CT Perfusion Versus Coronary CT Angiography in Patients With Suspected In-Stent Restenosis or CAD Progression.

OBJECTIVES: The goal of this study was to assess the diagnostic performance of coronary computed tomography angiography (CTA) alone, adenosine-stress myocardial perfusion assessed by computed tomography (CTP) alone, and coronary CTA + CTP by using a 16-cm Z-axis coverage scanner versus invasive coronary angiography (ICA) and fractional flow reserve (FFR) as the clinical standard. BACKGROUND: Diagnostic performance of coronary CTA for in-stent restenosis detection is still challenging. Recently, CTP showed additional diagnostic power over coronary CTA in patients with suspected coronary artery disease. However, few data are available on CTP performance in patients with previous stent implantation. METHODS: Consecutive stable patients with previous coronary stenting referred for ICA were enrolled. All patients underwent stress myocardial CTP and rest CTP + coronary CTA. Invasive FFR was performed during ICA when clinically indicated. The diagnostic rate and diagnostic accuracy of coronary CTA, CTP, and coronary CTA + CTP were evaluated in stent-, territory-, and patient-based analyses. RESULTS: In the 150 enrolled patients (132 men; mean age 65.1 ± 9.1 years), the CTP diagnostic rate was significantly higher than that of coronary CTA in all analyses (territory based [96.7% vs. 91.1%; p < 0.0001] and patient based [96% vs. 68%; p < 0.0001]). When ICA was used as gold standard, CTP diagnostic accuracy was significantly higher than that of coronary CTA in all analyses (territory based [92.1% vs. 85.5%, p < 0.03] and patient based [86.7% vs. 76.7%, p < 0.03]). The concordant coronary CTA + CTP assessment exhibited the highest diagnostic accuracy values versus ICA (95.8% in the territory-based analysis). The diagnostic accuracy of CTP was significantly higher than that of coronary CTA (75% vs. 30.5%; p < 0.001). The radiation exposure of coronary CTA + CTP was 4.15 ± 1.5 mSv. CONCLUSIONS: In patients with coronary stents, CTP significantly improved the diagnostic rate and accuracy of coronary CTA alone compared with both ICA and invasive FFR as gold standard.

Preventing treatment failures in coronary artery disease: what can we learn from the biology of in-stent restenosis, vein graft failure, and internal thoracic arteries?

Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and the availability of percutaneous or surgical revascularization procedures significantly improves survival. However, both strategies are daunted by complications which limit long-term effectiveness. In-stent restenosis (ISR) is a major drawback for intracoronary stenting, while graft failure is the limiting factor for coronary artery bypass graft surgery (CABG), especially using veins. Conversely, internal thoracic artery (ITA) is known to maintain long-term patency in CABG. Understanding the biology and pathophysiology of ISR and vein graft failure (VGF) and mechanisms behind ITA resistance to failure is crucial to combat these complications in CAD treatment. This review intends to provide an overview of the biological mechanisms underlying stent and VGF and of the potential therapeutic strategy to prevent these complications. Interestingly, despite being different modalities of revascularization, mechanisms of failure of stent and saphenous vein grafts are very similar from the biological standpoint.

Longitudinal Stent Deformation: Precise Diagnosis With Optical Coherence Tomography.

Longitudinal stent deformation is a recognized complication of coronary angioplasty; however, it is difficult to detect angiographically. This case illustrates the value of OCT to identify and correctly diagnose longitudinal stent deformation.

Diagnostic accuracy of coronary CT angiography performed in 100 consecutive patients with coronary stents using a whole-organ high-definition CT scanner.

