Author + information
- James A. Goldstein, MD∗ ()
- ↵∗Address for correspondence:
Dr. James A. Goldstein, Department of Cardiovascular Medicine, Beaumont Health System, 3601 West Thirteen Mile Road, Royal Oak, Michigan 48073.
- acute coronary syndrome
- clinical outcome
- coronary artery disease
- coronary computed tomography angiography
Despite advances in medical and revascularization therapies, complications of coronary artery disease (CAD) are still the number 1 cause of mortality in the Western World. Catastrophic acute ST-segment elevation myocardial infarction and sudden coronary death constitute persistent societal scourges that beg for novel approaches for detection and prevention. The concept of the “vulnerable plaque” (VP) is based on the hypothesis that a prospectively identifiable precursor lesion evolves into the culprit responsible for acute coronary syndromes (ACS). The implicit hope is that pacification of such lesions by novel medical therapies and/or pre-emptive focal stenting can reduce adverse events.
The Chang et al. (1) study of computed tomographic angiography (CTA) in this issue of the Journal should be congratulated for important observations that support and further the promise of noninvasive identification of patients and plaques “at risk.” This nested case-control study of 234 pairs of ACS and control patients (derived from a cohort of 25,251 cases undergoing CTA) assessed the association between baseline plaque characteristics and subsequent ACS events over 3 years. Lesion parameters analyzed focused on “high-risk plaque” (HRP) (≥2 features, including positive remodeling, low-attenuation plaque [LAP], and spotty calcification), together with plaque burden and composition. Key findings on a per-patient basis showed: 1) at baseline, one-half of ACS patients had HRPs (more frequent than control subjects), and the presence of such lesions was associated with subsequent ACS; and 2) lesion characteristics, including HRP, plaque burden, and burden composition, identified high-risk patients above and beyond stenosis severity and aggregate plaque burden. Analysis on a per-lesion basis showed that 75% of ACS culprit lesion precursors at baseline exhibited <50% stenosis. However, only 31% of culprit precursors exhibited HRP features. These findings have potential implications for characterizing at-risk patients who may benefit from systemic therapeutics designed to stabilize the atherosclerotic coronary vasculature, but they provide lesser evidence to support prospective identification of HRPs that might benefit from pre-emptive focal stenting.
Proving the VP Hypothesis: Satisfying Koch’s Postulates
Robert Koch (1843 to 1910) propounded a series of 4 generalized principles linking specific micro-organisms to specific diseases, a paradigm for proof of disease causation. Conversely, to validate the VP hypothesis, the following must be established: 1) definable VP characteristics (morphology and composition) delineated by an imaging “snapshot in time” are associated with a prevalence of focally linked ACS events sufficient to warrant interventions beyond aspirin and statins; and 2) novel systemic medical therapies and/or preemptive stenting can reduce adverse outcomes.
Portrait of the VP
The proximate cause of most ACS cases is rupture of a lipid-rich necrotic core plaque with inflamed disrupted fibrous cap and superimposed thrombus. Direct coronary imaging and histopathological studies characterize the putative precursor VP as a thin-capped fibroatheroma, with larger lipid-necrotic core plaque volume and reduced lumen imparting a greater risk of future instability (2). However, a paucity of natural history data has relegated such VPs to a status of “indicted but not yet convicted” (James Muller, personal communication, June 2013).
CTA: Identification of At-Risk Patients
The value of CTA can be considered from 3 basic perspectives: detection of patients with CAD, identification of at-risk patients, and delineation of VP. Extensive studies validate computed tomographic coronary calcium scoring alone as a marker of atherosclerosis and establish the relationship of elevated scores with increased risk of adverse outcomes. Prior studies have shown that CTA provides incremental benefit in risk stratification and prediction of events in those with diabetes. Focal CTA plaque characterization adds further prognostic value. The present findings are consonant with prior CTA observations (3) demonstrating that patients harboring “2-feature positive” plaque (LAP and positive remodeling) are at greater risk of adverse events over time (3). CTA delineates additional HRP morphological features, including “napkin ring” enhancement, a lesion with a discrete pocket of very LAP (presumably reflecting lipid-necrotic core), which may add further pathophysiological insight and prognostic value (4).
