Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia.

Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)- and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted bradykinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocin-induced DM (DM + HFD, n = 5). Responses of small (∼300-µm-diameter) coronary arteries to BK, ET-1, and the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine (n = 12). Blood glucose was elevated in DM + HFD (17.6 ± 4.5 mmol/l) compared with HFD (5.1 ± 0.4 mmol/l) and Normal (5.8 ± 0.6 mmol/l) swine, while cholesterol was markedly elevated in DM + HFD (16.8 ± 1.7 mmol/l) and HFD (18.1 ± 2.6 mmol/l) compared with Normal (2.1 ± 0.2 mmol/l) swine (all P < 0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly, DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P < 0.05), resulting mainly from ETB receptor-mediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P < 0.05). In conclusion, 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-derived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ETB receptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD.

The effect of bioresorbable vascular scaffold implantation on distal coronary endothelial function in dyslipidemic swine with and without diabetes.

BACKGROUND: We studied the effect of bioresorbable vascular scaffold (BVS) implantation on distal coronary endothelial function, in swine on a high fat diet without (HFD) or with diabetes (DM+HFD). METHODS: Five DM+HFD and five HFD swine underwent BVS implantation on top of coronary plaques, and were studied six months later. Conduit artery segments >5mm proximal and distal to the scaffold and corresponding segments of non-scaffolded coronary arteries, and segments of small arteries within the flow-territory of scaffolded and non-scaffolded arteries were harvested for in vitro vasoreactivity studies. RESULTS: Conduit segments proximal and distal of the BVS edges showed reduced endothelium-dependent vasodilation as compared to control vessels (p≤0.01), with distal segments being most prominently affected(p≤0.01). Endothelial dysfunction was only observed in DM±HFD swine and was principally due to a loss of NO. Endothelium-independent vasodilation and vasoconstriction were unaffected. Surprisingly, segments from the microcirculation distal to the BVS showed enhanced endothelium-dependent vasodilation (p<0.01), whereas endothelium-independent vasodilation and vasoconstriction were unaltered. This enhanced vasorelaxation was only observed in DM+HFD swine, and did not appear to be either NO- or EDHF-mediated. CONCLUSIONS: Six months of BVS implantation in DM+HFD swine causes NO-mediated endothelial dysfunction in nearby coronary segments, which is accompanied by a, possibly compensatory, increase in endothelial function of the distal microcirculation. Endothelial dysfunction extending into coronary conduit segments beyond the implantation-site, is in agreement with recent reports expressing concern for late scaffold thrombosis and of early BVS failure in diabetic patients.

Neoatherosclerosis development following bioresorbable vascular scaffold implantation in diabetic and non-diabetic swine.

BACKGROUND: DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS. AIM: The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a 'fast-food' diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology. METHODS: Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed. RESULTS: Late lumen loss was high (~60%) within the first 3M after BVS-implantation (P<0.01 FF-DM vs. FF-NDM) and stabilized between 3M and 6M (<5% change in FF-DM, ~10% in FF-NDM; P>0.20). Neointimal coverage was highly heterogeneous in all swine (DM vs. NDM P>0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (~2% at 3M, ~5% at 6M;P>0.20) and not associated with DM or inflammation. CONCLUSION: Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes.

Safety of optical coherence tomography in daily practice: a comparison with intravascular ultrasound.

AIMS: Previous studies have reported the safety and feasibility of both time-domain optical coherence tomography (TD-OCT) and Fourier-domain OCT (FD-OCT) in highly selected patients and clinical settings. However, the generalizability of these data is limited, and data in unselected patient populations reflecting a routine cathlab practice are lacking. We compared safety of intracoronary FD-OCT imaging to intravascular ultrasound (IVUS) imaging in a large real-world series of consecutive patients who underwent invasive imaging during coronary catheterization in our centre. METHODS AND RESULTS: This is a prospective, single-centre registry of patients scheduled for coronary angiography or intervention undergoing intracoronary imaging with FD-OCT or IVUS between April 2008 and December 2013. Intra-procedural and major in-hospital adverse events that could be possibly related to invasive imaging were registered routinely by the operator as part of our clinical report and prospectively recorded in our database. These events were retrospectively individually adjudicated by an independent safety committee. Between April 2008 and December 2013, 13 418 diagnostic or interventional coronary catheterization procedures were performed. Of these, 1142 procedures used OCT and 2476 procedures used IVUS. Invasive imaging-related complications were rare, did not differ between the two imaging methods (OCT: n = 7, 0.6%; IVUS: n = 12, 0.5%; P = 0.6), and were self-limiting after retrieval of the imaging catheter or easily treatable in the catheterization laboratory. No major adverse events, prolongation of hospital stay, or permanent patient harm was observed. CONCLUSION: FD-OCT is safe in an unselected and heterogeneous group of patients with varying clinical settings.

