Risk Stratification for CV Disease Gets Personal
Stratifying cardiac disease risk is evolving along with the advancements in imaging technology, which help risk stratification become more highly individualized, taking us further toward personalized medicine.

PET imaging

Dedicated cardiac PET scanners, through improved hardware and software, enable faster imaging and higher resolution compared with conventional SPECT imaging. While cardiac PET was typically confined to those patients who could not be optimally scanned with SPECT, it is now securing its place in cardiology as a valuable tool in the fight against heart disease.

An important advance in the last several years has been demonstrating the ability to measure myocardial blood flow reserve with rubidium-82 (Rb-82) PET, which "increases PET's capability to identify patients at risk for developing cardiac events," says Daniel S. Berman, director of cardiac imaging at Cedars-Sinai Heart Institute in Los Angeles. Cardiac PET excels at identifying perfusion defects, particularly in specific patient populations that might be suboptimally imaged with SPECT. But rather than comparing one region of the heart with another, as with SPECT, measuring absolute blood flow reserve allows each region to be compared to itself and to determine how much blood flow can increase in that region in a given vessel.

Myocardial blood flow with 13N-ammonia and 15O-water as PET flow tracers has been validated. For example, Herzog et al found that myocardial blood flow reserve measured by 13N-ammonia added prognostic predictive value over perfusion findings alone (J Am Coll Cardiol 2009;54;150-156). In fact, an abnormal coronary flow reserve in patients with normal perfusion "allowed further discrimination of patients with high annual event rates from those with low annual event rates."

Herzog et al concluded that coronary flow reserve is a strong predictor of disease progression once disease is present. "This may be due to the fact that impaired coronary flow reserve may indicate extension of the disease beyond the epicardial coronary arteries down to the microcirculation, representing a more advanced disease stage that is, thus, more prone to deterioration."

However, both 13N-ammonia and 15O-water require an onsite cyclotron and have short physical half-lives (10 and two minutes, respectively). Rb-82 does not rely on a cyclotron and already is commonly used to assess perfusion.

El Fakhri et al determined that myocardial blood flow reserve measurement using Rb-82 was accurate and reproducible, with a good intra- and interobserver reliability, compared with 13N-ammonia (J Nucl Med 2009;50:1062-1071).

In another study, Anagnostopoulos et al found that the myocardial blood flow and coronary vasodilator reserve as measured by Rb-82 were inversely and non-linearly correlated to stenosis severity (Eur J Nucl Med Mol Imaging 2008;35:1593–1601). They concluded, "Quantitative Rb-82 PET can be a clinically useful tool for an accurate functional assessment of CAD [coronary artery disease]."

Imaging inflammation

Inflammation is known to play an important role in atherosclerosis and researchers are seeking ways to better use FDG-PET to stratify patients with greater risk as determined by their inflammation as shown by uptake of FDG.  

Rogers et al found that FDG accumulation was increased in patients with recent acute coronary syndromes, both within the culprit lesion as well as in the ascending aorta and left main coronary artery (J Am Coll Cardiol Img 2010;3:388-397). Their finding, they concluded, "suggests inflammatory activity within atherosclerotic plaques in acute coronary syndromes and supports intensification of efforts to refine PET methods for molecular imaging of coronary plaques."

Yoo et al used FDG-PET imaging to assess whether seemingly healthy individuals have inflammation as measured by FDG uptake (J Nucl Med 2011;52:10-17). Researchers noted that 40 percent of deaths from cardiovascular disease occur in patients with low cholesterol levels. Subjects were stratified by levels of high-sensitivity C-reactive protein (hsCRP), a marker for inflammation, and low-density lipoprotein cholesterol (LDL-C). They found that high levels of FDG uptake in the carotid arteries were associated with higher levels of hsCRP, despite any level of LDL-C.

Previously, Yoo and colleagues showed that patients with impaired glucose tolerance or type 2 diabetes had higher uptake of FDG-PET, representing inflammation, compared with healthy subjects, again as measured in the carotid arteries (Circulation Cardiov Img 2010;3:142-148). In addition, patients with metabolic syndrome had increased FDG uptake compared with those without metabolic syndrome.

