The Use of Coronary Imaging for Predicting Future Cardiovascular Events

Abstract

Background

Despite advancements in coronary artery disease (CAD) treatment with drug-eluting stent, its morbidity and mortality remain high. In context, intravascular imaging-guided percutaneous coronary intervention (PCI) is increasingly recommended for better clinical outcomes in patient with CAD. Near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), as one of the intravascular imaging methods, is effective in detecting lipid-rich plaques, which is crucial for identifying high-risk or vulnerable plaques employing near-infrared light. High lipid core burden, as identified by NIRS-IVUS, correlates with an increased risk of adverse cardiac events and shows varying degrees of efficacy in plaque management and event prevention.

Summary

This article addresses about how NIRS-IVUS can be used to predict event of CAD. The study highlights the crucial role of NIRS-IVUS in predicting future cardiovascular events. Findings indicate that the presence of high lipid core burden is related to increased risks of periprocedural myocardial infarction and reduced coronary flow during PCI. The study also outlines the predictive value of NIRS-IVUS in non-culprit lesions, where plaques with high lipid core burden significantly increase the occurrence of major adverse cardiac events as demonstrated in the PROSPECT II trial. In terms of therapeutic strategies, the study reviews the effectiveness of high-intensity lipid-lowering strategies in stabilizing vulnerable plaques, as evidenced in trials such as the YELLOW and PACMAN AMI trials.

Key Messages

NIRS-IVUS emerges as a valuable diagnostic tool in treating CAD. It effectively identifies vulnerable plaques and aids in predicting and preventing future adverse cardiac events. However, to enhance its practicality and promote widespread adoption in clinical settings, further long-term outcome research of NIRS-IVUS-guided PCI is necessary. These efforts can potentially make NIRS-IVUS a more accessible and indispensable tool in cardiovascular disease management.

Introduction

Coronary artery disease (CAD) remains a significant contributor to morbidity and mortality on a global scale [1, 2]. Although the development and utilization of novel devices and pharmaceuticals have brought better clinical outcomes for CAD, the efficacy of stent implantation continues to rely heavily on the expertise and skill of physicians. In context, it is essential to furnish operating physicians with comprehensive knowledge on the lesion characteristics in order to enhance clinical outcomes. The invasive coronary angiography images were used for assessment of lesions during percutaneous coronary intervention (PCI). However, the resolution of coronary angiography was not enough to discriminate detailed lesion characteristics such as vulnerable plaque, which had high-risk cause of cardiovascular events. Thus, the current guidelines recommended that intravascular imaging can be led better clinical outcomes in patient with PCI [1–4]. And there were randomized controlled studies that demonstrated better clinical outcomes of image-guided PCI than those of angiographic-guided PCI [5, 6]. However, there was a lack of knowledge about the role of intravascular imaging in predicting subsequent future cardiovascular events. In context, near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) might be used as a way to predict subsequent future cardiovascular event by detecting vulnerable plaque especially in lipid-rich plaque. So, this study reviews the possible medical and scientific uses of NIRS-IVUS for lipid plaques in the coronary arteries in people with CAD.

Near-Infrared Spectroscopy-Intravascular Ultrasound

The near-infrared light spectrum (wavelength: 700–2,500 nm; not visible to the naked eye) is optimal for diagnostic applications, because its low energy does not cause tissue damage [7]. NIRS establishes a unique fingerprint for each chemical by analyzing the manner in which organic molecules within the target react with NIR light in accordance with the configuration of their molecular bonds. Specifically, in cases of positive remodeling of the vessel with lipid-laden necrotic foci [8, 9], NIRS-IVUS is a viable option for determining the lipid content of atherosclerotic plaques.

The TVC Imaging System™ and Makoto Intravascular Imaging System™, both of which are presently available commercially (Infraredx Inc., Bedford, MA, USA), are utilized for the purpose of atherosclerotic plaque detection in coronary artery. The Makoto system, in its most recent iteration, employs a velocity of 0.5, 1.0, or 2.0 mm/s for the retraction of the imaging core and an 1,800 rpm rotational speed. This configuration enables the acquisition of approximately 130,000 NIRS measurements per 100 mm over a maximal imaging length of 150 mm. The TVC System discriminates the presence of lipid core by decoding complex composite signals in near real time using NIRS-IVUS. Yellow signifies the maximum probability of a lipid core’s presence; the results are displayed as a chemogram utilizing a color scale ranging from red to yellow. For the purpose of generating an easier-to-understand image, the probability score is correlated with the corresponding color at each location where the measurement was taken, as well as the minuscule spaces between measurements [10].

A numerical lipid core burden index (LCBI) is automatically generated as a quantitative image metric. It denotes that the proportion of valid pixels of a lipid core plaque being present is greater than 0.6, multiplied by one thousand. LCBI provides a number value to the lipid core plaque that is found in a scanned coronary artery [11]. In addition, number value of LCBI is present by using segments of scans or defined width windows within segments, such as the maxLCBI4mm, a 4-mm sliding window with the highest LCBI value.