OCT-measured plaque free wall angle is indicative for plaque burden: overcoming the main limitation of OCT?

The aim of this study was to investigate the relationship between the plaque free wall (PFW) measured by optical coherence tomography (OCT) and the plaque burden (PB) measured by intravascular ultrasound (IVUS). We hypothesize that measurement of the PFW could help to estimate the PB, thereby overcoming the limited ability of OCT to visualize the external elastic membrane in the presence of plaque. This could enable selection of the optimal stent-landing zone by OCT, which is traditionally defined by IVUS as a region with a PB < 40 %. PB (IVUS) and PFW angle (OCT and IVUS) were measured in 18 matched IVUS and OCT pullbacks acquired in the same coronary artery. We determined the relationship between OCT measured PFW (PFWOCT) and IVUS PB (PBIVUS) by non-linear regression analysis. An ROC-curve analysis was used to determine the optimal cut-off value of PFW angle for the detection of PB < 40 %. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. There is a significant correlation between PFWOCT and PBIVUS (r(2) = 0.59). The optimal cut-off value of the PFWOCT for the prediction of a PBIVUS < 40 % is ≥220° with a PPV of 78 % and an NPV of 84 %. This study shows that PFWOCT can be considered as a surrogate marker for PBIVUS, which is currently a common criterion to select an optimal stent-landing zone.

Three-dimensional registration of intravascular optical coherence tomography and cryo-image volumes for microscopic-resolution validation.

Evidence suggests high-resolution, high-contrast, [Formula: see text] intravascular optical coherence tomography (IVOCT) can distinguish plaque types, but further validation is needed, especially for automated plaque characterization. We developed experimental and three-dimensional (3-D) registration methods to provide validation of IVOCT pullback volumes using microscopic, color, and fluorescent cryo-image volumes with optional registered cryo-histology. A specialized registration method matched IVOCT pullback images acquired in the catheter reference frame to a true 3-D cryo-image volume. Briefly, an 11-parameter registration model including a polynomial virtual catheter was initialized within the cryo-image volume, and perpendicular images were extracted, mimicking IVOCT image acquisition. Virtual catheter parameters were optimized to maximize cryo and IVOCT lumen overlap. Multiple assessments suggested that the registration error was better than the [Formula: see text] spacing between IVOCT image frames. Tests on a digital synthetic phantom gave a registration error of only [Formula: see text] (signed distance). Visual assessment of randomly presented nearby frames suggested registration accuracy within 1 IVOCT frame interval ([Formula: see text]). This would eliminate potential misinterpretations confronted by the typical histological approaches to validation, with estimated 1-mm errors. The method can be used to create annotated datasets and automated plaque classification methods and can be extended to other intravascular imaging modalities.

Automated characterisation of lipid core plaques in vivo by quantitative optical coherence tomography tissue type imaging.

AIMS: Qualitative criteria for plaque tissue characterisation by OCT are well established, but quantitative methods lack systematic validation in vivo. High optical attenuation coefficient µt has been associated with unstable plaque features, such as lipid core. The purpose of this study was to validate optical coherence tomography (OCT) attenuation imaging for tissue characterisation in vivo, specifically to detect lipid core in coronary atherosclerotic plaques, and to evaluate quantitatively the ability of OCT attenuation imaging to differentiate thin-cap (TCFA) and thick-cap fibroatheroma (FA). METHODS AND RESULTS: We prospectively enrolled 85 patients undergoing imaging of a native coronary segment by both OCT and near-infrared spectroscopy and intravascular ultrasound (NIRS-IVUS). Ninety-eight NIRS-positive 4 mm plaque segments were selected and matched to the OCT data. Two experienced OCT readers classified the plaque type using OCT criteria. A cap thickness of 65 µm was used to differentiate TCFA and FA. We computed an index of plaque attenuation (IPA) in the 4 mm blocks, and assessed the association of this index with plaque type. IPA differentiated between TCFA and FA (AUC=0.82 in ROC analysis; p<0.0001). LCBI was numerically, but not significantly, higher in TCFA compared to FA (p=0.097). CONCLUSIONS: IPA is an unbiased reproducible measure of tissue optical properties. The fraction of pixels with attenuation coefficient ≥11 mm-1 can identify TCFA.

