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Acetylsalicylic acid (ASA) represents a cornerstone of antiplatelet therapy for the treatment of atherosclerotic coronary artery disease (CAD). ASA is in fact indicated in case of an acute coronary syndrome or after a percutaneous coronary intervention with stent implantation. Aspirin hypersensitivity is frequently reported by patients, and this challenging situation requires a careful evaluation of the true nature of the presumed sensitivity and of its mechanisms, as well as to differentiate it from a more frequent (and more easily manageable) aspirin intolerance. Two main strategies are available to allow ASA administration for patients with CAD and suspected ASA hypersensitivity: a low-dose ASA challenge, aimed at assessing the tolerability of ASA at the antiplatelet dose of 100 mg, and desensitization, a therapeutic procedure which aims to induce tolerance to ASA. For those patients who cannot undergo ASA challenge and desensitization due to previous serious adverse reactions, or for those in whom desensitization was unsuccessful, a number of further alternative strategies are available, even if these have not been validated and approved by guidelines. The aim of this state-of-the-art review is therefore to summarize the established evidence regarding pathophysiology, clinical presentation, diagnosis, and management of aspirin hypersensitivity and to provide a practical guide for cardiologists (and clinicians) who have to face the not uncommon situation of a patient with concomitant coronary artery disease and aspirin hypersensitivity.

Coronary calcific disease represents one of the main challenges for the interventional cardiologist, for whom optimal lesion preparation and percutaneous coronary intervention optimization are paramount for correct management. In this perspective, intravascular imaging using optical coherence tomography (OCT) is becoming an increasingly indispensable tool. This work aims to provide a detailed overview of the complexity of calcified lesions, first analyzing their various morphologies and their clinical impact: spotty calcium seems to be more present in plaques at higher risk of destabilization, while diffuse calcification is typical of stable coronary stenosis; the eruptive calcific nodule is one of the three culprit lesion phenotypes responsible for acute coronary syndromes.In the second part of this review, the available technologies for the treatment of calcified lesions are described, with the aid of illustrative OCT images. Intravascular lithotripsy causes fractures at various levels of the calcified plaque, both circumferentially and longitudinally, with an improvement in vessel compliance; atherectomy acts by modifying the composition of the plaque with selective action on the hard calcific component. OCT, providing a comprehensive overview of lesion characteristics, can guide in the selection of the most appropriate therapeutic strategy, while also offering important information on the effectiveness of the chosen treatment.

Background: Ticagrelor improves clinical outcomes in patients with acute coronary syndromes compared with clopidogrel. Ticagrelor also inhibits cell uptake of adenosine and has been associated with cardioprotective effects in animal models. We sought to investigate the potential cardioprotective effects of ticagrelor, as compared with clopidogrel, in stable patients undergoing percutaneous coronary intervention (PCI)., Methods and Results: This was a Prospective Randomized Open Blinded End-points (PROBE) trial enrolling stable patients with coronary artery disease (CAD) requiring fractional flow reserve-guided PCI of intermediate epicardial coronary lesions. ST-segment elevation at intracoronary electrocardiogram (IC-ECG) during a two-step sequential coronary balloon inflations in the reference vessel during PCI was used as an indirect marker of cardioprotection induced by ischemic preconditioning (IPC). The primary endpoint of the study was the comparison of the delta (Δ) (difference) ST-segment elevation measured by IC-ECG during two-step sequential coronary balloon inflations., Results: Fifty-three patients were randomized to either clopidogrel or ticagrelor. The study was stopped earlier because the primary endpoint was met at a pre-specified interim analysis. ΔST-segment elevation was significantly higher in ticagrelor as compared to clopidogrel arms (P < 0.0001). Ticagrelor was associated with lower angina score during coronary balloon inflations. There was no difference in coronary microvascular resistance between groups. Adenosine serum concentrations were increased in patients treated with ticagrelor as compared to those treated with clopidogrel., Conclusions: Ticagrelor enhances the cardioprotective effects of IPC compared with clopidogrel in stable patients with CAD undergoing PCI. Further studies are warranted to fully elucidate the mechanisms through which ticagrelor may exert cardioprotective effects in humans., Clinical Trial Registration: http://www.clinicaltrials.gov. Unique Identifier: NCT02701140., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Funding Support and Author Disclosures Prof Burzotta and Prof Trani have received speaker fees from Abbott Vascular, Abiomed, Medtronic, and Terumo. Dr Francesco Bianchini has received a research grant from Abbott Vascular. Dr Aurigemma has received speaker fees from Abbott Vascular, Abiomed, Medtronic, Terumo, and Daiichi Sankyo. Dr Romagnoli has received speaker fees from Abbott Vascular and Terumo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Coronary artery disease (CAD) is prevalent in c. 50% of patients with severe aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI). The impact of CAD on TAVI outcomes and optimal management strategies remains unclear. This article considers the latest evidence on assessing CAD in TAVI patients and determining the timing for treating it to optimize clinical outcomes and resource utilization. We discuss the current methods for CAD diagnosis, including invasive coronary angiography (ICA), coronary computed tomography angiography, and the role of functional assessment indices such as fractional flow reserve and instantaneous wave-free ratio in guiding revascularization decisions. While ICA remains the standard for determining CAD severity in TAVI candidates, coronary computed tomography angiography has shown the potential to reduce unnecessary ICA procedures. When indicated, fractional flow reserve seems more reliable than the instantaneous wave-free ratio in aortic valve stenosis patients, particularly when evaluated post-TAVI. Recent data suggests that percutaneous coronary intervention post-TAVI may be associated with improved outcomes compared to pre-TAVI interventions. In summary, the optimal management of CAD in TAVI patients is still under investigation. The current evidence supports a tailored approach, considering pre- and post-TAVI percutaneous coronary intervention strategies based on individual patient characteristics and procedural complexities. Further randomized trials are needed to establish definitive guidelines.

Myocardial infarction with non-obstructive coronary artery disease (MINOCA) is a heterogeneous clinical condition affecting 5% to 8% of patients presenting with acute myocardial infarction. Initially it was considered a favorable clinical diagnosis, nowadays it is known that MINOCA can significantly affect patient quality of life and portends a guarded prognosis. Therefore, it is of utmost importance to identify the specific pathophysiological mechanism underlying this clinical condition in order to set up a targeted pharmacological and non-pharmacological therapy. Coronary angiography is still a mandatory diagnostic test to rule out obstructive coronary artery disease but has limited capability to identify other potential functional and structural etiologies of MINOCA. The purpose of this review is to provide an overview of the invasive diagnostic work-up of patients with MINOCA, highlighting the diagnostic tools warranted beyond coronary angiography inside the cath lab (intracoronary provocation tests, intracoronary imaging and indexes for the assessment of coronary microvascular dysfunction), and the remaining essential knowledge gaps in this field.