Predict Subsequent Cardiovascular Events Using NIRS-IVUS

Vulnerable Plaque

The abundance of lipids is a significant factor in the characterization of vulnerable plaques [12]. The significance of lipid-rich plaques, commonly referred to as high-risk plaques, has been underscored due to the considerable proportion of sudden death by acute coronary syndrome [12–14]. Therefore, the occurrence of acute coronary syndrome and sudden cardiac death should be mitigated through the enhancement of treatments targeting susceptible plaques. Naghavi et al. [12, 15] introduced a set of histopathological diagnostic criteria for identifying susceptible plaques, which gained widespread consensus among researchers. The primary diagnostic criteria encompass the presence of inflammatory activation within the plaque, characterized by either monocyte/macrophage infiltration or T lymphocyte infiltration. Additionally, a thin fibrous cap with a thickness less than 65 μm and a large lipid core occupying more than 40% of the plaque area are one of major criteria. Other indicators include vascular endothelial cell ablation accompanied by platelet aggregation on the surface, the presence of fissures or damaged plaques, and severe luminal stenosis exceeding 90%. Additional diagnostic criteria that can be considered are intraplaque hemorrhage, endothelial dysfunction, superficial nodules or calcifications, yellow plaques, and positive remodeling of vascular walls [12]. Several techniques have been developed and employed to evaluate vulnerable plaques, including coronary computed tomography, angiography, intravascular ultrasound, optical coherence tomography, positron emission tomography, and computational fluid dynamics analysis [12, 13]. Meanwhile, the implementation of NIRS-IVUS came about at a later stage compared to the aforementioned modalities. Consequently, there exists a scarcity of data regarding the potential clinical applications using NIRS-IVUS. In comparison with other modalities, NIRS has demonstrated particular validated label claims pertaining to the detection of the lipid core of the atherosclerotic plaque. Furthermore, a proper assessment of significant lipid-rich core burden in patients with ST-elevation myocardial infarction can serve as a reliable predictor for both culprit and non-culprit lesions [10, 16, 17].

Predict Cardiovascular Events of Culprit Lesion Using NIRS-IVUS

In terms of the procedural features, the presence of high lipid core burden is related to an increased risk of periprocedural myocardial infarction or the incidence of reduced coronary flow during PCI [18, 19] (Table 1) (Fig. 1a). Although there is still insufficient evidence for the association between degree of lipid-rich plaques detectable by NIRS-IVUS and procedural success, the PREVENT NO-REFLOW trial (NCT05427786), which is examining the effects of preprocedural administration of nicorandil via intracoronary in patients undergoing PCI with lipid-rich plaques confirmed by NIRS-IVUS, will possibly answer this question. In addition, NIRS-IVUS can provide additional information on lipid-rich plaque regions to evaluate stent location or stent length [20], in comparison with IVUS-guided PCI. This information can be used to determine the stent length.

Table 1.

The use of NIRS-IVUS for predicting subsequent cardiovascular event

	Publication	Aim	Design	Sample size	Primary endpoint	Results
Culprit
Goldstein et al. [11]	2011	To determine whether intracoronary NIRS-IVUS can identify plaques that are likely to cause periprocedural MI in patients undergoing elective PCI	Cohort	62	Rate of periprocedural MI	50% (high LCBI) versus 4.2% (low LCBI) (p = 0.0002)
Lim et al. [19]	2022	To identify association between LCBI and decreased TIMI flow in patients undergoing PCI	Cohort	636	Association between a decreased TIMI flow and LCBI	Odds ratio of high LCBI for decreased TIMI flow (2.59, 95% CI 1.33–5.04; p = 0.005)
Non-culprit
Waksman et al. [21]	2019	Assessing the ability of NIRS-IVUS imaging to detect vulnerable patients and vulnerable plaques	Cohort	1,271	Association between maxLCBI4mm and non-culprit major adverse cardiovascular events	Hazard ratio of high LCBI for NC-MACE (1.89, 95% CI 1.26–2.83; p = 0.0021)
Stone et al. [22]	2020	Pilot randomized trial of PCI treatment of vulnerable plaques to inform a future large-scale pivotal study	RCT	182	IVUS-derived minimum lumen area	BVS versus GDMT alone
					Target lesion failure	MLA: 6.9±2.6 mm2 versus 3.0±1.0 mm2; p < 0.0001
						TLF: 4.3% versus 10.7%; p = 0.12
Erlinge et al. [23]	2021	To validate the use of NIRS-IVUS for identification of non-obstructive lipid-rich plaques that are prone to cause future cardiac events	Cohort	898 (3,629 vessel)	Composite endpoint including cardiac death, myocardial infarction, unstable angina, or progressive angina arising from untreated non-culprit lesions	Hazard ratio of high LCBI for NC-MACE (2.27, 95% CI 1.25–4.13; p = 0.0071)
Biccirè et al. [24]	2023	To analyze the proportions, determinants, and prognostic implications of triple regression (atheroma volume reduction, lipid content reduction, and increase in fibrous cap)	RCT	265	The composite endpoint of death, myocardial infarction, and ischemia-driven revascularization	Triple regression for composite endpoints (yes vs. no; 8.3% vs. 18.2%; p = 0.04)

Fig. 1.

