Cardiovascular disease (CVD) afflicts greater than 70 million patients in the US alone, and accounts for over half of all deaths. Non-invasive cardiac imaging modalities are used to provide enhanced methods of diagnosis of CVD, guidance of patient-specific therapy, and prognostication of cardiac-related risk.
Non-invasive cardiovascular imaging has traditionally been stratified into two distinct types: anatomic imaging and functional imaging. The chief aim of anatomic imaging is the identification of atherosclerosis, while functional imaging provides information relating to the hemodynamic significance of that atherosclerosis. Anatomic imaging modalities include multi-detector computed tomography (MDCT), electron beam computed tomography (EBCT) and magnetic resonance angiography (MRA), while functional imaging modalities include single photon emission computed tomography (SPECT), myocardial perfusion imaging (MPI), stress echocardiography (SE), cardiac magnetic resonance imaging (CMR), and positron emission tomography (PET) perfusion imaging. Currently, the assessment of functionally significant coronary heart disease (CHD) has relied primarily upon nuclear MPI or stress echocardiography (SE). Both MPI and SE have demonstrated robust ability to diagnose significant CHD, as well as the capability to prognosticate future outcomes. In this manner, these modalities are notable for their ability to not only diagnosis CHD, but also to risk stratify individuals who at increased risk for future CHD events.
Since the release of current generation 16- and 64-slice CT scanners, MDCT has reached levels of temporal and spatial resolution necessary for anatomic evaluation of the coronary arteries. The majority of MDCT investigations thus far have concentrated on the comparison of the diagnostic accuracy of MDCT with invasive coronary angiography (ICA) for the detection of obstructive coronary artery stenosis. This report focuses instead on evolving questions of MDCT that relate to patient risk, namely which patient populations are most suitable for MDCT coronary angiography, whether MDCT can provide accurate and reliable data relating to ventricular function and perfusion, and whether MDCT permits accurate risk stratification and prediction of clinical outcomes.
Indications for Anatomic Evaluation in Patient Subpopulations
Particularly with current generation 64-slice scanners, MDCT has evolved into a non-invasive modality with extremely high sensitivity and specificity for the detection of obstructive coronary artery stenosis. In comparison with MPI and SE, MDCT demonstrates superior ability to detect significant stenosis with ICA serving as the reference standard. Moreover, dating back to even early generation 4-slice scanners, MDCT has demonstrated exceedingly high negative predictive value (NPV) for excluding obstructive coronary artery stenosis. These two qualities have catapulted MDCT into routine clinical use for assessment of patients with chest symptoms.
However, the optimism for widespread clinical application of MDCT coronary angiography must be balanced by recognition of its current limitations. Due to still limited temporal and spatial resolution, the ability of MDCT to accurately detect coronary artery stenosis is impaired in patients with high or irregular heart rates and excessive calcified plaque. Thus, it remains necessary to identify patient populations in which MDCT may rival or exceed current non-invasive diagnostic strategies. One group of patients who may benefit most are those in whom other non-invasive modalities have been historically challenging, and where MDCT may afford such patients avoidance of an invasive procedure.
One such subset of patients studied is those with underlying complete left bundle branch block (LBBB). This group of individuals exhibits a poorer cardiac prognosis as LBBB is most commonly associated with coronary atherosclerosis. Furthermore, the evaluation of patients with LBBB by non-invasive imaging (e.g. MPI or SE) has been notoriously difficult. Ghostine et al. studied 66 consecutive patients admitted for ICA with underlying complete LBBB. These patients underwent coronary evaluation with 64-slice MDCT. MDCT appropriately diagnosed significant stenoses in 28 of 29 (97%) patients with significant stenosis, and 35 of 37 patients without significant stenosis (95%). The overall accuracy, sensitivity, specificity, positive predictive value (PPV) and NPV of 64-slice MDCT for the identification of significant CAD was 95%, 97%, 95%, 93% and 97%, respectively, on a per-patient basis. Results for per-segment basis were similarly good with values of 97%, 72%, 99%, 91%, and 97%, respectively. Bolstering the highly accurate per-patient results is the finding of high NPV for detection of significant coronary stenosis, a theme which has been present in virtually every coronary MDCT study. These exciting results demonstrate the capability of MDCT to identify patients with LBBB who may avoid invasive diagnostic procedures.
