Technique
Imaging benefit
Intravascular ultrasound (IVUS)
Quantify plaque burden, identify positive remodeling, calculate area stenosis, calcification
IVUS + virtual histology
Better define plaque characteristics; identify pathological intimal thickening, thick and thin capped fibroatheromas, degree of calcification
Optical coherence tomography (OCT)
Quantify fibrous cap thickness, identify plaque rupture, erosion, calcification
Infrared spectroscopy (LipiScan)
Quantify plaque lipid content
CT coronary angiography
Identify low attenuation plaques, determine presence of positive remodeling, identify ruptured plaque, punctate calfication
The first study to attempt to define invasively the natural history of vulnerable plaque was the landmark PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial [10]. Patients undergoing percutaneous intervention for an acute coronary syndrome were evaluated. After all culprit and other severe lesions were intervened upon, based on the decision of the angiographer, the remaining non culprit arteries were evaluated with angiography, intravascular ultrasound and virtual histology. Patients were followed for 3 years and those with another event- either a myocardial infarction, need for another angiogram because of increasing or unstable angina or aborted sudden death were restudied to assess the cause (culprit lesion) for the syndrome. At 3 years follow up, 23 % had an event and this was nearly equally distributed between the prior culprit lesion/lesions that had been intervened upon or a different lesion in a non culprit vessel. While Stone et al. found that the presence of a TCFA identified by VH technology, with a large plaque burden on IVUS (>70 %) and a plaque area <4 mm2 had an 18 % incidence of a non culprit event at 3 years, there were only 6 non culprit myocardial infarctions and no documented sudden deaths at follow up. Most non culprit events were increasing or unstable angina. Furthermore, identification of a TCFA was a non specific finding as there were nearly 600 TCFA’s at baseline but so few acute events at follow up.
Thus, more date on plaques responsible for subsequent acute events are required. We still do not know the natural history of presumed vulnerable plaques and a plaque that looks vulnerable on an initial evaluation may change at some later point and appear stabilized [11]. Additional studies are required if the local approach to reducing subsequent acute events will become a viable option. There are additional studies, some on-going that are trying to address the natural history question. Utilizing IVUS, angiography and infrared spectroscopy to identify lipid core, PROSPECT 2 (Prospective natural history of coronary atherosclerosis – NCT02171065). will try to further characterize this plaque. Furthermore, a subset with lipid-rich plaques will be randomized to a bio-absorbable stent and optimal medical therapy versus optimal medical therapy alone to test whether this local approach can reduce subsequent events on follow up.
One concern with an invasive methodology is the fact that all of the detectors are concentrating on finding the responsible TCFA and not considering plaque erosion which is not an infrequent cause of STEMI, NSTEMI or SCD. Several studies have suggested that acute myocardial infarctions secondary to plaque erosion may constitute more than 30 % of all acute coronary syndromes [12, 13]. Furthermore, if the detector is invasive, what about individuals in whom the first presentation of symptomatic coronary disease is AMI or SCD. In the Framingham study, 53 % of men and 36 % of women respectively, presented with either AMI or SCD [14]. While a non invasive detector of a vulnerable plaque would be preferable to an invasive detector, there is no consensus, at present, as to the appropriate technique/s and additional prospectively evaluation is required.
The Vulnerable or High Risk Patient
While there are established therapies to reduce subsequent events for patients with known cardiovascular disease manifestations or coronary disease equivalents, can one identify the vulnerable or high risk patient particularly in primary prevention? This is the most difficult challenge to prevent the initial acute event. Nearly half of all patients who die from cardiovascular disease will do so as a result of sudden cardiac death, and this is often the initial presenting symptom of coronary artery disease [15]. Table 3.2 lists common tools used to assess patient risk.