Introduction: The association of coronary stent malapposition (SM) and adverse clinical outcomes after percutaneous coronary intervention (PCI) remains unclear. We aimed to perform a systematic review and meta-analysis of randomized and observational studies to assess the association between acute and persistent SM detected using intravascular ultrasound (IVUS) or optical coherence tomography (OCT) and adverse cardiovascular outcomes., Evidence Acquisition: Available studies were identified through a systematic search of PubMed, reference lists of relevant articles, and Medline. Main efficacy outcomes of interest were: device-oriented composite endpoint (DoCE, including cardiac death, myocardial infarction [MI], target lesion revascularization [TLR], and stent thrombosis [ST]), major safety events (MSE, including cardiac death, MI and ST), TLR, and ST. A sensitivity analysis regarding the impact of major malapposition was also performed., Evidence Synthesis: A total of 9 studies enrolling 6497 patients were included in the meta-analysis. After a mean follow-up of 24±14 months, overall acute and/or persistent malapposition was not significantly associated with the occurrence of all the outcomes of interest, including DoCE (risk ratio [RR] 1.00, 95% confidence interval [CI, 0.79-1.26], P=0.99), MSE (RR 1.42, 95%CI [0.81-2.50], P=0.22), TLR (RR 0.84, 95%CI [0.59-1.19], P=0.33), and ST (RR 1.16, 95%CI [0.48-2.85], P=0.74). In the sensitivity analysis, we found a significant increase of MSE in patients with major malapposition (RR 2.97, 95%CI [1.51-5.87], P=0.001)., Conclusions: Acute and persistent SM were not overall associated with adverse cardiovascular clinical outcomes at follow-up. However, major malapposition was associated with an increased risk of major safety events, including cardiac death, MI and ST. These findings should be taken into account during stent implantation and PCI optimization.

Background: The use of Impella support is increasingly adopted to "protect" patients with severe coronary artery disease (CAD) and left ventricle (LV) dysfunction undergoing percutaneous coronary intervention (PCI)., Aims: To evaluate the impact of Impella-protected (Abiomed, Danvers, Massachusetts, USA) PCIs on myocardial function recovery., Methods: Patients with significant LV dysfunction undergoing multi-vessel PCIs with pre-intervention Impella implantation were evaluated by echocardiography before PCI and at median follow up of 6 months: global and segmental LV contractile function were assessed by LV ejection fraction (LVEF) and wall motion score index (WMSI), respectively. Extent of revascularization was graded using the British Cardiovascular Intervention Society Jeopardy score (BCIS-JS). Study endpoints were LVEF and WMSI improvement, and its correlation with revascularization., Results: A total of 48 high surgical risk (mean EuroSCORE II 8) patients with median LVEF value of 30%, extensive wall motion abnormalities (median WMSI 2.16), and severe multi-vessel CAD (mean SYNTAX score 35) were included. PCIs brought a significant reduction of ischemic myocardium burden with BCIS-JS decrease from mean value of 12 to 4 (p < 0.001). At follow-up, WMSI reduced from 2.2 to 2.0 (p = 0.004) and LVEF increased from 30% to 35% (p = 0.016). WMSI improvement was proportional to the baseline impairment (R - 0.50, p < 0.001), and confined to revascularized segments (from 2.1 to 1.9, p < 0.001)., Conclusions: In patients with extensive CAD and severe LV dysfunction, multi-vessel Impella-protected PCI was associated to an appreciable contractile recovery, mainly determined by regional wall motion improvement in revascularized segments., Competing Interests: Declaration of Competing Interest Dr. Romagnoli, Dr. Burzotta, Dr. Aurigemma, and Dr. Trani has received speaker's fees by Medtronic, Abiomed, and St. Jude. The other authors disclose no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: In patients with complex coronary bifurcation lesions undergoing percutaneous coronary intervention (PCI), various 2-stent techniques might be utilised. The Visible Heart Laboratories (VHL) offer an experimental environment where PCI results can be assessed by multimodality imaging., Aims: We aimed to assess the post-PCI stent configuration achieved by 2-stent techniques in the VHL and to evaluate the procedural factors associated with suboptimal results., Methods: Bifurcation PCI with 2-stent techniques, performed by expert operators in the VHL on explanted beating swine hearts, was studied. The adopted bifurcation PCI strategy and the specific procedural steps applied in each procedure were classified according to Main, Across, Distal, Side (MADS)-2 and to their adherence to the European Bifurcation Club (EBC) recommendations. Microcomputed tomography (micro-CT) was used to assess the post-PCI stent configuration. The primary endpoint was "suboptimal stent implantation", defined as a composite of stent underexpansion (<90%), side branch ostial area stenosis >50% and the gap between stents., Results: A total of 82 PCI with bifurcation stenting were assessed, comprised of 29 crush, 25 culotte, 28 T/T and small protrusion (TAP) techniques. Suboptimal stent implantation was observed in as many as 53.7% of the cases, regardless of baseline anatomy or the stenting strategy. However, less frequent use of the proximal optimisation technique (POT; p=0.015) and kissing balloon inflations (KBI; p=0.027) and no adherence to EBC recommendations (p=0.004, p multivariate=0.006) were significantly associated with the primary endpoint., Conclusions: Commonly practised bifurcation 2-stent techniques may result in imperfect stent configurations. More frequent use of POT/KBI and adherence to expert recommendations might reduce the occurrence of post-PCI suboptimal stent configurations.

Background: The combination of coronary imaging assessment and blood flow perturbation estimation has the potential to improve percutaneous coronary intervention (PCI) guidance., Objectives: We aimed to evaluate a novel method for fast computation of Murray law-based quantitative flow ratio (μQFR) from coregistered optical coherence tomography (OCT) and angiography (OCT-modulated μQFR, OCT-μQFR) in predicting physiological efficacy of PCI., Methods: Patients treated by OCT-guided PCI in the OCT-arm of the Fractional Flow Reserve versus Optical Coherence Tomography to Guide RevasculariZAtion of Intermediate Coronary Stenoses trial (FORZA, NCT01824030) were included. Based on angiography and OCT before PCI, simulated residual OCT-μQFR was computed by assuming full stent expansion to the intended-to-treat segment. Plaque composition was automatically characterized using a validated artificial intelligence algorithm. Actual post-PCI OCT-μQFR pullback was computed based on coregistration of angiography and OCT acquired immediately after PCI. Suboptimal functional stenting result was defined as OCT-μQFR ≤ 0.90., Results: Paired simulated residual OCT-μQFR and actual post-PCI OCT-μQFR were obtained in 76 vessels from 74 patients. Simulated residual OCT-μQFR showed good correlation (r = 0.80, p < 0.001), agreement (mean difference = -0.02 ± 0.02, p < 0.001), and diagnostic concordance (79%, 95% confidence interval: 70%-88%) with actual post-PCI OCT-μQFR. Actual post-PCI in-stent OCT-μQFR had a median value of 0.02 and was associated with left anterior descending artery lesion location (β = 0.38, p < 0.001), higher baseline total plaque burden (β = 0.25, p = 0.031), and fibrous plaque volume (β = 0.24, p = 0.026)., Conclusions: This study based on patients enrolled in a prospective OCT-guidance PCI trial shows that simulated residual OCT-μQFR had good correlation, agreement, and diagnostic concordance with actual post-PCI OCT-μQFR. In OCT-guided procedures, OCT-μQFR in-stent pressure drop was low and was significantly predicted by pre-PCI vessel/plaque characteristics., (© 2023 Wiley Periodicals LLC.)