Another group of patients in whom MDCT coronary angiography may be useful are those undergoing cardiac surgery for reasons other than CAD. In the majority of these patients, non-invasive stress imaging or pre-operative coronary angiography is often performed prior to cardiac surgery to exclude the need for concomitant coronary artery bypass surgery. In this light, two recent studies have examined the role of MDCT coronary angiography in patients undergoing cardiac valve surgeries. Gilard et al. performed 16-slice MDCT in 55 patients undergoing ICA for pre-operative coronary assessment prior to aortic valve surgery. The sensitivity of MDCT to detect a significant stenosis was 100%, while specificity was 80%. The NPV to accurately exclude non-obstructive CAD was 100%. When stratified by coronary artery calcium (CAC) score, MDCT correctly excluded all patients without significant coronary artery stenosis, which allowed avoidance of ICA in 80%. In a similar study, Meijboom et al expanded upon these results with the use of 64-slice MDCT in a group of patients referred for a variety of cardiac valve surgeries. Of the 70 patients undergoing MDCT coronary angiography the sensitivity, specificity, and positive and negative predictive values were 100%, 92%, 82%, and 100%, respectively. As noted in the Gilard study, Meijboom et al. observed a deterioration in the per-segment sensitivity and specificity with increasing CAC scores (75% and 88%, respectively, for CAC >1,000 versus 100% and 98%, respectively, for CAC 11-400).
Nonetheless, the high NPV in both studies provides further evidence and underscores the unparalleled ability of MDCT to non-invasively identify patients without significant CAD. Further studies are necessary to examine other patient populations in which non-invasive imaging has historically experienced difficulty, including women and obese patients.
In addition to providing coronary artery information, retrospectively-gated MDCT angiography may also evaluate cardiac structure and function. Evaluation of left ventricular (LV) structure and function is critical for determination of cardiovascular prognosis as well as for determination of therapeutic options. Traditionally, 2-D echocardiography (2DE) has been the most widely used non-invasive modality for the assessment of LV ejection fraction (LVEF). Numerous potential limitations exist for current measures of LVEF by 2DE, including poor acoustic windows, indiscriminate endocardial border definition and geometric assumptions. Through retrospective ECG gating, MDCT has been employed in several studies for assessment of LV function.
Dewey et al performed a very careful study utilizing 16-slice MDCT in 88 consecutive patients with suspected coronary artery disease. MDCT assessment of LV function was compared with contrast biplane cineventriculography, echocardiography and CMR. In comparison with CMR, which was employed as the reference standard, MDCT was most correlative and was superior to estimations of EF by biplane ventriculography (±10.2% versus ±16.8%, p<0.001) and echocardiography (±11.0% versus ±21.2%, p<0.001). More variability existed with limits of agreement with biplane ventriculography for both end-diastolic and end-systolic volumes. Moreover, accurate identification of patients with myocardial segmental wall motion abnormalities as well as myocardial segmental wall motion abnormalities themselves was significantly higher for MDCT (84% and 95%, respectively) when compared with biplane ventriculography (63% and 90%, respectively) (p<0.002 and p<0.001, respectively). Lang and colleagues performed a similar study in a population without known CAD, comparing MDCT with CMR and realtime 3-D echocardiography (RT3DE) in 31 patients undergoing all imaging tests the same day. MDCT, performed on a 16-slice scanner, demonstrated high correlation to CMR (r2 >0.85) but with less variability than RT3DE.
An advantage of MDCT in the patient with suspected ventricular dysfunction may reside in its ability to simultaneously assess both left and right ventricles with great precision. A non-invasive modality that is accurate for quantification of function of both ventricles may be important in the understanding of a heart failure process as well as to aid in the decision analysis of treatment options. Kim et al. studied 20 patients undergoing both MDCT and first-pass radionuclide angiography for evaluation of right ventricular (RV) function. Reconstructing only two phases of the cardiac cycle representing end-systole and end-diastole, these investigators found high correlation between both methods (R=0.854, p=0.001). MDCT was useful for not only assessing function, but providing end-systolic and end-diastolic RV volumes and RV mass, features not possible with RNA. Moreover, MDCT is able to provide this RV information without compromising LV assessment, thus permitting evaluation of both ventricles in a single sitting.
These initial studies demonstrating the accurate assessment of ventricular function by retrospective ECG-gated cardiac MDCT provide potentially valuable prognostic information. Future studies examining the additive value of ventricular function consideration to coronary artery plaque identification will be useful to determine the precise prognostic value of MDCT coronary angiography.
Evaluation of Myocardium
In addition to coronary artery plaque identification and ventricular function assessment, other potential prognostic data identifiable by MDCT include MPI and myocardial viability. To date, the demonstration of potential myocardial viability has been primarily the domain of CMR and PET. Other modalities that have been employed include dobutamine SE and MPI. These results are pertinent to identify which regions of myocardium benefit from revascularization and which do not. Recently, Mahnken et al. studied the ability of cardiac MDCT for the assessment of myocardial viability. Utilizing 16-slice MDCT, they investigated 28 patients with reperfused myocardial infarction (MI), acquiring images 15 minutes following contrast-enhanced arterial phase imaging. These individuals also underwent standard delayed enhancement CMR within five days. Mean infarct size by MDCT and MRI was 33.3% and 31.2%, respectively (r=0.878), reflecting the similar pharmacokinetic properties shared by gadolinium and iodinated contrast. Paul et al. performed a similar study in 34 patients after reperfused MI. Delayed enhancement MDCT predicted enduring perfusion defects in the six-week follow-up period and correlation of resting infarct size to MPI reflected a sensitivity, specificity and accuracy of 93%, 100%, and 94%, respectively, per patient.