Table 3.2
Common tools for estimating patient risk of atherosclerotic cardiovascular disease
Traditional scoring systems | Imaging techniques |
Pooled Cohort Risk Equation | Magnetic Resonance Imaging Coronary Angiography (MRA) |
Framingham Risk Core | Positron Emesion Tomography/Computed Tomography (PET-CT, SPECT) |
European Society Risk Score | Coronary calcium scoring |
PROCAM Study Risk Score | Molecular Imaging |
Reynolds Risk Score | Ankle brachial index (ABI) |
Carotid intimal medial thickness | |
Iliac-femoral imaging | |
Non-traditional markers of CV risk | Biomarkers |
Left ventricular Hypertrophy | High sensitivity C-reactive protein (hsCRP) |
Triglycerides | Homosystine |
Small dense Low density lipoprotein (LDL) | Fibrinogen |
Apo-lipoprotein B | Lipoprotein associated phospholipas A2 (LP-PLA2) |
Microalbuminuria | Myeloperoxidase |
Abdominal obesity | Oxidized LDL |
Physical inactivity | Fractalkine |
Poor socioeconomic status (QRISK, ASSIGN) | CD36 |
Erectile dysfunction | |
Physiologic assessment of atherosclerosis | Genetic markers |
Stress testing | Single nucleotide polymorphism (Microarray) |
Endothelial dysfunction techniques | |
Arterial compliance |
In an effort to better characterize and treat these lower risk populations that might be at risk for AMI or SCD (most events not in the high risk population by Framingham), the new cholesterol guidelines have broadened their recommendations for statin therapy to include individuals 40–75 years of age with a 10 years risk of ≥7.5 % [16]. Other markers of atherosclerosis have been studied to enhance risk prediction. These include calcium scoring, carotid intima-medial thickness measurements, hsCRP and several others. On-going studies such as the High Risk Plaque initiative and the Progression and Early detection of Subclinical Atherosclerosis (PESA) study are assessing the additive benefit of some of these non invasive imaging markers above standard risk factors in predicting first adverse cardiac events [17, 18].
Serum markers of inflammation have been predictive of plaque vulnerability in multiple studies. Paul Ridker and collegues have demonstrated that high sensitivity CRP is predictive of the development of cardiovascular events, and that the use of potent statins in patients with elevated hsCRP reduces the incidence of cardiac events [19, 20]. The JUPITER study randomized 17,802 low to medium risk patients with normal levels of LDL cholesterol and an elevated HsCRP to either 20 mg of rosuvastatin or placebo. The group receiving statin therapy had a 53 % relative risk reduction in the composite endpoint of myocardial infarction, stroke, or cardiovascular death. However, the event rates at follow up were low. Several other potential markers of plaque vulnerability including lipoprotein phospholipase A2, osteoglycan and NGAL/MMP9 have also demonstrated the ability to predict some coronary events but have yet to be demonstrated to be effective reducing cardiovascular events in primary prevention trials [21, 22].
The High-Risk Plaque Initiative as previously mentioned, is an ongoing research and development effort designed to evaluate the role of a variety of biomarkers and advanced imaging techniques in providing a more accurate assessment of cardiovascular risk [17]. This ambitious effort should shed some light regarding the role of genetic analysis, coronary calcium scoring, ankle-brachial index, carotid intimal thickness, iliofemoral ultrasound and other emerging technologies on estimating the risk of silent atherosclerotic cardiovascular disease. The 2013 ACC/AHA joint guidelines on the assessment of cardiovascular risk suggest that all patients be screened for traditional atherosclerotic cardiovascular disease risk factors every 4–6 years in adults 20–79 years of age and to estimate a 10 years risk of an acute event [23]. The ACC/AHA has also endorsed a race and sex specific pooled cohort equation which was derived from the Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults (CARDIA) Study, and the original Framingham study as well as its offspring cohorts. These studies are well validated to provide a reasonable assessment of both 10 year and lifetime risk of ASCVD in non-hispanic whites and African Americans. In addition, the guidelines suggest that the same Pooled Cohort Equation may be used in populations other than non-hispanic African Americans and whites. Table 3.3 lists the properties of this risk stratification tool. When compared to the more traditional method of utilizing the Framingham data base to estimate risk, the Pooled Cohort Equations tend to encourage broader use of risk factor modification, particularly in terms of statin use, as mentioned previously. The guidelines go on to suggest that if, after undergoing risk assessment using the Pooled Cohort Equation, a therapeutic decision hasn’t been reached then it is reasonable to utilize either a hs CRP level, coronary artery calcium score, or ankle-brachial index for treatment making decisions. Citing the lack of outcomes data, the ACC/AHA joint guideline committee currently recommends against the use of carotid intima medial thickness, apolipoprotein B, albuminuria and cardiorespiratory fitness as part of a risk assessment for atherosclerotic cardiovascular disease [23].
Table 3.3
Components of the ACC/AHA pooled cohort equation
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