Background: There is uncertainty about which diagnostic strategy for detecting coronary artery disease (CAD) provides better outcomes., Purpose: To compare the effect on clinical management and subsequent health effects of alternative diagnostic strategies for the initial assessment of suspected stable CAD., Data Sources: PubMed, Embase, and Cochrane Central Register of Controlled Trials., Study Selection: Randomized clinical trials comparing diagnostic strategies for CAD detection among patients with symptoms suggestive of stable CAD., Data Extraction: Three investigators independently extracted study data., Data Synthesis: The strongest available evidence was for 3 of the 6 comparisons: coronary computed tomography angiography (CCTA) versus invasive coronary angiography (ICA) (4 trials), CCTA versus exercise electrocardiography (ECG) (2 trials), and CCTA versus stress single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) (5 trials). Compared with direct ICA referral, CCTA was associated with no difference in cardiovascular death and myocardial infarction (relative risk [RR], 0.84 [95% CI, 0.52 to 1.35]; low certainty) but less index ICA (RR, 0.23 [CI, 0.22 to 0.25]; high certainty) and index revascularization (RR, 0.71 [CI, 0.63 to 0.80]; moderate certainty). Moreover, CCTA was associated with a reduction in cardiovascular death and myocardial infarction compared with exercise ECG (RR, 0.66 [CI, 0.44 to 0.99]; moderate certainty) and SPECT-MPI (RR, 0.64 [CI, 0.45 to 0.90]; high certainty). However, CCTA was associated with more index revascularization (RR, 1.78 [CI, 1.33 to 2.38]; moderate certainty) but less downstream testing (RR, 0.56 [CI, 0.45 to 0.71]; very low certainty) than exercise ECG. Low-certainty evidence compared SPECT-MPI versus exercise ECG (2 trials), SPECT-MPI versus stress cardiovascular magnetic resonance imaging (1 trial), and stress echocardiography versus exercise ECG (1 trial)., Limitation: Most comparisons primarily rely on a single study, many studies were underpowered to detect potential differences in direct health outcomes, and individual patient data were lacking., Conclusion: For the initial assessment of patients with suspected stable CAD, CCTA was associated with similar health effects to direct ICA referral, and with a health benefit compared with exercise ECG and SPECT-MPI. Further research is needed to better assess the relative performance of each diagnostic strategy., Primary Funding Source: None. (PROSPERO: CRD42022329635)., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0231.

Background: Stepwise provisional stenting is the gold standard for percutaneous coronary intervention (PCI) on bifurcation lesions, but the optimal ballooning technique for eventual side branch treatment is not established. The objective of the present study was to compare the stent configuration obtained by 2 different side branch optimization techniques performed after main vessel (MV) stent implantation: proximal optimization technique+kissing balloon inflation+final proximal optimization technique (POT/KBI/POT [PKP]) versus proximal optimization technique+isolated side branch dilation+final proximal optimization technique (POT-side-POT [PSP])., Methods: We realized a 1:1 prospective randomized trial comparing bifurcation PCI conducted (under angiographic and angioscopic visualization) with either PKP or PSP in reanimated swine hearts using commercially available drug-eluting stents. After PCI, the obtained stent configuration (expansion, eccentricity, apposition) was assessed by optical coherence tomography and micro-computed tomography dividing the stent in 4 segments. Primary study end point was minimum stent expansion at the distal MV segment., Results: A total of 30 PCIs were successfully performed according to randomization obtaining overall good results (average minimum stent expansion >90% at optical coherence tomography and micro-computed tomography) with PSP or PKP. Minimum stent expansion at the distal MV segment was significantly higher with PKP as compared with PSP at optical coherence tomography (97.9±4.2% versus 91.0±7.7%; P =0.002) and micro-computed tomography (98.1±4.1% versus 91.3±7.9%; P =0.006). Other significant findings included higher stent eccentricity index at proximal MV with PSP, higher side branch scaffolding length and lower malapposition (at bifurcation core and distal MV) with PKP., Conclusions: This first prospective randomized trial in a unique non-atherosclerotic preclinical environment showed that bifurcation PCI conducted with PSP and PKP achieves different stent configurations. These findings might be useful in bifurcation PCI practice and call for further evaluations in clinical ground.

Introduction and Objectives: Coronary artery disease (CAD) is found in 30%-50% of patients with severe aortic stenosis (AS) undergoing treatment. The best management of CAD in AS patients undergoing transcatheter aortic valve implantation (TAVI) is still unclear. We investigated the clinical impact of the extent of jeopardized myocardium in patients with concomitant CAD and severe AS treated by TAVI., Methods: Consecutive patients who underwent TAVI procedures at our hospital were identified. In the presence of CAD, the myocardium jeopardized before TAVI was graded using the British Cardiovascular Intervention Society (BCIS) jeopardy score (JS). The study population was divided in 3 groups: patients without concomitant CAD (no-CAD), patients with CAD and BCIS-JS ≤ 4 (CAD BCIS-JS ≤ 4) and patients with concomitant CAD and BCIS-JS> 4 (CAD BCIS-JS> 4). The primary study endpoint was major adverse cardiovascular and cerebrovascular events (MACCE)., Results: A total of 403 patients entered the study: 223 no-CAD, 94 CAD BCIS-JS ≤ 4 and 86 CAD BCIS-JS> 4. At> 3 months of follow-up [range 104-3296 days], patients without CAD and CAD patients with BCIS-JS ≤ 4 had better survival free from MACCE compared with those with less extensive revascularization (BCIS-JS> 4) (P=.049). This result was driven by a significant reduction in death (P=.031). On multivariate analysis, residual BCIS-JS ≤ 4 and NYHA class III-IV independently predicted MACCE., Conclusions: In patients with concomitant CAD and severe AS, the extent of jeopardized myocardium before TAVI impacts on clinical outcomes., (Copyright © 2022 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: In provisional technique, main vessel (MV) drug-eluting stent (DES) diameter is usually selected according to distal MV to reduce carina shift. Proximal optimization technique (POT) is used to expand the DES in the proximal MV. Occasionally, the size discrepancy between left main (LM) and left anterior descending artery (LAD) may be huge and this may cause stent malapposition and poor vessel wall coverage in large-sized LM. Recently, some manufactures designed extra-large DES to treat large vessels., Methods: We developed an "adapted" provisional strategy based on under-deployment of extra-large DES in case of major size mismatch between LM and proximal LAD. Bench tests were realized in appropriately designed LM bifurcation model using an extra-large DES (Onyx XL, Medtronic, Santa Rosa, CA, USA). This technique was adopted when such "rare" anatomy was found in our clinical practice., Results: At bench test, Onyx XL 4.5 mm stent reaches 3.8 mm at 5-6 atmospheres, with favorable stent deformation achieved after POT, kissing balloon and re-POT. This technique was performed in 10 patients undergoing unprotected LM stenting with large LM and major mismatch toward LAD. Angiographic success was achieved in all cases and optical coherence tomography assessment was performed in 5 patients revealing optimal stent result. After a follow-up of 557 days (range: 90-1369 days), clinical course was uneventful in all treated patients., Conclusions: Under-deployment of extra-large DES is a technical option that can be considered to optimize the provisional stenting technique in selected patients with major diameter mismatch between large-sized LM and LAD.

