Novel Payloads to Mitigate Maladaptive Inward Arterial Remodeling in Drug-Coated Balloon Therapy

Abstract

Drug-coated balloon therapy is a minimally invasive endovascular approach to treat obstructive arterial disease, with increasing utilization in the peripheral circulation due to improved outcomes as compared to alternative interventional modalities. Broader clinical use of drug-coated balloons is limited by an incomplete understanding of device- and patient-specific determinants of treatment efficacy, including late outcomes that are mediated by postinterventional maladaptive inward arterial remodeling. To address this knowledge gap, we propose a predictive mathematical model of pressure-mediated femoral artery remodeling following drug-coated balloon deployment, with account of drug-based modulation of resident vascular cell phenotype and common patient comorbidities, namely, hypertension and endothelial cell dysfunction. Our results elucidate how postinterventional arterial remodeling outcomes are altered by the delivery of a traditional anti-proliferative drug, as well as by codelivery with an anti-contractile drug. Our findings suggest that codelivery of anti-proliferative and anti-contractile drugs could improve patient outcomes following drug-coated balloon therapy, motivating further consideration of novel payloads in next-generation devices.

Keywords: anti-proliferative and anti-contractile drugs; arterial remodeling; drug-coated balloon; hypertension; peripheral artery disease.

Fig. 1

Mechanical and histological data on the porcine femoral artery. Obtained mechanical response data include (a)pressure-outer diameter and (b) axial force-pressure relations when the artery is at fixed axial stretch ${(\lambda }_1=2.0)$ and under basal (■), maximally contracted (●), and fully relaxed (○) SMC states. (c) Histological preparations to assess arterial wall composition include (i) Resorcin Fuchsin with Woodstain Scarlet Acid Fuchsin counterstain, Direct Red (0.1% in saturated picric acid) using (ii) bright-field, and (iii) cross-polarized light, and (iv) a combination of Verhoeff–Masson's stain.

Fig. 2

Circumferential stress–stretch relations exhibited by the porcine femoral artery. The total (■), active (●), and passive (○) circumferential stress-circumferential stretch relations when the artery is at fixed axial stretch ${(\lambda }_1=2.0)$ and under (a) basal and (b) fully contracted SMC states. Points indicate experimental data; curves indicate fits with identified constitutive models.

Fig. 3

Geometrical and compositional outcomes of adaptive pressure-mediated arterial remodeling following traditional DCB deployment. Remodeling outcomes for AP dosing parameter ( $D_{\left[\mathrm{AP}\right]}$) ranging from $0-1$ in $0.2$ increments, with the arrow indicating the dosing associated with each curve. Outcomes include (a) undeformed inner radius, (b)undeformed wall thickness, (c) undeformed wall area, (d) deformed inner radius, (e) deformed wall thickness, (f)deformed wall area, (g) elastin mass fraction, (h) collagen mass fraction, and (i) SMC mass fraction.

Fig. 4

Geometrical and compositional outcomes of maladaptive pressure-mediated arterial remodeling following traditional DCB deployment. Remodeling outcomes for AP dosing parameter ( $D_{\left[\mathrm{AP}\right]}$) ranging from $0-1$ in $0.2$ increments, with the arrow/hash mark indicating the dosing associated with each curve. Outcomes include (a) undeformed inner radius, (b) undeformed wall thickness, (c) undeformed wall area, (d) deformed inner radius, (e) deformed wall thickness, (f) deformed wall area, (g) elastin mass fraction, (h) collagen mass fraction, and (i) SMC mass fraction.

Fig. 5

Geometrical and compositional outcomes of maladaptive pressure-mediated arterial remodeling following novel DCB deployment. Remodeling outcomes for a fixed AP dosing parameter ( $D_{\left[\mathrm{AP}\right]}=0.5$) with the AC dosing parameter ( $D_{\left[\mathrm{AC}\right]}$) ranging from $0-1$ in $0.2$ increments, with the arrow indicating the AC dosing associated with each curve. Outcomes include (a) undeformed inner radius, (b) undeformed wall thickness, (c) undeformed wall area, (d) deformed inner radius, (e) deformed wall thickness, (f) deformed wall area, (g) elastin mass fraction, (h) collagen mass fraction, and (i) SMC mass fraction.

Fig. 6

Comparison of remodeling outcomes. Predictions for the (a) deformed wall area and (b) deformed inner radius of the femoral artery after completion of pressure-mediated remodeling, where Case 1 refers to adaptive remodeling, Case 2 refers to maladaptive remodeling, Case 3 refers to maladaptive post-DCB remodeling with $D_{\left[\mathrm{AP}\right]}=0.5\hspace{0.17em}$(traditional DCB with intermediate drug dose), and Case 4 refers to maladaptive post-DCB remodeling with $D_{\left[\mathrm{AP}\right]}=0.5$ and $D_{\left[\mathrm{AC}\right]}=0.5\hspace{0.17em}$(novel DCB with intermediate drug dose). (c) Predictions for the vessel pressure-outer diameter relations after completion of remodeling under an intermediate degree of hypertension ${(P}^H=150\hspace{0.17em}\mathrm{mm}\hspace{0.17em}\mathrm{Hg})$ for Cases 1–4; dashed line indicates the baseline relation. (d) Predictions for deformed inner radius of the femoral artery after completion of pressure-mediated remodeling, where Case* refers to maladaptive post-DCB remodeling with $D_{\left[\mathrm{AP}\right]}=0.5$ and $D_{\left[\mathrm{AC}\right]}=0.74\hspace{0.17em}$(novel DCB with tuned drug dose).