Use of NIRS-IVUS in assessing coronary artery plaques, showing cross-sectional imaging and lipid core burden chemogram to predict future cardiovascular events in both culprit (a) and non-culprit (b) arteries.

Predict Cardiovascular Events of Non-Culprit Lesion Using NIRS-IVUS

According to a prospective cohort analysis of Lipid-Rich Plaque trial, atherosclerotic plaque with high lipid core burden and a maxLCBI4mm value of 400 or above had a significantly increased occurrence of major adverse cardiac events on non-culprit lesion, with an incidence rate four times greater than those without these characteristics [21, 25]. In addition, the utilization of NIRS-IVUS to acquire further information on lipid-rich plaque composition may predict the likelihood of future cardiovascular events [21, 26–28]. The findings of the PROSPECT II trial were consistent with those of the Lipid-Rich Plaque trial [23]. The PROSPECT II trial encompassed a cohort of 898 individuals who had experienced a recent myocardial infarction. In addition, the study was conducted using NIRS-IVUS on a total of 3,629 non-culprit lesions to investigate the rate of major adverse cardiovascular events, such as cardiac death, myocardial infarction, unstable angina, and progressive angina regarding the presence of lipid-rich cores (NIRS) and significant plaque volume (IVUS). The results showed individuals presenting with either of lipid-rich core or significant plaque volume exhibited a high risk of subsequent adverse cardiovascular events [23] (Table 1) (Fig. 1b).

Prevent Subsequent Cardiovascular Events Using NIRS-IVUS

The aforementioned observations have necessitated the development of a therapeutic modality for vulnerable plaques in order to mitigate the occurrence of subsequent adverse cardiovascular events. The PROSPECT ABSORB trial conducted a small-scale randomized control trial to examine the potential benefits of preventative stent implantation for vulnerable plaque [22]. A cohort of 182 individuals were subjected to a random allocation of two treatment modalities for their lesions: either the insertion of a bioresorbable vascular scaffold (BVS) with guideline-directed medical therapy (GDMT) or GDMT alone. The findings of the study suggest that the group receiving BVS exhibited a decreased target lesion failure compared to patients who had GDMT alone without statistical significance [22]. And even though BVS is no longer used in clinical practice, there are still some issues with using drug-eluting stents as a preventative strategy to treat vulnerable plaques.

Meanwhile, high-intensity lipid-lowering strategy showed stabilizing of vulnerable plaque through several studies. The YELLOW trial demonstrated the utility of NIRS-IVUS as a quantitative indicator of lipid-rich plaque in the context of comparing intensive statin therapy with standard statin therapy [29]. In this randomized controlled trial, the administration of 40 mg of rosuvastatin on a daily basis as part of intensive statin therapy demonstrated a significant reduction in the maxLCBI4mm in a significant coronary artery stenosis (fractional flow reserve ≤0.8) as compared to standard statin therapy [29] (Table 1). The PACMAN AMI trial recently reported the impact of adding alirocumab (PCSK9i) to high-intensity statin therapy in patients with acute myocardial infarction [30]. The trial revealed that after 52 weeks, the group receiving alirocumab experienced a significantly greater regression of coronary plaque in non-infarct-related arteries as well as superior reduction of low-density lipoprotein cholesterol compared to the placebo group [24, 30]. These findings suggest that lowering low-density lipoprotein cholesterol as much as possible is crucial to increase benefit for people who had acute myocardial infarction, reduce the amount of plaque, and prevent subsequent adverse cardiovascular events.

Conclusion

Despite the inherent limitations associated with its invasiveness, the combined utilization of NIRS and IVUS represents a valuable diagnostic approach for the identification of vulnerable plaques. Consequently, NIRS-IVUS has the potential to effectively identify individuals who are at risk of experiencing subsequent adverse coronary events, regardless of whether the events are attributed to culprit or non-culprit lesions.

Nevertheless, to enhance its practicality in clinical settings and promote widespread adoption, further research is necessary. Moreover, research on the long-term outcomes of NIRS-IVUS-guided PCI will provide crucial insights into its effectiveness and potential to revolutionize CAD treatment. By focusing on these research areas, NIRS-IVUS can potentially become a more accessible and indispensable tool in cardiovascular disease.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

All authors have nothing to declare regarding funding.

Author Contributions

Conceptualization, investigation, and visualization, J.-J.C. and S.J.H.; methodology and writing – original draft preparation, J.-J.C.; writing– review and editing, S.J.H., S.L., J.H.K., H.J.J., J.H.P., C.W.Y., and D.-S.L.; supervision, S.L., J.H.K., H.J.J., J.H.P., C.W.Y., and D.-S.L.; project administration, S.J.H.; all authors have read and agreed to the published version of the manuscript.

Funding Statement

All authors have nothing to declare regarding funding.