Aims: Wall shear stress (WSS) is involved in coronary artery plaque pathological mechanisms and modulation of gene expression. This study aims to provide a comprehensive haemodynamic and biological description of unstable (intact-fibrous-cap, IFC, and ruptured-fibrous-cap, RFC) and stable (chronic coronary syndrome, CCS) plaques and investigate any correlation between WSS and molecular pathways., Methods and Results: We enrolled 24 CCS and 25 Non-ST Elevation Myocardial Infarction-ACS patients with IFC (n = 11) and RFC (n = 14) culprit lesions according to optical coherence tomography analysis. A real-time PCR primer array was performed on peripheral blood mononuclear cells for 17 different molecules whose expression is linked to WSS. Computational fluid dynamics simulations were performed in high-fidelity 3D-coronary artery anatomical models for three patients per group. A total of nine genes were significantly overexpressed in the unstable patients as compared to CCS patients, with no differences between IFC and RFC groups (GPX1, MMP1, MMP9, NOS3, PLA2G7, PI16, SOD1, TIMP1, and TFRC) while four displayed different levels between IFC and RFC groups (TNFα, ADAMTS13, EDN1, and LGALS8). A significantly higher WSS was observed in the RFC group (p < 0.001) compared to the two other groups. A significant correlation was observed between TNFα (p < 0.001), EDN1 (p = 0.036), and MMP9 (p = 0.005) and WSS values in the RFC group., Conclusions: Our data demonstrate that IFC and RFC plaques are subject to different WSS conditions and gene expressions, suggesting that WSS profiling may play an essential role in the plaque instability characterization with relevant diagnostic and therapeutic implications in the era of precision medicine., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Coronary vasomotor abnormalities are important causes of myocardial ischemia in patients with nonobstructive coronary artery disease (NOCAD). However, the role of air pollution in determining coronary vasomotor disorders has never been investigated., Objectives: We aimed to evaluate the association between long-term exposure to particulate matter 2.5 (PM2.5) and 10 (PM10), and coronary vasomotor disorders in NOCAD patients., Methods: Patients with myocardial ischemia and NOCAD undergoing coronary angiography and intracoronary provocation test with acetylcholine were prospectively studied. Both patients with chronic myocardial ischemia and nonobstructive coronary arteries and myocardial infarction with nonobstructive coronary arteries (MINOCA) were enrolled. Based on each case's home address, exposure to PM2.5 and PM10 was assessed., Results: We included 287 patients (median age, 62.0 years [IQR: 52.0-70.0 years], 149 [51.9%] males); there were 161 (56.1%) myocardial ischemia and nonobstructive coronary arteries and 126 (43.9%) MINOCA cases. One hundred seventy-six patients (61.3%) had positive provocation test. Exposure to PM2.5 and PM10 was higher in patients with a positive provocation test (P < 0.001). At multivariate logistic regression analysis, PM2.5 and PM10 were independent predictors of a positive provocation test (P = 0.001 and P = 0.029, respectively). Interestingly, among these patients, PM2.5 and PM10 were both independent predictors of MINOCA (P < 0.001 and P = 0.001, respectively) as clinical presentation, whereas PM2.5 was independently associated with the occurrence of epicardial spasm as opposed to microvascular spasm (P = 0.001)., Conclusions: Higher exposure to PM2.5 and PM10 in patients with myocardial ischemia and NOCAD is associated with coronary vasomotor abnormalities. In particular, PM2.5 is an independent risk factor for the occurrence of epicardial spasm and MINOCA as clinical presentation., Competing Interests: Funding Support And Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Plaque rupture (PR) is the main cause of coronary thrombosis in non-ST segment elevation myocardial infarction (NSTEMI), but can be found in stable coronary artery disease (CAD). Our study compared the morphology and local inflammatory activity of ruptured plaques between stable CAD and NSTEMI patients using frequency-domain optical coherence tomography (FD-OCT)., Methods: We retrospectively evaluated 70 plaques with PR at the FD-OCT (25 in stable CAD patients and 45 in NSTEMI patients). Main clinical, angiographic, and morphological features were compared., Results: Besides an overall equivalence in clinical and angiographic features (except for more smokers among NSTEMI patients), some important FD-OCT differences in plaque morphology emerged: PR in NSTEMI was characterized by more macrophage infiltrates (78% in NSTEMI patients vs 20% in stable CAD patients; P<.001) and intraluminal thrombosis (84% in NSTEMI patients vs 48% in stable CAD patients; P<.01). Quantitative analysis showed a higher density of macrophages in NSTEMI than in stable CAD patients: median max normalized standard deviation (NSD) was 0.0934 (IQR, 0.0796-0.1022) vs 0.0689 (IQR, 0.0598-0.0787); P<.01 and mean NSD was 0.062 (IQR, 0.060-0.065) vs 0.053 (IQR, 0.051-0.060); P<.001. Other morphological features did not differ between stable CAD and NSTEMI patients. Main FD-OCT quantitative parameters like minimal lumen area and plaque length were also equivalent between the 2 groups., Conclusions: Differences in morphological features of PR between stable CAD and NSTEMI patients suggest that local inflammation contributes to the unstable fate of the atherosclerotic plaque.