This type of research speaks to the desire for clinicians to apply a more individualized risk stratification test to their patients, rather than population-based risk strategies such as the Framingham risk score.

Biomarker debate

Transverse, coronal and sagittal slices (left) as well as short-axis, long vertical-axis and horizontal-axis images (top right) and polar maps of Rb-82 PET. Source: J Nucl Med 2009; 50:1062–1071. 
Biomarker screening is typically performed in low- and intermediate-risk patients and has revolved around when to start statin therapy, but there may be more to it, says James A. de Lemos, MD, director of the coronary care unit at Parkland Memorial Hospital in Dallas. "Part of the personalized medicine approach is not just to identify who is at risk of heart disease, but also to look at different tests that predict different forms of heart disease. To date, we've focused only on predicting CAD and MI, which is absolutely critical, but the epidemic now is heart failure, due to either thickening or weakening of heart muscle, and it is likely there will be different sets of factors that predict these complications," he says.

De Lemos and colleagues used a highly sensitive assay to detect minute levels of troponin T, undetectable with the conventional assay, in patients enrolled in the Dallas Heart Study (JAMA 2010;304:2503-2512). Higher levels of the biomarker—that would not normally be found—correlated with the prevalence of hypertension, diabetes, left ventricular (LV) mass, LV wall thickness and the proportion of individuals classified as having LV hypertrophy. Self-reported heart failure, CAD and cardiovascular disease were more frequent with higher levels of troponin.

The median follow up of the more than 6,000 patients was six years and troponin levels remained independently associated with all-cause mortality. De Lemos sees this marker as an opportunity to detect subclinical disease and intervene early or to stratify those already at high risk for more targeted therapy.

Regarding conventional biomarkers such as the Framingham risk score and CRP to stratify CAD risk, De Lemos says they are imperfect, but cautions that newer candidates such as lipoprotein-associated phospholipase A2 must be rigorously tested before adopted into clinical practice.

SPECT & patient subgroups

Precisely defining short- and long-term cardiac risk is pivotal for guiding therapy in individual patients. SPECT myocardial perfusion imaging (MPI) has been shown to be an important method to risk stratify patients for CAD, and it has proved beneficial in a variety of patient subgroups.

For example, Al-Mallah et al evaluated more than 7,000 patients to better understand the link between kidney function and SPECT MPI results. Patients with a mean age of 64 years were followed for a mean of 2.6 years (Circ Cardiovasc Img 2009;2:429-36). Researchers found that the risk of death increased with worsening kidney function; however, at each stage of impaired renal function, patients with abnormal SPECT MPI had a significantly increased hazard of adverse events. In addition, the magnitude of the total perfusion deficit and ischemia on MPI was associated with worse outcomes.

"For any degree of ischemia, the worse the renal failure was, the worse the cardiac event rate was," says Berman. "The low-and high-risk groups, based on abnormal nuclear scans, were greatly separated in terms of their risk as the renal dysfunction progressed."

Berman notes that this patient population is not well suited for imaging with contrast-enhanced CT, given the propensity for dense calcification and the risk of kidney injury associated with iodinated contrast medium. Therefore, the use of nuclear imaging not only leads to improved risk stratification, compared with CT, but it also reduces the chance of acquiring suboptimal images and of inducing renal complications.

In another study, Hachamovitch et al followed 5,200 elderly patients (75 years or greater) for a median of 2.8 years who underwent either pharmacological or exercise stress imaging (Circulation 2009;120:2197-206) to determine SPECT's prognostic discrimination. They noted that CAD in the elderly frequently presents with silent ischemia, atypical symptoms or nonspecific functional status deterioration, making it challenging to identify those at risk.

They found that both reversible and fixed defects on MPI were associated with cardiac death, and that ejection fraction and perfusion data added incrementally to each other, "further enhancing risk stratification." They also noted that increasing ischemia was associated with increasing survival with early revascularization, whereas in the setting of little or no ischemia, medical therapy had improved outcomes.