3D registration of intravascular optical coherence tomography and cryo-image volumes for microscopic-resolution validation.

High resolution, 100 frames/sec intravascular optical coherence tomography (IVOCT) can distinguish plaque types, but further validation is needed, especially for automated plaque characterization. We developed experimental and 3D registration methods, to provide validation of IVOCT pullback volumes using microscopic, brightfield and fluorescent cryo-image volumes, with optional, exactly registered cryo-histology. The innovation was a method to match an IVOCT pull-back images, acquired in the catheter reference frame, to a true 3D cryo-image volume. Briefly, an 11-parameter, polynomial virtual catheter was initialized within the cryo-image volume, and perpendicular images were extracted, mimicking IVOCT image acquisition. Virtual catheter parameters were optimized to maximize cryo and IVOCT lumen overlap. Local minima were possible, but when we started within reasonable ranges, every one of 24 digital phantom cases converged to a good solution with a registration error of only +1.34±2.65µm (signed distance). Registration was applied to 10 ex-vivo cadaver coronary arteries (LADs), resulting in 10 registered cryo and IVOCT volumes yielding a total of 421 registered 2D-image pairs. Image overlays demonstrated high continuity between vascular and plaque features. Bland-Altman analysis comparing cryo and IVOCT lumen area, showed mean and standard deviation of differences as 0.01±0.43 mm2. DICE coefficients were 0.91±0.04. Finally, visual assessment on 20 representative cases with easily identifiable features suggested registration accuracy within one frame of IVOCT (±200µm), eliminating significant misinterpretations introduced by 1mm errors in the literature. The method will provide 3D data for training of IVOCT plaque algorithms and can be used for validation of other intravascular imaging modalities.

Serial Coronary Imaging of Early Atherosclerosis Development in Fast-Food-Fed Diabetic and Nondiabetic Swine.

Patients with diabetes mellitus (DM) are at increased risk for atherosclerosis-related events compared to non-DM (NDM) patients. With an expected worldwide epidemic of DM, early detection of anatomic and functional coronary atherosclerotic changes is gaining attention. To improve our understanding of early atherosclerosis development, we studied a swine model that gradually developed coronary atherosclerosis. Interestingly, optical coherence tomography, near-infrared spectroscopy (NIRS), vascular function, and histology demonstrated no differences between development of early atherosclerosis in fast-food-fed (FF) DM swine and that in FF-NDM swine. Coronary computed tomography angiography did not detect early atherosclerosis, but optical coherence tomography and near-infrared spectroscopy demonstrated coronary atherosclerosis development in FF-DM and FF-NDM swine.

Influence of the Accuracy of Angiography-Based Reconstructions on Velocity and Wall Shear Stress Computations in Coronary Bifurcations: A Phantom Study.

INTRODUCTION: Wall shear stress (WSS) plays a key role in the onset and progression of atherosclerosis in human coronary arteries. Especially sites with low and oscillating WSS near bifurcations have a higher propensity to develop atherosclerosis. WSS computations in coronary bifurcations can be performed in angiography-based 3D reconstructions. It is essential to evaluate how reconstruction errors influence WSS computations in mildly-diseased coronary bifurcations. In mildly-diseased lesions WSS could potentially provide more insight in plaque progression. MATERIALS METHODS: Four Plexiglas phantom models of coronary bifurcations were imaged with bi-plane angiography. The lumens were segmented by two clinically experienced readers. Based on the segmentations 3D models were generated. This resulted in three models per phantom: one gold-standard from the phantom model itself, and one from each reader. Steady-state and transient simulations were performed with computational fluid dynamics to compute the WSS. A similarity index and a noninferiority test were used to compare the WSS in the phantoms and their reconstructions. The margin for this test was based on the resolution constraints of angiography. RESULTS: The reconstruction errors were similar to previously reported data; in seven out of eight reconstructions less than 0.10 mm. WSS in the regions proximal and far distal of the stenosis showed a good agreement. However, the low WSS areas directly distal of the stenosis showed some disagreement between the phantoms and the readers. This was due to small deviations in the reconstruction of the stenosis that caused differences in the resulting jet, and consequently the size and location of the low WSS area. DISCUSSION: This study showed that WSS can accurately be computed within angiography-based 3D reconstructions of coronary arteries with early stage atherosclerosis. Qualitatively, there was a good agreement between the phantoms and the readers. Quantitatively, the low WSS regions directly distal to the stenosis were sensitive to small reconstruction errors.

