advances

MRI is another modality that has promise for cardiovascular applications, although so far it has been unable to reach the level of spatial resolution achieved by CT. In cardiovascular applications, MRI has the advantage of providing tissue characterization, making it a possible candidate for detection of vulnerable plaque. As discussed by Udo Sechtem, MD, of the Robert Bosch Medical Center (Stuttgart, Germany), at a Siemens Medical symposium held at the WCC meeting, MRI already is playing a valuable role in the diagnosis of conditions such as myocarditis, a common cardiac disease identified in up to 9% of post-mortem examinations that is a major cause of sudden cardiac death and cardiomyopathy.

Gadolinium-enhanced MRI provides the capability of distinguishing between ischemic and dilated cardiomyopathy and is a highly effective means of guiding myocardial biopsy to confirm or rule out myocarditis. Sechtem cited data showing that use of cardiac MR to determine if a biopsy is warranted as well as to guide specimen collection results in greater than 90% positivity.

MRI, like cardiac ultrasound, also has proven valuable in screening applications. For example, studies conducted by GE Healthcare using cardiac MRI in patients presenting with chest pain have shown a 40% reduction in the rate of cardiac catheterization. GE's newest MRI system, Signa HDx, can provide real-time cardiac images without gating, and is available in both 1.5T and 3.0T models.

Siemens has introduced a 16-slice cardiac MRI system within its Magnetom line that can cover the entire heart in one breath hold image. The system has been shown to provide a more accurate method for determining ejection fraction than echocardiography, and also offers a highly sensitive method for detection of cardiac scar tissue using an imaging technique called Phase Sensitive Inversion Recovery.

While SPECT has historically been used to detect scar tissue and non-viable myocardium, it requires about a half day to perform a SPECT exam. Siemens has recently replaced SPECT imaging with cardiac MRI in some clinics in Europe. In addition to more rapid turnaround time and avoidance of the use of radioactivity, MRI also has the advantage of allowing whole body imaging to be performed. For example, Siemens offers a mode called TIM (Total Imaging Matrix) that uses multiple synchronized body surface coils to capture a whole body angiographic image in 45 to 50 minutes. That capability is particularly useful in the work-up of diabetic patients, who often present with not only coronary disease but also disseminated peripheral vascular disease. For such patients, MRI offers an opportunity to significantly enhance clinic workflow.

Vulnerable plaque at the molecular level

Non-invasive imaging modalities are also being developed for detection of vulnerable plaque, potentially a major new application in cardiology. PET imaging, which provides the capability for molecular characterization of tissues, is one promising modality being investigated. As discussed by Paolo Camici, MD, of Imperial College of Science, Technology and Medicine (London) at a press conference sponsored by GE Healthcare, PET is a proven modality for measurement of microvascular circulation in the heart, and can detect changes in flow as well as lipid abnormalities even when coronary angiography images are normal.

Microvascular disease typically precedes classic coronary artery disease and is an independent predictor of myocardial ischemia. Now, Camici in collaboration with GE Healthcare is combining PET with CT imaging to obtain both high-resolution images of vascular anatomy including stenoses as well as information on the clinical impact of a stenosis. In the future, Camici foresees the use of PET/CT for simultaneous analysis of plaque metabolism and morphology.

Studies are already underway in carotid arteries using measurements of glucose uptake in plaque as an indicator of vulnerable plaque. A new imaging agent is also being evaluated for vulnerable plaque detection that has shown better sensitivity compared to deoxyglucose.

Clinical application of vulnerable plaque detection, however, is not likely to become a reality in the near future. As discussed by Peter Libby, MD, of Harvard Medical School (Boston), the concept of vulnerable plaque is currently one in evolution. The most recent investigations show that vulnerable plaques are numerous, and that vascular inflammation is often widespread. Often there is not just a single, localized region of vulnerable plaque, but rather there is a vulnerable artery, a vulnerable arterial bed, or even a vulnerable patient.

Libby says that methods used to identify plaque or vascular vulnerability will include both serum biomarkers as well as imaging methods capable of providing information on the morphological, functional, and molecular characteristics of plaque. Detection of vascular inflammation is likely to play a role. Tools to assess collagen formation and breakdown will also be important, due to the role played by collagen in determining the structural and mechanical characteristics of plaque. One potential factor being studied by Libby is collagenase, an enzyme induced by T-cells, and its role in determining plaque characteristics.

