Author + information
- Published online October 2, 2017.
- Michael Joner, MD∗ ( and )
- Erion Xhepa, MD
- Deutsches Herzzentrum München und Deutsches Zentrum für Herzkreislaufforschung e.V., München, Germany
- ↵∗Address for correspondence:
Dr. Michael Joner, Deutsches Herzzentrum München, Lazarettstrasse 36, 80636 München, Germany.
At the inception of interventional cardiology, understanding of the progression of atherosclerosis in diseased coronary arteries was identified as an important knowledge gap and subsequently considered a research topic of fundamental relevance for the entire medical community. Even today, dedicated clinical studies addressing the fate of atherosclerotic coronary plaque remain scarce, mostly because longitudinal observational cohort studies using intravascular imaging modalities to detect and characterize atherosclerotic plaque entail significant regulatory, ethical, and scientific hurdles, making clinical judgment, analysis, and interpretation of study results cumbersome and ineffective. In the largest study to date, the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial, a total of 697 patients presenting with acute coronary syndromes underwent 3-vessel coronary angiography and grayscale and radiofrequency intravascular ultrasound (IVUS) after percutaneous coronary intervention (1). Over a median of 3.4 years of follow-up, the cumulative rate of major cardiovascular events was 20.4%, with 12.9% of patients experiencing events related to culprit lesions and 11.6% experiencing events related to nonculprit lesions. Although most nonculprit lesions showed mild angiographic stenosis at baseline, multivariate analysis revealed that the presence of large plaque burden (>70%), a minimal luminal area of <4.0 mm2, and the presence of thin-cap fibroatheroma were significant predictors of future events. In this regard, the PROSPECT trial significantly enhanced our knowledge related to plaque progression over time in patients presenting with acute coronary syndromes. Yet the study at the same time was hampered by an unexpected low overall event rate, especially in those patients already identified at high risk by intravascular imaging (plaque burden >70%, luminal area <4.0 mm2, presence of thin-cap fibroatheroma). It was therefore concluded that despite their risk-stratifying nature, these parameters might be limited in the prediction of plaque progression on an individual patient level. In a very interesting substudy of the PROSPECT trial, the investigators examined the prevalence, distribution, and outcomes of patients exhibiting nodular calcification and reported that patients with nodular calcification were significantly older and presented with greater overall plaque volume but fewer vulnerable plaque features compared with patients without nodular calcification (2). Most strikingly, patients with presence of nodular calcification also had fewer nonculprit events compared with the rest of the patients, suggesting quiescence of plaque vulnerability emanating from vascular calcification.
In this issue of iJACC, Zeng et al. (3) report the findings of an interesting prospective intravascular imaging study focusing on the progression of calcification in stented and nonstented coronary segments of patients enrolled in the Absorb bioresorbable vascular scaffold B1/B2 cohort, comprising a total of 28 patients (29 lesions) with consecutive IVUS and optical coherence tomography (OCT) imaging assessment up to 5 years. Matching of imaging modalities was performed on a cross sectional level at each time point and, subsequently, longitudinally between 2 time points of consecutive follow-up. Three tissue components were identified on the basis of consensus of 5 analysts: fibrous, fibrocalcific, and lipid pool (defined as either lipid pool or necrotic core). The baseline OCT-derived tissue precursor of calcification at follow-up was defined as the tissue component constituting approximately 50% of the topographically matched calcified area. To improve the accuracy of diagnostic plaque imaging, off-line fusion of coregistered IVUS (grayscale IVUS, IVUS echogenicity) and OCT images was performed using commercially available software. A total of 72 cross sections of each of the 3 imaging modalities were matched and fused to characterize lesion progression over time in stented versus nonstented coronary segments. Calcification was absent in 41.8% (33 cross sections) of these coregistered frames at follow-up, while 58.2% (39 cross sections) showed presence of calcification (total of 46 calcified plaques). Twenty-two of these calcified plaques were absent at baseline, while 24 showed progression between baseline and follow-up imaging. The precursor tissue of calcification by OCT was identified as lipid pool (n = 33 [71.2%]), fibrous plaque (n = 2 [4.3%]), and fibrocalcific tissue (n = 11 [23.9%]). In addition, the investigators report a significantly greater increase in neointimal thickness in stented vascular segments compared with nonstented segments over time (Δ = 180 ± 152 μm vs. Δ = 16 ± 116 μm; p = 0.034). The investigators conclude that their findings prove the case for fusion imaging in the assessment of vascular calcification over time, in both stented and nonstented segments. Furthermore, they suggest that calcification progresses to a similar extent in stented and nonstented vascular segments. Third, they propose a shielding effect of bioresorbable vascular scaffolds with regard to protective neointimal growth above calcified vessel areas, and they suggest lipid pool and necrotic core to be the most important precursor tissue for the progression of calcification.