Background Myocardial bridging (MB) may represent a cause of myocardial ischemia in patients with non-obstructive coronary artery disease (NOCAD). Herein, we assessed the interplay between MB and coronary vasomotor disorders, also evaluating their prognostic relevance in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) or stable NOCAD. Methods and Results We prospectively enrolled patients with NOCAD undergoing intracoronary acetylcholine provocative test. The incidence of major adverse cardiac events, defined as the composite of cardiac death, non-fatal myocardial infarction, and rehospitalization for unstable angina, was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires summary score. We enrolled 310 patients (mean age, 60.6±11.9; 136 [43.9%] men; 169 [54.5%] stable NOCAD and 141 [45.5%] MINOCA). MB was found in 53 (17.1%) patients. MB and a positive acetylcholine test coexisted more frequently in patients with MINOCA versus stable NOCAD. MB was an independent predictor of positive acetylcholine test and MINOCA. At follow-up (median, 22 months; interquartile range, 13-32), patients with MB had a higher rate of major adverse cardiac events, mainly driven by a higher rate of hospitalization attributable to angina, and a lower Seattle Angina Questionnaires summary score (all P <0.001) compared with patients without MB. In particular, the group of patients with MB and a positive acetylcholine test had the worst prognosis. Conclusions Among patients with NOCAD, coronary spasm associated with MB may predict a worse clinical presentation with MINOCA and a higher rate of hospitalization attributable to angina at long-term follow-up with a low rate of hard events.

Background: Contrast fractional flow reserve (cFFR) is a relatively new tool for the assessment of intermediate coronary artery stenosis and represents a reliable surrogate of FFR with the advantage of potentially simplifying functional evaluation. We aimed to compare the incidence of major adverse cardiac events (MACE) in patients undergoing functional evaluation with both FFR and cFFR based on the results of the two indexes., Method and Result: We retrospectively analyzed outcomes in 488 patients who underwent functional evaluation with FFR and cFFR. Patients were divided into four groups using the cutoff values of 0.80 for FFR and 0.85 for cFFR: -/- (n = 298), +/+ (n = 134), -/+(n = 31) and +/- (n = 25). All patients were treated according to FFR value. MACE rate was assessed in each group, including death, myocardial infarction and urgent target vessel revascularization (TVR). Mean follow-up time was 22 ± 15 months. Incidence of MACE at follow-up was 8.3% in FFR-/cFFR-, 14.0% in FFR+/cFFR+, 16.0% in FFR-/cFFR+ and 8.0% in FFR+/cFFR- without a significant difference amongst the 4 groups (p = 0.2). Nevertheless, a significant difference in the rate of TVR comparing FFR-/cFFR- (n = 17) and FFR-/cFFR+ (n = 5) was found at 24 months (5.7% vs 16.0%; p = 0.027)., Conclusion: cFFR is accurate in predicting FFR and consequently reliable in guiding coronary revascularization. In the rare case of discordance, while FFR+/cFFR- patients show a prognosis similar to FFR-/cFFR- patients, FFR-/cFFR+ patients show a prognosis similar to FFR+/cFFR+ patients., Competing Interests: Declaration of Competing Interest A.M.L. received speaking honoraria from St. Jude Medical/Abbott, Medtronic, Abiomed and from Bracco Imaging, C.T, F.B. received speaker's fees from Abbott, Medtronic, and Abiomed. The other authors have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In humans, the most common anatomic variation of the left main (LM) stem is represented by its distal division in 3 branches (LM trifurcation) instead of 2. LM trifurcation disease accounts for ≈10% to 15% of all LM diseases and is often managed by cardiac surgery. Over the last decades, due to the improvement of interventional material and techniques, percutaneous coronary intervention started gaining acceptance to treat patients with LM disease including those with trifurcated anatomy. Yet, LM trifurcation stenosis with its intrinsic anatomic complexity (3 branches, at least 4 angles, wide variability in branch size and disease) is recognized as a challenging lesion subset for percutaneous coronary intervention. In this review, we summarize available data about LM trifurcation anatomy, its influence on percutaneous coronary intervention feasibility, and the evidence collected regarding the different technical options (including trissing balloon inflation).

Objective: The objective is to analyze the acute and midterm angiographic outcome of percutaneous treatment of left main coronary stem (LM-PCI) guided by optical coherence tomography (OCT)., Background: LM-PCI is a complex procedure, and several anatomical factors may impair its outcome. Intravascular imaging is emerging as a useful tool to guide the procedure., Methods: We conducted a retrospective analysis of patients undergoing LM-PCI at three European centers between 2014 and 2017 with a control angiography at 6-12 months. Patients were divided into two groups: OCT-guidance (pre- and post-PCI) and control group (standard angiographic guidance with/out intravascular ultrasound [IVUS]). A blinded core lab analyzed all angiographic images. Primary endpoint was late lumen loss (LLL) after 6 months., Results: A total of 112 patients entered the study, 55 in the OCT group and 57 in the control group (10 IVUS). Baseline and procedural characteristics were similar between groups. Overall, reference vessel diameter of the LM was 3.98 ± 0.65 mm. OCT guidance detected four cases of stent underexpansion (7.2%) and six cases of acute malapposition (10.9%). After a median of 207 ± 23 days, LLL of LM tended to be lower in the OCT group (0.12 ± 0.41 vs. 0.26 ± 0.52 mm, p = .10), and was significantly reduced in the distal portion of the main vessel (0.03 ± 0.45 vs. 0.24 ± 0.53 mm, p = .025). Percent diameter stenosis was also lower (14 ± 9 vs. 19 ± 16%, p = .05). Adverse event rates were similar in the two groups., Conclusions: In this study, systematic OCT guidance during LM-PCI allowed a timely detection and correction of acute stent underexpansion and malapposition, and was associated with signs of improved angiographic outcome at midterm, compared to standard practice., (© 2019 Wiley Periodicals, Inc.)

Background: PCI in CBL is common and technically demanding. Whether such patients have adverse outcome during the follow-up after successful PCI is unclear. We aim to compare the clinical outcome after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation of coronary bifurcation lesions (CBL) and non-CBL., Methods: We performed a systematic literature search to identify studies reporting the clinical outcome of patients undergoing PCI in CBL or not. Patients with left main disease constituted a predefined subgroup. Primary study end-point was major adverse cardiac events (MACE)., Results: Fifteen publications on 23 891 patients with coronary artery disease treated by DES in CBL or not were identified. Median follow-up length was 24 months (range: 12-60). MACE at the longest available follow-up were significantly higher in CBL as compared with non-CBL (19.0 vs. 12.1%, P < 0.001). Similar results were obtained in the subanalysis restricted to second-generation DES studies. The MACE rate was higher early, then decreased during the follow-up being, however, appreciable at all timings up to 36 months. In the left main (LM) subanalysis (four studies, 3210 patients), patients underwent DES implantation in distal LM, as compared with nondistal LM, had increased the MACE rate during the follow-up (27.4 vs. 17.4%, P < 0.001), which was driven by higher target vessel revascularization., Conclusions: In the contemporary DES era, CBL represent a subset of lesions associated with increased rate of MACE after PCI. This data prompt for studies aimed at improving the clinical outcomes of patients with CAD.

