Coronary artery disease (CAD) is the most common form of cardiovascular disease and the leading cause of death in the US (Murphy et al., 2021). CAD develops due to the accumulation of atherosclerotic tissue within the artery wall, and it can take decades before a flow-limiting narrowing that requires intervention presents. With the advent of coronary stents, percutaneous coronary intervention (PCI) is now the standard treatment for many CAD patients. However, poor clinical outcomes are still common in the form of restenosis (Aoki and Tanabe, 2021) and, to a lesser extent, stent thrombosis (Claessen Bimmer E. et al., 2014). These outcomes are particularly prone after treating plaques with adverse material characteristics, such as thin fibrous cap with high rupture vulnerability or highly calcific plaques with generally stiffer structure (Yang et al., 2022).

The widespread availability of medical imaging and computer models has brought structural and hemodynamic simulation to the leading edge of clinical decision making, providing insight into the impact of patient-specific characteristics (Rikhtegar et al., 2014; Chiastra et al., 2016; Ebrahimi and Fallah, 2022). While current imaging modalities are mostly geared toward morphology characterization, knowing material properties of the target lesion is a requirement to study plaque structural stress. Importantly, structural stress correlates strongly with poor outcomes of stent deployment including restenosis, stent thrombosis and plaque rupture (Teng et al., 2014; Kolandaivelu and Rikhtegar, 2016; Costopoulos et al., 2017; Conway et al., 2021; Kadry et al., 2021). Local artery stiffness also predicts delivery balloon under-expansion and elastic recoil through stent-plaque strain energy exchange after balloon deflation (Aziz et al., 2007). Consequently, suboptimal final artery geometry and associated adverse mechanical stimuli, such as wall shear stress (LaDisa et al., 2004; 2005; Nakagawa et al., 2014), can trigger proinflammatory, prothrombotic, and proatherogenic responses that progress to poor clinical outcomes (Thondapu et al., 2017).

An optimal PCI procedure can be defined as recovering coronary flow reserve with minimal stent-induced mechanical stimuli. In this regard, stent selection, deployment strategy, and controlled recoil all become important and are influenced by local morphology and material properties of the target lesion. However, there is a lack of feasible tools for patient-specific hyperelastic material characterization of coronary plaques. Importantly, current state-of-the-art virtual simulations have the potential to significantly improve clinical decision making toward personalized PCI by incorporating high-fidelity morphology and material characteristics of the target lesion. However, recent attempts for image-based characterization of plaque material properties have been limited to ex vivo approaches or multimodal intravascular imaging. Related work has also focused on physiological intravascular pressures (Guvenir Torun et al., 2021; Narayanan et al., 2021), while nonlinearity of the plaque deformation (i.e., hyperelastic behavior) is best quantified beyond physiological deformations as applied during PCI. In this paper a novel approach is presented using OCT imaging through angioplasty balloons at pre-dilation to 8 ATM. Pre-dilation inherently provides physical contact with the target lesion, which provides a unique opportunity for patient-specific material characterization within the PCI range of deformations. The feasibility of this method is empirically investigated using an ex vivo set up for coronary atherosclerotic human arteries.

Figure 1A shows the luminal surface of an example LAD coronary artery characterized through OCT conducted at the DBP (Table 1, Patient 1). Cross-sectional views of the artery are also shown for three longitudinal locations (Figures 1B–D) obtained during using the OCT-integrated angioplasty balloon. OCT identified the presence of fibrocalcific plaque at slices B and C, while distal regions of the artery (Figure 1D) more likely represent early stage fibroatheroma. Images taken at the same locations during pre-dilation identified spatial heterogeneity and balloon under-expansion relative to the nominal diameter that are represented in contour plots of Figures 1B–D. Considering under-expansion as a surrogate for local stiffness of the lesion, spatial variations observed were interpreted as differences in material properties across the target lesion. For example, at regions of fibrocalcific plaque (Figures 1B,C), more prominent radial resistance with up to 20% balloon under-expansion was observed. On the other hand, at distal regions with early stage fibroatheroma (Figure 1D), a more uniform distribution of under-expansion up to 10% was observed indicating less radial resistance and angular heterogeneity. Overall, the luminal expansion from diagnostic to pre-dilation images (i.e., DBP to 8 ATM via balloon inflation) were 65, 27, and 85%, respectively for each location. These results suggest the overall radial stiffness is higher at the proximal to middle section of the target lesion for Patient 1, while the distal region is more elastic with the highest luminal expansion flexibility. Lesions from other patients were similarly processed.