With respect to the key findings of this study, the investigators must be congratulated for advancing our understanding of lesion progression in the field of vascular calcification. The similar progress in calcification between stented and nonstented vascular segments observed by the investigators can, however, be differentially interpreted, resulting in nearly opposing conclusions. On one hand, vascular calcification has been proposed by the investigators to represent a final stage of atherosclerosis, at which the risk for future cardiovascular events may be decreased because of the passivating nature of calcification with regard to plaque vulnerability (4). This conclusion is supported by the significant finding of tissue precursors of calcification represented by lipid pool and/or necrotic core in the majority of cases, which deserves emphasis because it relates to an ongoing debate about progression of atherosclerosis from vulnerable to quiescent phenotypes and has been elegantly investigated by the investigators. Thin-cap fibroatheroma may either progress to plaque rupture, which has been suggested in several post-mortem autopsy studies (5,6), or regress to exhibit increased thickness of the fibrous cap (i.e., thick-cap fibroatheroma) along with calcification of necrotic core (Figure 1). In this regard, the same finding could also be interpreted with concern because incremental calcification over time has also been associated with increased overall plaque burden and mortality (7). Because the investigators focused only on calcified tissue areas over time, other tissue components, such as pathological intimal thickening and fibroatheroma, may also have progressed and developed vulnerable plaque features, causing future events. At the least, it may be concluded that bioresorbable vascular scaffolds neither accelerate nor offer protection against vascular calcification, an effect of unclear clinical impact that deserves further investigation in future trials.
Another important effect of bioresorbable scaffolds observed during consecutive follow-up in the present study is the increased neointimal thickness in stented relative to nonstented proximal and distal vascular segments. The investigators interpret this finding by suggesting a significant shielding effect of the Absorb bioresorbable vascular scaffold, whereby protective neointimal growth may prevent protrusion of calcified necrotic core with its inherent risk for atherothrombosis. One could have argued that following passivation of high-risk atherosclerotic plaque by calcification, shielding of underlying necrotic core may no longer be required. However, protective shielding of vulnerable plaque has not been achieved with any technology to date and may indeed be predicate to bioresorbable scaffolds. In contrast, the same finding may be interpreted with caution, because an expected healing response with incorporation of thick-strut bioresorbable scaffolds into neointimal tissue may cause additional luminal compromise and eventually cause symptoms of ischemia. It must be acknowledged that excessive neointimal growth was absent in the limited number of patients undergoing fusion imaging and is unlikely to occur beyond the 5-year time frame reported in the present study. Yet substantial selection bias must be considered because of the highly selective triage of patients (29 of 101) from the predecessor trial, which limits the generalizability of the current assessment.
Considering the ongoing discussion of the safety and efficacy of bioresorbable vascular scaffolds relative to their metallic counterparts, the current set of data sheds light on vessel healing as a function of time. Needless to argue for a disruptive technology with great potential for revolutionary impact, natural skepticism regarding the long-term fate of bioresorbable materials prevails.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Dr. Joner is a consultant for Biotronik, Orbus Neich, and AUM Medical; and has received speaking fees from Abbott Vascular, Orbus Neich, Boston Scientific, AstraZeneca, and Medtronic. Dr. Xhepa has reported that he has no relationships relevant to the contents of this paper to disclose.
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