The rupture of a vulnerable plaque, known as ulceration, is the most common cause of myocardial infarction. It can be recognized by angiographic features, such as prolonged intraluminal filling and delayed clearance of the contrast liquid. The diagnosis of such an event is an open challenge due to the limited angiographic resolution and acquisition frequency. The treatment of ulcerated plaques is an open discussion, due to the high heterogeneity and the lack of evidences that support particular strategies. Therefore, the therapeutic decision should follow a detailed investigation with angiography and intravascular imaging, such as optical coherence tomography (OCT), to locate the lesion, besides its geometric features and the lumen occlusion severity. The aim of this study is the application of a framework for the in-silico analysis of the disrupted hemodynamics due to an ulcerated lesion. The study employed a validated OCT-based reconstruction methodology and computational fluid dynamics (CFD) simulations for the computation of local hemodynamic quantities, such as wall shear stress. The reported findings, such as disrupted pre-operative flow conditions, proved the applicability of the developed framework for CFD analyses on complicated patient-specific anatomies that feature ulcerated plaques. The prediction of lesion expansion and the clinical decision making can benefit from a reliable computation of wall shear stress distributions that result from the peculiar anatomy of the lesion. The application of intravascular OCT imaging, high fidelity 3D reconstructions and CFD simulations might guide the treatment of such pathology., Competing Interests: Declaration of Competing Interest The authors have no professional or financial conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Ticagrelor is a reversibly binding, direct-acting, oral, P 2 Y 12 antagonist used for the prevention of atherothrombotic events in patients with coronary artery disease (CAD). Ticagrelor blocks adenosine reuptake through the inhibition of equilibrative nucleoside transporter 1 (ENT-1) on erythrocytes and platelets, thereby facilitating adenosine-induced physiological responses such as an increase in coronary blood flow velocity. Meanwhile, adenosine plays an important role in triggering ischemic preconditioning through the activation of the A1 receptor. Therefore, an increase in ticagrelor-enhanced adenosine bioavailability may confer beneficial effects through mechanisms related to preconditioning activation and improvement of coronary microvascular dysfunction., Methods: To determine whether ticagrelor can trigger ischemic preconditioning and influence microvascular function, we designed this prospective, open-label, pilot study that enrolled patients with stable multivessel CAD requiring staged, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI). Participants will be randomized in 1:1 ratios either to ticagrelor (loading dose (LD) 180 mg, maintenance dose (MD) 90 mg bid) or to clopidogrel (LD 600 mg, MD 75 mg) from 3 to 1 days before the scheduled PCI. The PCI operators will be blinded to the randomization arm. The primary endpoint is the delta (difference) between ST segment elevations (in millimeters, mm) as assessed by intracoronary electrocardiogram (ECG) during the two-step sequential coronary balloon inflation in the culprit vessel. Secondary endpoints are 1) changes in coronary flow reserve (CFR), index of microvascular resistance (IMR), and FFR measured in the culprit vessel and reference vessel at the end of PCI, and 2) angina score during inflations. This study started in 2018 with the aim of enrolling 100 patients. Based on the rate of negative FFR up to 30% and a drop-out rate up to 10%, we expect to detect an absolute difference of 4 mm among the study arms in the mean change of ST elevation following repeated balloon inflations. All study procedures were reviewed and approved by the Ethical Committee of the Catholic University of Sacred Heart., Discussion: Ticagrelor might improve ischemia tolerance and microvascular function compared to clopidogrel, and these effects might translate to better long-term clinical outcomes., Trial Registration: EudraCT No. 2016-004746-28. No. NCT02701140.  TRIAL STATUS: Information provided in this manuscript refers to the definitive version (n. 3.0) of the study protocol, dated 31 October 2017, and includes all protocol amendments. Recruitment started on 18 September 2018 and is currently ongoing. The enrollment is expected to be completed by the end of 2019., Trial Sponsor: Fondazione Policlinico Universitario A. Gemelli - Roma, Polo di Scienze Cardiovascolari e Toraciche, Largo Agostino Gemelli 8, 00168 Rome, Italy.

Objective: To investigate the effect of extent of revascularization in complex high-risk indicated patients (CHIP) undergoing Impella-protected percutaneous coronary intervention (PCI)., Background: Complete revascularization has been shown to be associated with improved outcomes. However, the impact of more complete revascularization during Impella-protected PCI in CHIP has not been reported., Methods: A total of 86 CHIP undergoing elective PCI with Impella 2.5 or Impella CP between April 2007 and December 2016 from 2 high volume Italian centers were included. Baseline, procedural, and clinical outcomes data were collected retrospectively. Completeness of coronary revascularization was assessed using the British Cardiovascular Intervention Society myocardial jeopardy score (BCIS-JS) derived revascularization index (RI). The primary end-point was all-cause mortality. A multivariate regression model was used to identify independent predictors of mortality., Results: All patients had multivessel disease and were considered unsuitable for surgery. At baseline, 44% had left main disease, 78% had LVEF ≤ 35%, and mean BCIS-JS score was 10±2. The mean BCIS-JS derived RI was 0.7±0.2 and procedural complications were uncommon. At 14-month follow-up, all-cause mortality was 10.5%. At follow-up, 67.4% of CHIP had LVEF ≥ 35% compared to 22.1% before Impella protected-PCI. Higher BCIS-JS RI was significantly associated with LVEF improvement (p=0.002). BCIS-JS RI of ≤ 0.8 (HR 0.11, 95% CI 0.01- 0.92, and p = 0.042) was an independent predictor of mortality., Conclusions: These results support the practice of percutaneous Impella use for protected PCI in CHIP. A more complete revascularization was associated with significant LVEF improvement and survival., Competing Interests: Dr. Burzotta discloses to have been involved in advisory board meetings or having received speaker's fees from Medtronic, St Jude Medical, Abiomed, Biotronic. Dr. Trani discloses to have been involved in advisory board meetings or having received speaker's fees from St Jude Medical, Abiomed, Biotronic. Dr. Aurigemma has been involved in advisory board activities by Biotronic. The remaining authors have nothing to disclose., (Copyright © 2019 Francesco Burzotta et al.)