Plaque rupture a key risk factor

Plaque characteristics, of course, play a central role in determining the risk of an acute coronary event. As discussed by Ruth Virmani, MD, of CVPath (Gaithersburg, Maryland), plaque rupture is seen at autopsy in 55%-60% of patients with coronary artery thrombosis, while plaque erosion is found in 30%-35%. Calcified nodules account for 2%-7%. Plaques that appear to be most prone to rupture (and therefore most vulnerable) are those with a thin (<65 micrometer) fibrous cap, low collagen content, macrophage infiltration, and a necrotic core. About 80% of thin cap atheromas occur in vessels with <50% stenosis, so use of luminal diameter as a risk factor does not appear to be valid.

One marker being studied by Virmani as a possible indicator of plaque instability is Lp-PLA2 (Lipoprotein-Associated Phospholipase A2). As discussed by Wolfgang Koenig, MD, of the University of Ulm Medical Center (Ulm, Germany), patients with elevated Lp-PLA2 have a double risk for coronary heart disease and stroke. At least 14 studies are now underway worldwide to evaluate Lp-PLA2 as a risk marker. The latest data indicate that the marker could possibly represent a link between lipid metabolism and inflammation, thus playing a key role in the development of vulnerable plaque.

A reliable serum marker of plaque instability could play a key clinical role by providing a means to screen the population to identify individuals who would benefit from non-invasive and perhaps invasive imaging studies to obtain a detailed characterization of the distribution and status of vulnerable plaques. While some single markers such as Lp-PLA2 look promising, many experts in biomarkers for cardiovascular disease now say that panels of markers that allow tracking of the various steps in vulnerable plaque development may ultimately be the most powerful tool for early detection.

A role still for invasive imaging

As described by Patrick Serruys, MD, PhD, of Rotterdam, The Netherlands, patients identified as at risk via biomarker testing could proceed to CT studies, and perhaps in the future MRI to take advantage of MRI's ability to characterize tissue properties and identify fatty streaks, lipid cores, and thin caps, although at present MRI technology is not able to perform such characterizations with sufficient reliability for clinical use. Individuals who are identified as at risk via markers and non-invasive imaging may in the future be referred for further studies using invasive, catheter-based methods for vulnerable plaque analysis.

The leading tool for invasive plaque imaging at present is intravascular ultrasound (IVUS), and enhancements of IVUS that employ signal analysis techniques to perform tissue characterization. An example is the Virtual Histology technique recently introduced by Volcano (Rancho Cordova, California).

As shown in Table 3, IVUS is presently utilized in a small percentage of coronary procedures. A companion technology, also marketed by Volcano as well as by Radi Medical Systems (Uppsala, Sweden), is functional measurement of intravascular pressure and flow, which allows characterization of the hemodynamic effects of a stenosis or other vascular anomaly. Volcano recently introduced a new system, the s5, that incorporates VH technology, and is priced at EUR 120,000, along with a new 45 MHz high-frequency IVUS catheter. In addition, Volcano is collaborating with GE Healthcare to integrate an IVUS module, the s5ge, into GE's Innova cath lab imaging system.

Longer-term, as discussed by Serruys, palpography — which uses ultrasound to characterize the mechanical properties of an artery — may provide the most definitive method for detecting hot spots in plaques that are most likely to rupture.

Other invasive methods discussed by Serruys that may play a role in vulnerable plaque detection in the future include intravascular MRI, near-infrared analysis, Raman spectroscopy, low-coherence interferometry, and optical coherence tomography (OCT).

Raman spectroscopy appears to have a role in fibrous cap detection, while OCT is a sensitive method for detecting thrombus. Near-infrared techniques are sensitive to the presence of inflammation, while intravascular MRI may provide a means for highly localized characterization of lipid composition and other molecular characteristics. While not all of those technologies may eventually reach the market, executives at companies in the sector say there are very large potential market opportunities.

For IVUS alone, the opportunity based on total diagnostic and interventional procedure volume in cardiology and radiology (for peripheral vascular applications) of 10 million combined with existing IVUS device pricing equates to a total worldwide market opportunity of over $6 billion. That would represent a significant increase from the current IVUS market estimated at $271 million worldwide in 2005 by suppliers, up 21% from $224 million in 2004.

Vulnerable plaque detection represents a significant upside opportunity, but significant technological barriers remain to be overcome, as well as barriers related to the increasingly cost-sensitive environment in interventional cardiology.

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