AIMS: To evaluate image quality, interpretability, diagnostic accuracy and radiation exposure of coronary CT angiography (CCTA) performed with a new scanner equipped with 0.23-mm spatial resolution, new generation iterative reconstruction, 0.28-second gantry rotation time and intra-cycle motion-correction algorithm in consecutive patients with coronary stents, including those with high heart rate (HR) and atrial fibrillation (AF). MATERIALS AND METHODS: We enrolled 100 consecutive patients (85 males, mean age 65 ±â€¯10 years) with previous coronary stent implantation scheduled for clinically indicated non-emergent invasive coronary angiography (ICA). Image quality, coronary interpretability and diagnostic accuracy vs. ICA were evaluated and the effective dose (ED) was recorded. RESULTS: Mean HR during the scan was 67 ±â€¯13 bpm. Twenty-six patients had >65 bpm HR during scanning and 13 patients had AF. Overall, image quality was high (Likert = 3.2 ±â€¯0.9). Stent interpretability was 95.8% (184/192 stents). Among 192 stented segments, CCTA correctly identified 22 out of 24 with >50% in-stent restenosis (ISR) (sensitivity 92%). In a stent-based analysis, specificity, positive and negative predictive values and diagnostic accuracy for ISR detection were 91%, 99%, 60% and 91%, respectively. In a patient-based analysis, CCTA diagnostic accuracy was 85%. Overall, mean ED of CCTA was 2.4 ±â€¯1.2 mSv. CONCLUSIONS: A whole-organ CT scanner was able to evaluate coronary stents with good diagnostic performance and low radiation exposure, also in presence of unfavorable HR and heart rhythm. TRANSLATIONAL ASPECT: The present study is the first to evaluate the CCTA capability of detecting in-stent restenosis in consecutive patients, including those with high HR and AF, using a recent scanner generation that combines improved spatial and temporal resolution with wide coverage. Using the whole-organ high-definition CT scanner we obtained high quality images of coronary stents with good interpretability and diagnostic accuracy combined with low radiation exposure, even in patients with unfavorable HR or heart rhythm for CCTA evaluation.

Epac1 deficiency inhibits basic fibroblast growth factor-mediated vascular smooth muscle cell migration.

Vascular smooth muscle cell (VSMC) migration and the subsequent intimal thickening play roles in vascular restenosis. We previously reported that an exchange protein activated by cAMP 1 (Epac1) promotes platelet-derived growth factor (PDGF)-induced VSMC migration and intimal thickening. Because basic fibroblast growth factor (bFGF) also plays a pivotal role in restenosis, we examined whether Epac1 was involved in bFGF-mediated VSMC migration. bFGF-induced lamellipodia formation and migration were significantly decreased in VSMCs obtained from Epac1-/- mice compared to those in Epac1+/+-VSMCs. The bFGF-induced phosphorylation of Akt and glycogen synthase kinase 3ß (GSK3ß), which play a role in bFGF-induced cell migration, was attenuated in Epac1-/--VSMCs. Intimal thickening induced by the insertion of a large wire was attenuated in Epac1-/- mice, and was accompanied by the decreased phosphorylation of GSK3ß. These data suggest that Epac1 deficiency attenuates bFGF-induced VSMC migration, possibly via Akt/GSK3ß pathways.

Fufang-Zhenzhu-Tiaozhi Capsule reduces restenosis via the downregulation of NF-kappaB and inflammatory factors in rabbits.

BACKGROUND: To investigate the effects of a Chinese herbal medicine Fufang-Zhenzhu Tiaozhi Capsule (FTZ) on restenosis and elucidate the mechanism of action. METHODS: A restenosis model was established by balloon rubbing the endothelium of the abdominal aorta followed by high fat diet. Rabbits were divided into blank control group, restenosis group, FTZ group (0.66 mg/kg/day), atorvastatin group (5 mg/kg/day) and FTZ + atorvastatin group (n = 8). Vascular stenosis was analyzed by X-ray. Serum levels of chemokines and cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were measured by ELISA. The levels of NF-κB, IκB-α, P-IκBα, IKK-α, and P-IKKα/ß from injured abdominal arteries were detected by Western blotting. RESULTS: Restenosis was induced successfully via abdominal artery balloon injuries and high fat diet. Restenosis was significantly decreased in FTZ group compared with restenosis group (P < 0.05). FTZ group had markedly reduced serum lipid levels (P < 0.05). In addition, the levels of TNF-α, IL-1, IL-6, IL-8, IL-12, ICAM-1 and MCP-1 decreased by FTZ treatment (P < 0.05). The expression of NF-κB in the atherosclerotic lesions was significantly attenuated in FTZ group (P < 0.05). CONCLUSION: FTZ could reduce restenosis via reducing NF-κB activity and inflammatory factor expression within the atherosclerotic lesion in a rabbit restenosis model. FTZ may be a new therapeutic agent for restenosis.