Background: Optical-coherence-tomography (OCT) is an emerging invasive coronary imaging with still undefined clinical value. Recent data have underlined daily impact of such technique in several clinical settings such as acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) guidance. We aimed at assessing the trends and outcomes of OCT use in a high-volume percutaneous coronary interventions (PCI)-center., Methods: Over 6 years, 1025 coronary artery segments in 877 patients underwent OCT evaluation. Clinical and procedural characteristics were prospectively collected. Clinical setting for OCT was: "Diagnostic OCT" (OCT for lesion evaluation after coronary angiography without further PCI); "PCI-guidance OCT" (OCT as a guidance for complex PCI, both by intention or after diagnostic OCT). Primary study end-point was the occurrence of target-vessel-failure (TVF) during the follow-up., Results: Overall, OCT was successful in 99.1% of attempted lesions. Only one complication (coronary dissection requiring urgent PCI) occurred during OCT. After a follow-up of 695 ± 562 days, TVF occurred in 8.2% of cases. Despite similar baseline characteristics, TVF-free survival curves were different in the two populations (5.4% after diagnostic OCT and 9.9% after PCI-guidance OCT). Minimal-lumen-area (MLA) of target lesion was independently associated with TVF (HR 0.7, 95% CI 0.6-0.8). This was mainly driven by a significant impact of MLA in patients not revascularized (HR 0.6, 95% CI 0.4-0.9). TVF did not change according to the study period despite the selection of patients with increasing complexity., Conclusions: OCT has a good safety profile across a broad spectrum of patients encountered in daily practice. The easy-to-assess MLA parameter may help stratify prognosis of patients undergoing OCT. These data call for further evaluations of OCT clinical impact., Summary: OCT is a light-based imaging tool which had subvert the quite ordinary world of coronary imaging and the present study evaluates OCT use in a high-volume center. Our results suggest that application of OCT in "real world" patients presenting higher risk has a good safety profile. Several factors could predict a worse long-term outcome in patients undergoing OCT evaluation, mostly related to more complex clinical conditions. These findings could encourage even low-to intermediate volume centers to improve their OCT use in daily practice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To assess the impact of lesion predilation with kissing inflation using under-sized balloons (pre-kissing [PK]) on the procedural outcome of percutaneous intervention (PCI) on coronary bifurcation lesions (CBLs)., Methods: Patients who underwent PCI with second-generation drug-eluting stenting on a complex CBL (Medina 1,1,1 or 1,0,1 or 0,1,1) were selected. The study population was divided according to the lesion preparation into the PK group and the control group. To adjust for higher anatomic complexity of PK patients, a 2:1 propensity-matched (PM)-control group was selected. The PCI procedural details were assessed to evaluate occurrence of "side-branch trouble" (primary procedural endpoint) after main-vessel (MV) stenting. Angiographic characteristics, including side-branch TIMI flow during PCI, were also systematically evaluated., Results: A total of 538 patients were identified, with 66 patients in the PK group, 472 patients in the control group, and 126 patients in the PM-control group. Side-branch trouble was less common in side-branch PK patients vs the PM-control patients (7.5% vs 18.0%, respectively; P=.03). In multivariable analysis, the absence of PK independently predicted side-branch trouble. Among selected patients with a long side-branch lesion (122 patients), the PK technique improved post-MV stenting side-branch TIMI flow., Conclusions: Use of PK with under-sized balloons may facilitate side-branch management after MV stenting in patients with complex CBL undergoing provisional stenting.

Background: Long drug-eluting stents may limit the need of stent overlaps in patients with diffusely diseased coronary arteries. We evaluated the clinical results of percutaneous-coronary-intervention (PCI) using a novel ultra-long (48 mm) everolimus-eluting stent (EES) in a real-word population., Methods: Patients who underwent PCI with 48 mm EES between June 2015 and April 2017 in our Center were enrolled. The only exclusion criteria was cardiogenic shock established before PCI. Target vessels were divided in "very long lesion" (>38 mm) and "multiple focal disease" (multiple stenoses separated by healthy coronary segments >10 mm). Clinical follow-up was obtained to evaluate the occurrence of device-oriented composite endpoint (DOCE) (primary end-point)., Results: A total of 216 patients were identified (70.6±11 years, 48.1% acute coronary syndrome) who were treated on 230 vessels. The target vessel appearance was "very long lesion" in 44.8% of cases and "multiple focal disease" in 55.2%. A single 48-mm EES was implanted in 129 (56.1%), while additional overlapping stents were needed in 101 cases (43.9%). Total stent length was 64.9±24.0 mm. The median follow-up time was of 474 (411-614) days, DOCE occurred in 7% of patients. No stent thrombosis was noticed. At multivariate analysis, diabetes was associated with DOCE increase (P=0.02), while "multiple focal disease" predicted lower DOCE (P=0.02)., Conclusions: The present real-world experience shows promising clinical results with the use of ultra-long stents in order to limit the need of stents overlaps in patients with diffuse coronary disease undergoing PCI.

Aims: Stent implantation in ST-segment elevation myocardial infarction (STEMI) patients can be challenging and sometimes associated with immediate and long-term suboptimal results. Stent malapposition and strut uncoverage, predictors of stent thrombosis, are frequently detected in STEMI patients at medium/long-term follow-up. Nevertheless, data at a short follow-up are missing. We aimed to assess the extent of stent malapposition and struts coverage in the subacute phase of STEMI after stent implantation in primary or rescue percutaneous coronary intervention (PCI)., Methods: STEMI patients undergone primary or rescue PCI and scheduled for a second coronary angiography after 2-7 days were enrolled. During the second procedure, frequency domain optical coherence tomography (FD-OCT) was performed to assess percentage of malapposed struts (MS%), percentage area of malapposition (MA%), percentage of uncovered struts (US%), percentage area of atherothrombotic prolapse (PA%) and optical coherence tomography thrombus score (OCT-TS)., Results: Twenty patients were included and 21 stents (19 865 struts) were evaluated. Strut uncoverage was relatively limited [US% = 11.1 (8.1-13.6) %]. Stent malapposition was observed frequently, even if at low degree [MS% = 6.4 (3.3-13.3) %, MA% = 1.80 (0.46-2.76) %] as well as atherothrombotic prolapse [PA% = 0.09 (0.00-1.06) %]. Both MA% and PA% were significantly related to residual OCT-TS (R = -0.52, P = 0.02 and R = 0.71, P < 0.001, respectively), use of thrombolysis (P = 0.001 and P = 0.004, respectively) and time elapsed from PCI to FD-OCT analysis (P = 0.001)., Conclusion: In the subacute phase after stenting in STEMI patients, strut uncoverage is relatively limited, while stent malapposition and atherothrombotic prolapse are common albeit limited features. Residual thrombus burden influences the degree of both stent malapposition and atherothrombotic prolapse.