In addition to its ability to demonstrate absence or presence of myocardial viability, MDCT has also been evaluated for its potential to detect stress-induced myocardial perfusion changes. Lima and colleagues evaluated eight dogs with prepared left anterior descending artery stenosis with contrast-enhanced MDCT imaging after five minutes of adenosine infusion. Examining myocardial blood flow with microspheres, it was noted that stenosed territories of myocardium exhibited significantly lower Hounsfield unit density properties in comparison with non-stenosed myocardial regions (92.3 ± 39.5 HU versus 180.4 ± 41.9 HU, p<0.001). Moreover, a linear relationship was identified between the signal density ratio and myocardial blood flow in stenosed regions (R=0.98, p=0.001). These data provided the first demonstration of MDCT to allow for stress-induced MPI. In an ensuing preliminary investigation, this same group evaluated seven chest pain patients referred for conventional coronary angiography who also exhibited abnormal nuclear SPECT imaging. Sixty-four-detector row MDCT imaging after five minutes of adenosine infusion in these individuals revealed substantial hypoattenuation in myocardial territories exhibiting stress-induced perfusion deficits by MPI (64 ± 26.9 versus 124.6 ± 25.7, p<0.001).
These animal and human studies demonstrate the feasibility with which MDCT may concomitantly assess coronary artery anatomy while providing valuable rest and stress myocardial perfusion data. These early data provide optimism that MDCT may be utilized as a 'one-stop shop' evaluation for CHD, permitting non-invasive coronary angiography, rest and stress perfusion myocardial imaging and assessment of myocardial viability, all in a single setting.
Risk Stratification and Prognosis
That MDCT is able to provide such diverse data in a single test is exciting. However, once this CT data is interpreted, it remains largely unknown whether they provide incremental prognostic value above traditional risk factors or other non-invasive modalities for determining whether a particular individual is at increased or decreased risk of future adverse outcomes.These data are only now beginning to emerge.
One contemporary study attempted to determine whether MDCT could successfully identify strata of risk in 103 consecutive patients who presented with acute chest pain to the emergency department. The ability to stratify risk by MDCT in this particular group of patients is exceptionally important as standard acute coronary syndrome work-up still fails to identify a significant minority of patients with MI. Hoffman et al. utilized a blinded expert panel that was responsible for adjudicating absence or presence of ACS. In these patients, who all underwent MDCT coronary angiography, the extent of plaque detected by MDCT improved prediction of ACS, adding incremental value to models that utilized only cardiovascular risk factors or clinical estimates of probability.
Although this initial study illustrates the feasibility of performing MDCT in chest pain patients in the ED, longer term outcomes studies are necessary. In this light, Shaw et al. examined the ability of MDCT coronary angiography to predict future adverse events in an intermediate-term follow-up in a prospective analysis of 1,138 patients taken from outpatient clinics, in-patient wards, and the emergency department who underwent MDCT. In this study, the authors utilized a modified Duke prognostic index, which graded coronary artery plaque by severity as well as location. Patients undergoing MDCT coronary angiography were noted to have stepwise poorer prognosis with worsening Duke prognostic index scores. For example, patients with two moderate stenoses or one severe stenosis exhibited 96% survival at 1.5-year follow-up, compared with 85% survival in patients with moderate or severe stenosis of the left main artery (p<0.0001).
Shaw and colleagues further analyzed this data in a comparative analysis of MDCT patients to a matched cohort of 7,849 patients undergoing MPI. The annual mortality for the MDCT group (1.16%) was similar to the annual mortality for the MPI group (1.13%). Moreover, stepwise higher Duke prognostic index scores by MDCT paralleled percent ischemic myocardium by MPI with respect to prediction of overall mortality risk. These early findings are the first to demonstrate the prognostic value of MDCT coronary angiography for the prediction of death by all causes. These data also suggest that the prognostic ability of MDCT may be similar to that of MPI.
The recent introduction of high-detector row CT scanners has stimulated great interest in the clinical use of MDCT coronary angiography. Numerous studies have already demonstrated the high sensitivity and specificity of MDCT for the detection of obstructive coronary artery stenosis. Early studies are emerging that examine the suitability of specific patient populations for MDCT, the reliability and accuracy of MDCT for the assessment of ventricular function and perfusion, and the ability of MDCT to risk stratify and predict clinical outcome. Future studies examining more diverse populations and end-points are necessary in this early stage of the field for better delineation of which patient populations derive greatest benefit from evaluation by MDCT coronary angiography and how to use the MDCT information to best guide patient therapy.