Intraoperative transit-time flowmetry in patients undergoing coronary surgery to determine relationships between graft flow and patency and prior coronary interventions and flow demand: a retrospective study.

BACKGROUND: The aim of this study was to delineate impacts of percutaneous coronary intervention (PCI), flow demand, and status of myocardium on graft flow. METHODS: We retrospectively assessed 736 individual coronary artery bypass grafts that had been created as the sole bypass graft for a vascular region in 405 patients. The grafts comprised 334 internal thoracic artery (ITA) to left anterior descending (LAD), 129 ITA and 65 saphenous vein grafts (SVG) to left circumflex (LCX), and 142 gastroepiploic artery (GEA) and 66 SVG to right coronary artery (RCA). Minimal luminal diameter, size of revascularized area, history of myocardial infarction, and PCI in the relevant area were examined to determine whether these factors are associated with flow insufficiency (FI), which was defined as ≤ 20 mL/min. RESULTS: FI developed in 123/736 grafts (16.7%) and correlated significantly with stenosis in the distal portion (23.0% vs. 12.8%, p = 0.0003). Prior myocardial infarction significantly correlated with FI in GEA-RCA (p = 0.002) and ITA-LCX grafts (p = 0.04). There was a history of PCI to the LAD (PCI group) in 54 ITA to LAD bypass grafts (16.2%), whereas the remaining 280 had no history of PCI to the LAD (no-PCI group). Graft flow was significantly greater in the no-PCI than in the PCI group (53 ± 29 vs. 42 ± 27; p = 0.006). The incidences of FI and graft failure were significantly higher in the PCI than the no-PCI group (22.2%, vs. 8.2%; p = 0.003; 9.2% vs. 1.8%; p = 0.003, respectively). CONCLUSIONS: Prior PCI has a negative impact on graft flow. The influences of small revascularized area, myocardial infarction, and PCI are greater, necessitating consideration of factors associated with flow demand or microvasculature when planning revascularization.

Local adventitial anti-angiogenic gene therapy reduces growth of vasa-vasorum and in-stent restenosis in WHHL rabbits.

BACKGROUND: Antiproliferative drugs in drug eluting stents (DES) are associated with complications due to impaired re-endothelialization. Additionally, adventitial neovascularization has been suggested to contribute to in-stent restenosis (ISR). Since Vascular Endothelial Growth Factors (VEGFs) are the key mediators of angiogenesis, we investigated feasibility and efficacy of local gene therapy for ISR utilizing soluble decoy VEGF receptors to reduce biological activity of adventitial VEGFs. METHOD: Sixty-nine adult WHHL rabbit aortas were subjected to endothelial denudation. Six weeks later catheter-mediated local intramural infusion of 1.5x10e10 pfu adenoviruses encoding soluble VEGF Receptor-1 (sVEGFR1), sVEGFR2, sVEGFR3 or control LacZ and bare metal stent implantation were performed in the same aortic segment. Marker protein expression was assessed at 6d in LacZ cohort. Immunohistochemistry, morphometrical analyses and angiography were performed at d14, d42 and d90. RESULTS: Transgene expression was localized to adventitia. All decoy receptors reduced the size of vasa-vasorum at 14d, AdsVEGFR2 animals also had reduced density of adventitial vasa-vasorum, whereas AdsVEGFR3 increased the density of vasa-vasorum. At d42, AdsVEGFR1 and AdsVEGFR2 reduced ISR (15.7 ±â€¯6.9% stenosis, P < 0.01 and 16.5 ±â€¯2.7%, P < 0.05, respectively) vs. controls (28.3 ±â€¯7.6%). Moreover, AdsVEGFR-3 treatment led to a non-significant trend in the reduction of adventitial lymphatics at all time points and these animals had significantly more advanced neointimal atherosclerosis at 14d and 42d vs. control animals. CONCLUSIONS: Targeting adventitial neovascularization using sVEGFR1 and sVEGFR2 is a novel strategy to reduce ISR. The therapeutic effects dissipate at late follow up following short expression profile of adenoviral vectors. However, inhibition of VEGFR3 signaling accelerates neoatherosclerosis.