Figure 2 shows hyperelastic characterization of the coronary plaques (n = 13) in circumferential and longitudinal directions for locations where balloon under-expansion was observed. For general comparison, Cauchy stress was compared close to the knee point, i.e., point of maximum curvature, where the transition from linear to hyperelastic portions of the stress-strain curves were observed (Claes et al., 2010), i.e., at 1.15 stretch ratio in both directions according to the current datasets. The average circumferential Cauchy stress was 66.5, 130.2, and 300.4 kPa for regions with <15, 15-30, and >30% balloon under-expansion. Similarly, the average longitudinal Cauchy stress was 68.1, 172.6, and 412.7 kPa, respectively. Consequently, strong Pearson Correlation Coefficients of 0.90 and 0.89 were observed between balloon under-expansion and stiffness for circumferential and longitudinal directions, respectively.

The circumferential/longitudinal stress ratios were 0.98 ± 0.12, 0.79 ± 0.14, 0.76 ± 0.30 for <15, 15-30, and >30% under-expansion, respectfully, indicating mild anisotropy with a general pattern of stiffness toward the longitudinal direction. Therefore, the corresponding constitutive parameter ψ was fixed at 1.22 radians to reflect the same anisotropy level while other non-dimensional constitutive parameters (i.e., k 2 and ρ ) were fixed at 8.21 ad 0.25 according to the literature (Holzapfel et al., 2005). These simplifications reduced sensitivity while tuning the Neo-Hookean and Exponential stress-like constitutive parameters of μ and k 1 listed in Table 2. Results showed significant differences between stress-like constitutive parameters obtained from regions with <15, 15-30, and above 30% under-expansion with p-values of 0.0015 and 0.0250 for Neo-Hookean and Exponential constitutive parameters, respectively (Table 2).

Figure 3 describes the transfer functions for the stiffness interpretation of balloon under-expansion at pre-dilation (i.e., 8 ATM). Under-expansion was averaged over the locations where experimental samples were dissected from with spatial resolution equal to the sample dimensions, i.e., 4.7 × 4.7 mm. Overall, a strong linear correlation was observed both in Neo-Hookean and Exponential constitutive parameters, i.e., μ and k 1 , respectively, with R ² of 0.82 and 0.64 and significant non-zero slopes (p-values <0.001).

The material properties used with computational PCI simulations often coincide with available hyperelastic constitutive relationships for a limited range of developed plaques (Kragel et al., 1989; Lee et al., 1991; Loree et al., 1994) (e.g., lipid rich, fibrous, and calcified plaque (Schroeder et al., 2004; Brodoefel et al., 2008)) as well as early stages of atherosclerosis (e.g., intimal thickening) (Holzapfel et al., 2005; Pericevic et al., 2009). The utility of this prior data is limited when the goal is, for example, to predict the likelihood of restenosis for a given patient using imaging data from the PCI period. Recent literature echoes this need for more data since arterial tissue is often obtained after autopsy when mechanical properties have degraded, and few studies account for plaque substructure in constitutive models of atherosclerotic coronary arteries (Akyildiz et al., 2014; Chen and Kassab, 2016; McKittrick et al., 2016). The current work presents a novel approach for constitutive characterization of target coronary artery lesions using a specially fabricated angioplasty balloon that allows for quantification of balloon under-expansion via OCT as a surrogate for local stiffness of the artery wall. Empirical quantification of balloon under-expansion at pre-dilation and corresponding hyperelastic material properties of the atherosclerotic plaques identified a transfer function (Figure 3) for direct constitutive characterization of coronary lesions during pre-dilation. Importantly, the inflation pressure of 8 ATM was used, consistent with the nominal pressure in many commercially available coronary artery stent delivery systems.