A novel method to assess coronary artery bifurcations by OCT: cut-plane analysis for side-branch ostial assessment from a main-vessel pullback.

AIMS: In coronary bifurcations assessment, evaluation of side-branch (SB) ostia by an optical coherence tomography (OCT) pullback performed in the main branch (MB) could speed up lesion evaluation and minimize contrast volume. Dedicated software that reconstructs the cross-sections perpendicular to the SB centreline could improve this assessment. We aimed to validate a new method for assessing the SB ostium from an OCT pullback performed in the MB. METHODS AND RESULTS: Thirty-one sets of frequency-domain OCT pullbacks from 28 patients, both from the MB and the SB of a coronary artery bifurcation were analysed. Measurements of the SB ostium from the SB pullback were used as a reference. Measurements of the SB ostium from the MB pullback were then performed in a laboratory setting by (i) conventional analysis and (ii) cut-plane analysis, and the measurement error for each analysis was estimated. Correlations of SB ostium measurements acquired from the MB pullback in comparison with reference measurements acquired from the SB pullback were higher with cut-plane analysis compared with conventional analysis, albeit not reaching statistical significance (area: rcut-plane = 0.927 vs. rconventional = 0.870, P = 0.256; mean diameter: rcut-plane = 0.918 vs. rconventional = 0.788, P = 0.056; minimum diameter: rcut-plane = 0.841 vs. rconventional = 0.812, P = 0.734; maximum diameter: rcut-plane = 0.770 vs. rconventional = 0.635, P = 0.316). Cut-plane analysis was associated with lower absolute error than conventional analysis (area: 0.56 ± 0.45, vs. 1.50 ± 1.31 mm(2), P < 0.001; mean diameter: 0.18 ± 0.14 vs. 0.44 ± 0.30 mm, P < 0.001). CONCLUSION: Measurements of SB ostium performed in a laboratory setting by cut-plane analysis of an OCT pullback of the main branch have high correlation with reference measurements performed in a SB OCT pullback and lower error compared with conventional analysis.

Early systemic microvascular damage in pigs with atherogenic diabetes mellitus coincides with renal angiopoietin dysbalance.

BACKGROUND: Diabetes mellitus (DM) is associated with a range of microvascular complications including diabetic nephropathy (DN). Microvascular abnormalities in the kidneys are common histopathologic findings in DN, which represent one manifestation of ongoing systemic microvascular damage. Recently, sidestream dark-field (SDF) imaging has emerged as a noninvasive tool that enables one to visualize the microcirculation. In this study, we investigated whether changes in the systemic microvasculature induced by DM and an atherogenic diet correlated spatiotemporally with renal damage. METHODS: Atherosclerotic lesion development was triggered in streptozotocin-induced DM pigs (140 mg/kg body weight) by administering an atherogenic diet for approximately 11 months. Fifteen months following induction of DM, microvascular morphology was visualized in control pigs (n = 7), non-diabetic pigs fed an atherogenic diet (ATH, n = 5), and DM pigs fed an atherogenic diet (DM+ATH, n = 5) using SDF imaging of oral mucosal tissue. Subsequently, kidneys were harvested from anethesized pigs and the expression levels of well-established markers for microvascular integrity, such as Angiopoietin-1 (Angpt1) and Angiopoietin-2 (Angpt2) were determined immunohistochemically, while endothelial cell (EC) abundance was determined by immunostaining for von Willebrand factor (vWF). RESULTS: Our study revealed an increase in the capillary tortuosity index in DM+ATH pigs (2.31±0.17) as compared to the control groups (Controls 0.89±0.08 and ATH 1.55±0.11; p<0.05). Kidney biopsies showed marked glomerular lesions consisting of mesangial expansion and podocyte lesions. Furthermore, we observed a disturbed Angpt2/Angpt1 balance in the cortex of the kidney, as evidenced by increased expression of Angpt2 in DM+ATH pigs as compared to Control pigs (p<0.05). CONCLUSION: In the setting of DM, atherogenesis leads to the augmentation of mucosal capillary tortuosity, indicative of systemic microvascular damage. Concomitantly, a dysbalance in renal angiopoietins was correlated with the development of diabetic nephropathy. As such, our studies strongly suggest that defects in the systemic microvasculature mirror the accumulation of microvascular damage in the kidney.