Rationale and design of advantage (additional diagnostic value of CT perfusion over coronary CT angiography in stented patients with suspected in-stent restenosis or coronary artery disease progression) prospective study.

BACKGROUND: Recent studies demonstrated a significant improvement in the diagnostic performance of coronary CT angiography (CCTA) for the evaluation of in-stent restenosis (ISR). However, coronary stent assessment is still challenging, especially because of beam-hardening artifacts due to metallic stent struts and high atherosclerotic burden of non-stented segments. Adenosine-stress myocardial perfusion assessed by CT (CTP) recently demonstrated to be a feasible and accurate tool for evaluating the functional significance of coronary stenoses in patients with suspected coronary artery disease (CAD). Yet, scarce data are available on the performance of CTP in patients with previous stent implantation. AIM OF THE STUDY: We aim to assess the diagnostic performance of CCTA alone, CTP alone and CCTA plus CTP performed with a new scanner generation using quantitative invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR) as standard of reference. METHODS: We will enroll 300 consecutive patients with previous stent implantation, referred for non-emergent and clinically indicated invasive coronary angiography (ICA) due to suspected ISR or progression of CAD in native coronary segments. All patients will be subjected to stress myocardial CTP and a rest CCTA. The first 150 subjects will undergo static CTP scan, while the following 150 patients will undergo dynamic CTP scan. Measurement of invasive FFR will be performed during ICA when clinically indicated. RESULTS: The primary study end points will be: 1) assessment of the diagnostic performance (diagnostic rate, sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy) of CCTA, CTP, combined CCTA-CTP and concordant CCTA-CTP vs. ICA as standard of reference in a territory-based and patient-based analysis; 2) assessment of sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of CCTA, CTP, combined CCTA-CTP and concordant CCTA-CTP vs. invasive FFR as standard of reference in a territory-based analysis. CONCLUSIONS: The ADVANTAGE study aims to provide an answer to the intriguing question whether the combined anatomical and functional assessment with CCTA plus CTP may have higher diagnostic performance as compared to CCTA alone in identifying stented patients with significant ISR or CAD progression.

GuideLiner extension catheter-facilitated side strut stenting technique for the treatment of right coronary artery ostial in-stent restenosis.

Percutaneous coronary intervention (PCI) for the treatment of right coronary artery (RCA) ostial in-stent restenosis (ISR) can be challenging. The technical difficulties are compounded by excessive stent protrusion into the aorta, preventing coaxial engagement of the guiding catheter and wiring through the central stent lumen. Through this review, we aim to highlight the practical challenges encountered during the treatment of ostial RCA ISR through PCI and evaluate the various interventional techniques that have been used. We describe the first reported case of a GuideLiner extension catheter-facilitated side-strut stenting for the treatment of ostial RCA ISR and demonstrate the safety and feasibility of this novel technique.

Utility of stress perfusion-cardiac magnetic resonance in follow-up of patients undergoing percutaneous coronary interventions of the left main coronary artery.