Finally, Hachamovitch et al found that even in the elderly, risk increased "dramatically with increasing age and other clinical factors, thus marking these cohorts as heterogeneous and necessitating examination of multiple patient subsets to understand prognostic test performance."

Calcium scoring

While an abnormal SPECT scan is prognostic for cardiac events, a normal SPECT scan is not necessarily an indication of the absence of disease. Chang et al found that as the coronary artery calcium (CAC) score, as measured by noncontrast CT, increased in asymptomatic people with normal perfusion scans, the risk of having a cardiac event also increased significantly, especially in those with severe CAC scores—greater than 400 (J Am Coll Cardiol 2009;54;1872-1882).

Researchers, who followed more than 1,100 patients for a median of 6.9 years, found that approximately half of the 977 patients with a normal SPECT had a CAC score of at least moderate severity, signaling cardiac risk that would not otherwise have been predicted. In addition, an abnormal SPECT result increased with increasing CAC score, from less than 1 percent (CAC score less than 10) to 29 percent (CAC score greater than 400).

"The premise is not just to identify high-risk people with normal SPECT studies; it's also to identify people with early disease so we can intervene and prevent cardiac events," says senior author John J. Mahmarian, MD, chief of the division of nuclear cardiology and CT Services at the Methodist DeBakey Heart and Vascular Center in Houston. "At this point, however, it is more speculation rather than a proven concept."

There are supportive data, however, mostly from intravascular ultrasound (IVUS) studies that lipid-lowering therapy can reduce noncalcified, or vulnerable, plaque burden. "If someone has evidence of calcification, he or she most likely has five-times as much noncalcified plaque, which is more prone to rupture and cause an occlusion," Mahmarian says.

Interestingly, Inoue et el used serial coronary CT angiography (CCTA) imaging to demonstrate noncalcified plaque regression in a small cohort of statin-treated patients (J Am Coll Cardiol Img 2010;3:691-698). They said the technique could be used for clinical trials designed to assess plaque progression and regression. In fact, Voros et al recently initiated the AFRICA (Atorvastatin plus Fenofibric acid in the Reduction of Intermediate Coronary Atherosclerosis) trial, a single-center, prospective, double-blind, randomized, placebo-controlled study intending to enroll nearly 400 patients (J Cardiovas CT 2010;4,164-172).

While IVUS has been the standard of care to measure plaque morphology, it is not appropriate in the primary prevention setting, said Voros and colleagues. "Therefore, the validation of CT as a noninvasive tool to potentially characterize plaque progression in primary prevention patients is an important aspect of this trial."

Cardiac CTA

While there have been many declamations about overutilization of diagnostic medical imaging, in general, imaging is suboptimally utilized for risk stratification, says Udo Hoffmann, MD, MPH, director of the cardiac MR, CT, and PET program at Massachusetts General Hospital in Boston. In a recent study, researchers combed the CathPCI Registry of the National Cardiovascular Data Registry (NCDR), to determine the diagnostic yield for invasive catheter angiograms. They found that more than half of all referrals to the cath lab had no significant CAD (N Engl J Med 2010; 362:886-895).

Hoffmann says these results provide a gateway for the use of CCTA to improve patient management. "CCTA has a very high negative predictive value for ruling out stenosis; it also can detect noncalcified plaque, which further helps to stratify risk; and radiation exposure for the exam can be as low as 1 to 3 mSv."

The National Institutes of Health recently initiated the PROMISE trial, which will compare anatomic (CT) and functional testing (stress echo, nuclear and/or exercise treadmill) results to understand the value they bring to patient care. "This type of comparative-effectiveness research is rarely done in medical imaging," Hoffmann says. Researchers hope to enroll 10,000 low- to intermediate-risk patients who present to the ED and analyze results for health and economic outcomes.

The debate on the various ways to better stratify cardiac risk will continue, and rightly so. Researchers are increasingly focused on ways to make risk stratification more personal. CAC scoring is evolving into a highly effective means to personalize risk, while advances in SPECT, PET and CT will carry into the next era of improved risk stratification.