Hemodynamics and Endothelial Cell Biology in Cardiovascular Diseases

Atherosclerotic plaques develop preferentially in curved and branching arteries in-vivo. Lipids and inflammatory cells accumulation in the intimal layer of the arterial wall is considered as the main driving mechanism in the disease progression. Evidences suggest that this focal distribution of plaques may result from the combination of systemic risk factors including high plasma cholesterol, smoking, diabetis, hypertension or genetic pre-disposition and local hemodynamic risk factors such as low and oscillatory flows. The exact mechanism of the biological and biomechanical interactions between the endothelium, blood flow and the growing lesion underneath still remains unclear. This thesis is a study on the relationship between biomechanical factors found in proatherogenic flow and endothelial inflammation. The thesis focuses in particular on the effect of secondary flows on wall shear stress and mass transport distribution. To that end, we have combined different techniques from flow imaging, 3D flow reconstruction, vascular biology and mathematical simulation of biological network. In particular, shear stress is involved in the regulation of the pro-inflammatory transcription factor nuclear factor -kB (NF-kB) and the vasoregulator Nitric Oxide. The role of endothelial Nitric Oxide and wall shear stress on NF-kB activation is still controversial. We investigated here the hypothesis that NO negatively regulates NF- kB activation in flow chamber with sheared endothelial cells and using a mathematical model of the NF-kB-NO pathway. Understanding the underlying relationship between hemodynamic factors and inflammatory cells transport to the wall may contribute to the development of better therapies or interventional practices to treat patients with atherosclerotic diseases

Coronary evaginations and peri-scaffold aneurysms following implantation of bioresorbable scaffolds: incidence, outcome, and optical coherence tomography analysis of possible mechanisms

Background Peri-stent coronary evaginations may disturb flow and have been proposed as possible risk factor for late stent thrombosis. We describe incidence, predictors, and possible mechanisms of coronary evaginations 12 months after implantation of bioresorbable vascular scaffolds (BVS).Methods and results One hundred and two BVS implanted in 90 patients (age 63 ± 13 years, 71 males, 14 diabetics) were analysed with angiography and optical coherence tomography (OCT) 12 months after implantation. Evaginations were identified as any hollow in the luminal vessel contour between well-apposed struts and were classified as major when extending ≥3 mm with a depth ≥10% of the BVS diameter. Fifty-five (54%) of the BVS (50(56%) of the patients) had at least one evagination (6.1 ± 6.2 evaginations per BVS), with a mean volume of 1.9 ± 1.9 mm³. Major evaginations were only found in one patient, and in-BVS aneurysms in three patients (4BVS). The presence of evaginations was strongly associated with that of malapposition (P = 0.003) and strut fractures (P = 0.01). No association could be shown between the presence and volume of the evaginations and any clinical variable or the presence of uncovered struts (P > 0.5). Peri-strut low- intensity areas (PSLIA) were present in 29 (53%) of the BVS with evaginations and 12 (26%) of those without (P = 0.0049); their presence was independently associated with the presence, the number (P P = 0.004) and with that of strut fracture. Conclusions Optical coherence tomography-detected evaginations are relatively common after BVS implantation, but, as for modern drug-eluting metallic stents, major evaginations are very rare. Optical coherence tomography evidence of immature neointima and strut fractures were associated with more severe development of evaginations

Noninvasive Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography For Identification Of Ischemic Lesions: A Systematic Review and Meta-Analysis

Detection of coronary ischemic lesions by fractional flow reserve (FFR) has been established as the gold standard. In recent years, novel computer based methods have emerged and they can provide simulation of FFR using coronary artery images acquired from coronary computed tomography angiography (FFRCT). This meta-analysis aimed to evaluate diagnostic performance of FFRCT using FFR as the reference standard. Databases of PubMed, Cochrane Library, EMBASE, Medion and Web of Science were searched. Seven studies met the inclusion criteria, including 833 stable patients (1377 vessels or lesions) with suspected or known coronary artery disease (CAD). The patient-based analysis showed pooled estimates of sensitivity, specificity and diagnostic odds ratio (DOR) for detection of ischemic lesions were 0.89 [95%confidence interval (CI), 0.85–0.93], 0.76 (95%CI, 0.64–0.84) and 26.21 (95%CI, 13.14–52.28). At a per-vessel or per-lesion level, the pooled estimates were as follows: sensitivity 0.84 (95%CI, 0.80–0.87), specificity 0.76 (95%CI, 0.67–0.83) and DOR 16.87 (95%CI, 9.41–30.25). Area under summary receiver operating curves was 0.90 (95%CI, 0.87–0.92) and 0.86 (95%CI, 0.83–0.89) at the two analysis levels, respectively. In conclusion, FFRCT technology achieves a moderate diagnostic performance for noninvasive identification of ischemic lesions in stable patients with suspected or known CAD in comparison to invasive FFR measurement

Noninvasive Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography For Identification Of Ischemic Lesions: A Systematic Review and Meta-Analysis