To assess the accuracy of cardiac magnetic resonance (CMR) for the diagnosis of angiographic stenosis after percutaneous coronary intervention (PCI) of left main coronary artery (LMCA). Patients undergone in the last year PCI of unprotected LMCA and scheduled for conventional X-ray coronary angiography (CXA) were evaluated with stress perfusion CMR within 2 weeks before CXA. Main contraindications to CMR were exclusion criteria. Stress perfusion CMR was performed to follow a bolus of contrast Gadobutrol after 3 min of adenosine infusion. Between the 50 patients enrolled, only 1 did not finish the CMR protocol and 49 patients with median age 71 (65-75) years (38 male, 11 female) were analyzed. Between 784 coronary angiographic segments evaluated we found 75 stenosis or occlusions (prevalence 9.5%), but only 13 stenosis or occlusions in proximal segments (prevalence 6.6%). Patients with coronary stenosis (n = 12, 24%) showed a significantly (p = 0.002) higher prevalence of diabetes (7 of 12, 58%). At CMR examination, late gadolinium enhancement was present in 25 (51%), reversible perfusion defects in 12 (24%), and fixed perfusion defects in 6 subjects (12%). The only patient with LMCA restenosis resulted positive at perfusion CMR. The accuracy of stress perfusion CMR in diagnosis of coronary stenosis was higher when the analysis was performed only in proximal coronary arteries (95%, CI 86-99) compared to overall vessels (84%, CI 70-92). Stress perfusion CMR could strongly reduce the need for elective CXA in follow up of LMCA PCI and should be validated in further multicenter prospective studies.

Restenosis after Coronary and Peripheral Intervention: Efficacy and Clinical Impact of Cilostazol.

Restenosis is one of the main complications in patients undergoing coronary or peripheral revascularization procedures and is the leading cause for their long-term failures. Cilostazol is the only pharmacotherapy that showed an adequate efficacy for preventing restenosis in randomized, controlled studies after coronary or peripheral revascularization procedures. The present review sums up the main clinical evidence supporting the use of cilostazol after revascularization interventions, focusing on all its benefits, warnings, and administration schedules.

A Closer Look at Fractional Flow Reserve in Complex Anatomic Subsets: Left Main Disease, Bifurcation Lesions, and Saphenous Vein Grafts.

Fractional flow reserve (FFR) is a well-validated tool for determining the functional significance of a coronary artery stenosis, facilitating clinical decisions regarding the need for revascularization. FFR-guided revascularization improves clinical and economic outcomes. However, its application remains challenging in certain complex anatomic subsets, including left main coronary artery stenosis, bifurcation disease, and saphenous vein graft disease. This article reviews recent data supporting the use of FFR in these complex anatomic subsets.

Association of coronary microvascular dysfunction with restenosis of left anterior descending coronary artery disease treated by percutaneous intervention.

BACKGROUND: Several patients with successful percutaneous coronary interventions (PCIs) show evidence of coronary microvascular dysfunction (CMVD), which can be responsible for persistent positivity of electrocardiographic exercise stress test (EST). In this study, we assessed whether post-PCI CMVD may predict clinical outcome in patients undergoing successful elective PCI of an isolated stenosis of the left anterior descending (LAD) coronary artery. METHODS: We studied 29 patients (age 64±6, 23 M) with stable coronary artery disease and isolated stenosis (>75%) of the LAD coronary artery who underwent successful PCI with stent implantation. Coronary blood flow (CBF) velocity response to adenosine and to cold-pressor test (CPT) was assessed in the LAD coronary artery by transthoracic Doppler echocardiography 24h and 3months after PCI. The primary end-point was a combination of death, admission for acute coronary syndromes (ACS) or target vessel revascularization (TVR). RESULTS: No death or ACS occurred during 36months of follow-up, but TVR was performed in 5 patients (17.2%). CBF response to CPT at 3months after PCI was 1.31±0.2 vs. 1.71±0.4 in patients with or without TVR, respectively (p=0.03), whereas CBF response to adenosine at 3months in these two groups was 1.70±0.3 vs. 2.05±0.4 (p=0.059). CONCLUSIONS: Our data suggest that, in patients with successful PCI of LAD coronary artery stenosis, lower CBF response to the endothelium-dependent vasodilator stimulus CPT is associated with long-term recurrence of restenosis.