Capturing spatial variations at the micron-scale is difficult using traditional extension testing methods due to relatively large dimension of the samples (5 × 5 mm), whereas heterogeneities obtained through the proposed OCT-integrated balloon angioplasty method are at the micron-scale. Some of the image-based heterogeneity is lumped into the larger size samples dissected for experimental testing of material properties for the current work, since under-expansion was averaged over the locations where experimental samples were dissected from. Despite these differences in image-based vs. empirical resolutions, characterization of constitutive parameters resulting from Figure 3 allows for estimation of local material properties in novel ways and within a reasonable level of certainty given the infancy of the current approach. Figure 4A provides an example of the clinical utility of advancements afforded by the current work. Balloon under-expansion is shown over the luminal surface in response to pre-dilation for three representative LAD coronary arteries generally spanning the range of plaques tested for the current study. Results indicate spatial heterogeneity of balloon under-expansion that varies between arteries as a result of differences in stiffness and plaque types across patients.

Figure 4B shows the corresponding distribution of stress-like constitutive parameters (i.e., Neo-Hookean and Exponential) over the target lesions when applying the transfer functions shown in Figure 3. Figure 4C indicates the corresponding strain energy density at a virtually applied 1.15 equibiaxial stretch ratio that shows heterogenous absorption of energy when applied to the same stretch. This representation of the data can predict stent-plaque strain energy exchange that is important for accurate virtual PCI and risk assessment.

The current results from a large sample size (n = 13) relative prior work serve as a proof-of-concept for pre-operative patient-specific hyperelastic material characterization using a single commercially-available imaging approach (i.e., OCT) to capture hyperelastic behavior at physiologic and supra-physiologic deformations (Guvenir Torun et al., 2021; Narayanan et al., 2021) applied during PCI. The current results extend the work of Narayanan et al. who used inverse finite element methods to estimate the material properties of arterial plaque components (Narayanan et al., 2021). The authors leveraged intravascular OCT imaging data acquired during imaging wire pullback in vivo and an in silico (i.e., simulated) target geometry corresponding to 60 mmHg above the acquired geometry for three patients. Five material regions were identified based on literature including fibrous, lipid, calcium, mixed, and healthy wall tissue. The current OCT-integrated balloon angioplasty methods extend this prior work by allowing for material characterization using local balloon under-expansion as a surrogate for material properties and heterogeneity. Clinical translation of the current methods may ultimately allow for real-time material characterization that is useful clinically for several applications, such as determining when a stent with increased radial strength may need to be selected from current FDA-approved stents, or for better understanding of lesion properties in patients nearing chronic total occlusion.

The current study should be interpreted relative to several potential limitations. Difficulty in dissecting samples from morphologically distorted atherosclerotic plaques can be difficult and may result in as much as 30% loss of available samples during handling. The application of inverse computational methods such as inverse finite element analysis (iFEA) can substantially reduce lost data as well as allow for characterization of samples too small to be tested using available biaxial extension testing machines. Despite image-based under-expansion data being available at the micron-scale, these data were averaged over the dimension of prepared samples for comparison to empirical data. Hence, the spatial resolution of the current manuscript was limited to samples dimensions, i.e., 4.7 × 4.7 mm, in the reported correlation study (Figure 3). The application of iFEA in future work may allow for reducing the spatial resolution to the full potential of the proposed OCT-integrated angioplasty method, i.e., 15 microns. In vivo curvature was not replicated in the current methods. It is worth noting that the force exerted during balloon expansion limits curvature in the longitudinal direction, resulting in an almost straight segment. Nonetheless, future work may aim to conduct the current methods while matching in vivo curvature, likely using a reconstruction approach combining conventional and intravascular approaches as described previously (Slager et al., 2000; Ellwein et al., 2011; Timmins et al., 2016; Athanasiou et al., 2018; Wu et al., 2020).

The current advancements allow for high-fidelity constitutive characterization of coronary artery target lesions using an angioplasty balloon that accommodates the OCT imaging wire during pre-dilation. We are optimistic that state-of-the-art computational and virtual stent implantation methods can now be further advanced with patient-specific material properties identified during pre-dilation, as well as within the super-physiological range of deformations normally applied during PCI.