Optical coherence tomography-guided bifurcation stenting of a coronary artery dissection.

Periprocedural guide wire-induced coronary artery dissection is a rare but potentially serious complication of percutaneous coronary intervention. Immediate stenting of the entry point is one of the therapeutic options but engaging the guide wire in the true lumen might be challenging. We report a case of a 55-year-old woman with a guide wire-induced coronary dissection that occurred during treatment of a bifurcation lesion. Optical coherence tomography was instrumental in distinguishing true from false lumen and thereby guide correct positioning of the guide wire to successfully treat the lesion using a dedicated bifurcation stent.

OCT assessment of the long-term vascular healing response 5 years after everolimus-eluting bioresorbable vascular scaffold.

BACKGROUND: Although recent observations suggest a favorable initial healing process of the everolimus-eluting bioresorbable vascular scaffold (BVS), little is known regarding long-term healing response. OBJECTIVES: This study assessed the in vivo vascular healing response using optical coherence tomography (OCT) 5 years after elective first-in-man BVS implantation. METHODS: Of the 14 living patients enrolled in the Thoraxcenter Rotterdam cohort of the ABSORB A study, 8 patients underwent invasive follow-up, including OCT, 5 years after implantation. Advanced OCT image analysis included luminal morphometry, assessment of the adluminal signal-rich layer separating the lumen from other plaque components, visual and quantitative tissue characterization, and assessment of side-branch ostia "jailed" at baseline. RESULTS: In all patients, BVS struts were integrated in the vessel and were not discernible. Both minimum and mean luminal area increased from 2 to 5 years, whereas lumen eccentricity decreased over time. In most patients, plaques were covered by a signal-rich, low-attenuating layer. Minimum cap thickness over necrotic core was 155 ± 90 µm. One patient showed plaque progression and discontinuity of this layer. Side-branch ostia were preserved with tissue bridge thinning that had developed in the place of side-branch struts, creating a neo-carina. CONCLUSIONS: At long-term BVS follow-up, we observed a favorable tissue response, with late luminal enlargement, side-branch patency, and development of a signal-rich, low-attenuating tissue layer that covered thrombogenic plaque components. The small size of the study and the observation of a different tissue response in 1 patient warrant judicious interpretation of our results and confirmation in larger studies.

Invasive Imaging of Bioresorbable Coronary Scaffolds - A Review.

Various fully bioresorbable stents (BRS) have been recently developed, allowing for temporary scaffolding of the vessel wall. The potentially unique advantage of BRS to temporary scaffold the vessel could reduce the risk of adverse clinical outcomes caused by acute vessel geometry changes, late malapposition, jailed side branches or inflexibility of permanent stents. The design of BRS is, however, not similar for all stents, resulting in differences in degradation and behaviour. To assess the performance of BRS, the effect of degradation and behaviour on the vessel wall should be accurately evaluated. Intracoronary imaging techniques such as intravascular ultrasound (IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS) allow for detailed longitudinal evaluation of the stent and the vessel wall and might therefore aid in improving design and behaviour of BRS.

Plaque and thrombus evaluation by optical coherence tomography.

Intravascular Optical Coherence Tomography has been explored as an imaging tool for vessel wall and thrombus characterization. OCT enables a high resolution arterial wall imaging, and light properties allow tissue characterization. It has been proved one of the most valuable imaging modalities for the evaluation of vulnerable plaque and thrombus. OCT has a unique capacity in volumetric quantification of calcium, and unlike ultrasound, light can easily penetrate calcified plaques. Finally, this review paper will address aspects of the validation method of plaque characterization and potential pitfalls and put in perspective new approaches that may help the evolution of the field.