Intracoronary Brachytherapy for Recurrent Drug-Eluting Stent Failure.

OBJECTIVES: The study sought to report safety and long-term clinical efficacy of intravascular brachytherapy (VBT) for recurrent drug-eluting stent in-stent restenosis (DES-ISR). BACKGROUND: Recurrent DES-ISR remains a therapeutic challenge, and VBT has been used selectively in recurrent DES failure. METHODS: Patients undergoing VBT for recurrent DES-ISR were enrolled from a percutaneous coronary intervention registry. Clinical, procedural, VBT, and outcome data were collected for DES-ISR treated with radiation. Follow-up was obtained by phone call and clinic visits. RESULTS: A total of 186 patients (283 lesions) were included. Mean age was 65 ± 11 years, and 115 (61.8%) were men. Mean time to failure from last failed DES implantation was 450.65 ± 50 days. Majority (95%) had >2 episodes of target lesion revascularization (TLR). Commonest presentation of DES-ISR was unstable angina (68, 30%). All lesions were treated with balloon angioplasty followed by VBT using Beta-Cath system (Best Vascular Inc., Springfield, Virginia) with a dose of 23 to 25 Gy at 2 mm from source center. Radiation was delivered to site of ISR, without procedural adverse events, in 99% cases. Incidence of TLR was 3.3% at 6 months, 12.1% at 1 year, 19.1% at 2 years, and 20.7% at 3 years. No subacute thrombosis event was noted. One patient had late thrombosis during a 3-year follow-up. CONCLUSIONS: VBT for recurrent DES-ISR is safe, with low recurrence rates at 12 months post-procedure, and can be safely used as an effective short-term strategy. Overtime, there is a gradual attrition in patency requiring repeat intervention.

Relationship of Intraoperative Transit Time Flowmetry Findings to Angiographic Graft Patency at Follow-Up.

Early and late graft occlusion remains a significant complication of coronary artery bypass grafting. Transit time flowmetry is the most commonly used imaging technique to assess graft patency intraoperatively. Although the value of transit time flowmetry for intraoperative quality control of coronary anastomosis is well established, its standard variables for predicting eventual graft failure remain controversial. This review readdresses the issue of intraoperative transit time flowmetry, with a particular emphasis on defining cutoff values for standard variables and correlating them with the ability to predict midterm and long-term graft patency for arterial and venous conduits. Further research is warranted to support clinically useful recommendations on the intraoperative application and interpretation of transit time flowmetry.

The Same Angiographic Factors Predict Venous and Arterial Graft Patency: A Retrospective Study.

To evaluate the value of angiographic factors in predicting failure of both venous and arterial coronary artery bypass graft. We retrieved from our angiographic database 148 patients who underwent venous and/or arterial CABG and for whom a control coronary angiography at more than 1 month after surgery was available. Pre-CABG and follow-up angiographies were analyzed in order to evaluate diameter stenosis (DS,%), stenosis length (mm), Bogaty score (extent index), Sullivan score, and Gensini score for the extent of coronary artery disease, and Jeopardy Duke score for the extent of myocardial area supplied by an artery. Thirty-nine patients (26%) experienced graft failure at follow-up (mean follow-up 11.3 ± 4.6 months). Patients with venous graft failure [26 (20%)] had significantly smaller DS (P = 0.013), shorter stenosis length (P = 0.01), and lower extent index (P = 0.015), Sullivan score (P = 0.013), Gensini score (P = 0.04) as compared with those without venous graft failure. Patients with arterial graft failure [13 (11%)] had significantly lower DS (P = 0.008), shorter stenosis length (P = 0.001), and lower extent index (P = 0.03) and Sullivan score (P = 0.023) as compared with those without arterial graft failure. Venous and arterial graft failure are associated with less severe stenosis and less extensive atherosclerosis of the grafted vessel.