Detection of coronary ischemic lesions by fractional flow reserve (FFR) has been established as the gold standard. In recent years, novel computer based methods have emerged and they can provide simulation of FFR using coronary artery images acquired from coronary computed tomography angiography (FFRCT). This meta-analysis aimed to evaluate diagnostic performance of FFRCT using FFR as the reference standard. Databases of PubMed, Cochrane Library, EMBASE, Medion and Web of Science were searched. Seven studies met the inclusion criteria, including 833 stable patients (1377 vessels or lesions) with suspected or known coronary artery disease (CAD). The patient-based analysis showed pooled estimates of sensitivity, specificity and diagnostic odds ratio (DOR) for detection of ischemic lesions were 0.89 [95%confidence interval (CI), 0.85–0.93], 0.76 (95%CI, 0.64–0.84) and 26.21 (95%CI, 13.14–52.28). At a per-vessel or per-lesion level, the pooled estimates were as follows: sensitivity 0.84 (95%CI, 0.80–0.87), specificity 0.76 (95%CI, 0.67–0.83) and DOR 16.87 (95%CI, 9.41–30.25). Area under summary receiver operating curves was 0.90 (95%CI, 0.87–0.92) and 0.86 (95%CI, 0.83–0.89) at the two analysis levels, respectively. In conclusion, FFRCT technology achieves a moderate diagnostic performance for noninvasive identification of ischemic lesions in stable patients with suspected or known CAD in comparison to invasive FFR measurement

Invasive or non-invasive imaging for detecting high-risk coronary lesions?

INTRODUCTION: Advances in our understanding about atherosclerotic evolution have enabled us to identify specific plaque characteristics that are associated with coronary plaque vulnerability and cardiovascular events. With constant improvements in signal and image processing an arsenal of invasive and non-invasive imaging modalities have been developed that are capable of identifying these features allowing in vivo assessment of plaque vulnerability. Areas covered: This review article presents the available and emerging imaging modalities introduced to assess plaque morphology and biology, describes the evidence from the first large scale studies that evaluated the efficacy of invasive and non-invasive imaging in detecting lesions that are likely to progress and cause cardiovascular events and discusses the potential implications of the in vivo assessment of coronary artery pathology in the clinical setting. Expert commentary: Invasive imaging, with its high resolution, and in particular hybrid intravascular imaging appears as the ideal approach to study the mechanisms regulating atherosclerotic disease progression; whereas non-invasive imaging is expected to enable complete assessment of coronary tree pathology, detection of high-risk lesions, more accurate risk stratification and thus to allow a personalized treatment of vulnerable patients

T and small Protrusion (TAP) vs double-kissing crush technique: Insights from in vitro models

BACKGROUND: Percutaneous coronary interventions on complex bifurcation lesions may require implantation of two stents to appropriately treat diffuse side-branch (SB) disease. Comparisons among different bifurcation stenting techniques are continuously attempted by various study designs (bench tests, computer simulations, clinical studies). Among different techniques, double kissing crush (DKC) represents the last evolution for "crushing" while T and small Protrusion (TAP) represents the evolution of "T stenting". Both techniques are actually gaining popularity, but head-to-head comparisons are lacking. METHODS AND RESULTS: Two last generation drug-eluting stents (Synergy™, Boston Scientific, MA, USA and Ultimaster™,Terumo Corp., Japan) were implanted in left main bifurcation bench models using TAP (n = 6 sets) and DKC (n = 6 sets) techniques. A peristaltic pump with fresh porcine blood was used to perfuse the blood through the silicone model at a flow rate of 200 ml/min for 4 min. Optical coherence tomography (OCT) was used to assess stent struts geometry and thrombus formation. SB cross sectional area as well as SB obstruction did not significantly differ between the two techniques. Numerical (but not statistically significant) differences were found in terms of malapposed struts (fewer with TAP) and floating struts (fewer with DKC). Thrombus formation after blood perfusion was similar between TAP and DKC technique (1.53 ± 1.12 vs. 1.20 ± 1.01 mm2, p = 0.6). CONCLUSION: The result of the present in-vitro study shows the absence of significant difference between TAP and DKC in terms of stent struts apposition and acute thrombus formation potential. Despite the completely different technical steps required, both techniques have similar performance according to such articulated pre-clinical evaluation. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?: Due to its limited complexity, T and Protrusion (TAP) technique is considered the to-go technique for bifurcation lesions with good long-term results. Recently, double kissing crush (DKC) technique has been gaining popularity and demonstrated promising results in randomized clinical trials. WHAT DOES THIS STUDY ADD?: This in-vitro bench test study provides a unique detailed OCT comparison and local hemodynamic environment analysis of the two techniques. HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE?: New insights of acute thrombogenicity and computational flow model simulation may guide percutaneous therapeutic strategies of bifurcation lesions

Inducing Persistent Flow Disturbances Accelerates Atherogenesis and Promotes Thin Cap Fibroatheroma Development in \u3ci\u3eD374Y\u3c/i\u3e-PCSK9 Hypercholesterolemic Minipigs

Background—Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma (TCFA). Methods and Results—D374Y-PCSK9 hypercholesterolemic minipigs (N=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately post-stent, 19, and 34 weeks and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially-collected histological sections and co-registered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ~3-fold higher downstream of the SMS compared to both upstream of the SMS and in the control artery (pppp\u3c0.005). Conclusions—These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of TCFA