Can CTA Identify VPs?
The interventionist’s quest for VP is based on the concept that a precursor lesion can be prospectively identified and adverse events can be prevented by pre-emptive stenting. In the present study, only one-third of ACS culprit lesions exhibited baseline HRP features, and not all baseline HRPs evolved to induce ACS. The present CTA observations thus support the concept that the presence of high-risk lesion morphology and composition are predictive of ACS events, but more powerfully identify patients at risk than necessarily target specific lesions at risk. In aggregate, neither the present nor past data yet provide sufficient evidence over time of CTA-delineated HRPs as reliably predictable precursors of focal subsequent ACS culprit lesions.
Plaque Instability: “A Riddle Wrapped in a Mystery Inside an Enigma”
Winston Churchill’s quote (5) describing the Soviet Union in 1939 aptly characterizes the conundrum of conquering ACS. Despite intense investigation over several decades, fundamental gaps in our understanding of the pathophysiology of plaque instability remain. Atherosclerosis is a chronic indolent disease punctuated by clinically acute flares. Frustratingly, the precise inciting and causative factors that trigger the transition from stable atherosclerosis to unstable plaques have remained elusive. Further, pertinent to considerations of whether imaging modalities can detect VP leading to pre-emptive therapeutics, we have little insight into the true pathophysiological time course of plaque instability. That is, an ACS event in which thrombus forms on a lipid-laden inflamed frankly disrupted lesion is the abrupt and dramatic clinical expression of plaque instability, but likely represents the end stage rather than the beginning of plaque instability. Based on available evidence, it is likely that in many cases, plaque destabilization smolders over a subacute temporal course until it spontaneously “heals” and becomes quiescent or erupts into a frank disruptive event, such as erosion, rupture, or intraplaque hemorrhage; only some of these events are clinically manifest, whereas others are “beneath the clinical radar.”
CTA Delineation of Plaque Instability
Recent studies (6,7) document that CTA can delineate features indicative of both overt (frank ulceration) and subtle (intraplaque dye penetration) plaque disruptions, in some cases presaging subsequent abrupt plaque instability (Figure 1). Such CTA evidence of plaque instability has been detected not only in ACS cases, but also in clinically stable patients, consistent with the concept that stable or even asymptomatic patients may experience episodes of silent plaque rupture and intraplaque hemorrhage. Whether these additional plaque features may add predictive value for general and focal risk requires further study.
Implications for CTA Screening and Monitoring
CTA powerfully documents the presence and quantifies the burden of coronary atherosclerosis. Accumulating evidence supports the notion that plaque characterization identifies patients at risk. These attributes may bring value to various patient populations. But, will CTA constitute a realistic screening or monitoring strategy to detect VP? I am both hopeful and doubtful. As a moment’s “snapshot in time,” imaging (CTA or invasive direct coronary imaging) typically documents a multitude of plaques, only some of which exhibit HRP features, and not all such induce ACS; further, many ACS culprits do not exhibit HRP features at a prior moment in time. Further problematic is that given the chronic nature of atherosclerosis, sequential imaging over time would be necessary to detect plaque transitions from stable to VP, and even regular intervals may never sufficiently provide for this purpose; thus, as a monitoring strategy, CTA seems unrealistic (futile). Regardless, in those cases in which CTA does document HRPs, further natural history studies will be necessary to satisfy Koch’s postulates to convict such lesions as VPs, let alone justify pre-emptive stenting of such putative culprit precursors.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Goldstein has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
- Chang H.-J.,
- Lin F.Y.,
- Lee S.-E.,
- et al.
- Motoyama S.,
- Ito H.,
- Sarai M.,
- et al.
- Otsuka K.,
- Fukuda S.,
- Tanaka A.
- Churchill W.
- Corresponding Author
- Proving the VP Hypothesis: Satisfying Koch’s Postulates
- Portrait of the VP
- CTA: Identification of At-Risk Patients
- Can CTA Identify VPs?
- Plaque Instability: “A Riddle Wrapped in a Mystery Inside an Enigma”
- CTA Delineation of Plaque Instability
- Implications for CTA Screening and Monitoring