Background: Percutaneous ventricular-assistance by Impella (IMP) represents an emerging strategy to manage patients with reduced left-ventricular (LV) ejection-fraction (EF) undergoing percutaneous-coronary-intervention (PCI). The hemodynamic behave during IMP-protected PCI has been scarcely investigated., Methods: We reviewed the IMP console's function and hemodynamic data (which are continuously recorded during assistance) in a consecutive series of 37 patients who underwent elective IMP-protected PCI in two high-volume centers. All patients had multivessel disease and impaired LVEF. Coronary artery disease burden was graded using the British-Cardiovascular-Intervention-Society jeopardy-score (BCIS-JS) score. IMP motor speed and pressure signals (systolic blood pressure, SBP, and mean blood pressure, MBP) were analyzed. Primary hemodynamic end-points were "critical systolic blood pressure (SBP) drop" (SBP decrease ≥ 20 mm Hg reaching ≤90 mm Hg values) and "critical mean blood pressure (MBP) drop" (MBP decrease reaching ≤60 mm Hg)., Results: Over mean assistance duration of 254 ± 549 min, no IMP motor drop occurred. During PCI, SBP and MBP significantly decreased but all patients had SBP values >78 mm Hg. Critical SBP and MBP drops occurred in 10.8% of patients. Among all baseline and procedural characteristics, BCIS-JS was the only significant predictor of SBP drop (p = 0.001) while BCIS-JS and LV end-diastolic volume significantly predicted MBP drop (p = 0.001 for both)., Conclusions: In patients with reduced EF undergoing IMP-protected PCI, a significant pressure decrease occurs during PCI but pressure is systematically maintained at levels warranting vital organ perfusion. Critical pressure drops during PCI occur in some patients with higher jeopardized myocardium and left ventricular diastolic volumes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The completeness of revascularization in patients with multivessel coronary artery disease (CAD) remains an unanswered question. Despite 20 years of investigation there are still major doubts in this topic, reaching as far as to the lack of a standardized definition. The employment of different definition and the multiplicity of confounding variables that in general favor patients who receive a complete revascularization (CR) are the reason of difficult comparisons between studies. The complexity of coronary anatomy diseases and the clinical features play important role in the revascularization strategy. However, the clinical impact of CR is different in particular clinical subsets, such as diabetes, ST-segment elevation myocardial infarction, cardiogenic shock, ischemic heart failure. The CR is a desirable objective, but it is not mandatory and sometimes a reasonable incomplete revascularization (IR) offers comparable results. Clinical variables, including patient's age, life expectancy, the severity of symptoms at presentation, comorbidities (particularly diabetes mellitus), left ventricular function and myocardial viability, as well as coronary anatomy should be considered in the decision making whether to attempt CR or to follow a reasonable IR strategy, for both percutaneous coronary intervention and coronary artery bypass graft surgery, in patients with multivessel CAD.

Background: Patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES) on unprotected left main (ULM) represent a complex subset. The role of routine coronary angiography at follow up in this subset remains debated., Methods: At the documented center, all patients undergoing successful PCI on ULM lesions performing angiographic follow-up is suggested, but adherence to such a recommendation is inhomogeneous. Consecutive patients undergoing DES PCI on ULM were enrolled and experienced no adverse events during the first 6 months. Patients were then allocated to two groups: those undergoing routine control angiography (CA) and those undergoing clinical follow-up (CF). Primary endpoint was major adverse cardiac events (MACE) defined as cardiac death, myocardial infarction and urgent repeat target vessel revascularization., Results: A total of 190 patients underwent successful DES implantation on ULM and the study population was without early events. CA was performed at 6 months after the index procedure in 91 (48%) patients. After 35 ± 21 months, MACE rates were significantly more common in the CF group as compared with the CA group (16.2% vs. 4.3%, p = 0.009). At multivariable analysis, CA was associated with reduced MACE risk (HR 0.13, 95% CI 0.1-0.7, p = 0.028). Of note, this was mainly driven by higher cardiac death rate in those undergoing CF than in those undergoing CA (p = 0.01)., Conclusions: CA after complex PCI, such as ULM PCI, is associated with reduced MACE. Such an observation calls for appropriately designed randomized trials.

Background: Left main (LM) atherosclerotic lesions affect clinical outcomes. Frequency domain-optical coherence tomography (FD-OCT) allows detailed characterization of non-ostial coronary atherosclerotic lesions. The clinical impact of FD-OCT assessment of LM bifurcation disease on the revascularization decision is unknown., Methods: Patients who underwent FD-OCT assessment to guide management of angiographically intermediate distal LM stenosis were retrospectively selected. The FD-OCT LM criteria for percutaneous or surgical revascularization were: Clinical follow-up was obtained to evaluate the occurrence of target vessel failure (TVF) defined as cardiac death and/or acute myocardial infarction (AMI) not related to other vessel and/or target vessel revascularization., Results: Out of 131 patients underwent FD-OCT assessment of LM, 122 patients (93%) entered the study. Based on FD-OCT features, 58 (48%) patients were conservatively managed, while the remaining 64 (52%) were revascularized by stenting (n=48) or surgery (n=16). After a mean follow-up of 18months, TVF-free survival was not different between patients undergoing conservative management vs. revascularization (HR 0.40, CI 95% 0.10-1.61, P=0.20). Of note, two patients only in the conservative management group had TVF (elective LM stenting, no death or myocardial infarction)., Conclusions: This preliminary experience suggests that a FD-OCT based management for patients with angiographically-intermediate LM bifurcation stenosis may help identify patients in whom revascularization could be deferred. Such observation calls for further evaluations by appropriately designed trials., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The cause for discrepancy in the clinical presentation and outcome of coronary artery disease (CAD) between men and women is not established. Different prevalences of risk factors or specific sex-related atherosclerotic aspects have been advocated as possible explanations. We investigated coronary plaque morphology looking at possible differences in plaque vulnerability between men and women with stable CAD., Patients and Methods: We retrospectively collected and analyzed clinical data and coronary plaque morphology by frequency-domain optical coherence tomography in men and women with stable CAD., Results: A total of 181 (139 were in men and 42 in women) plaques from 138 patients were analyzed. The mean age was similar between men and women. Besides an overall absence of significant differences in the vast majority of risk factors and comorbidities, men had a higher prevalence of active smoking (19 vs. 2%, P=0.006), previous myocardial infarction (17 vs. 2%, P=0.01), and previous percutaneous coronary interventions (42 vs. 17%, P=0.003). Frequency-domain optical coherence tomography in women showed significantly more plaque-vulnerability features as testified by higher percent of lipid-rich plaques (55 vs. 36%, P=0.03), macrophages (21 vs. 5%, P=0.003), and microvessels (24 vs. 8%, P=0.01). Multivariate analysis showed that female sex was associated independently with lipid-rich plaques (P=0.034) and macrophages (P=0.001). In the analysis restricted to the more severe lesions that were revascularized, women continued to be characterized by more adverse morphological features, such as macrophages (30 vs. 7%, P=0.004) and lipid-rich plaques (63 vs. 39%, P=0.045)., Conclusion: Women with stable CAD may be characterized by plaques that have increased prevalence of vulnerability compared with men. These findings support the hypothesis of sex-specific differences in the development of atherosclerosis.

Background: The role of exercise stress test (EST)-induced ST-segment elevation (STE) in electrocardiographic lead aVR in predicting severe coronary artery disease (CAD) is controversial., Hypothesis: Assessment of lead aVR during EST can be helpful to identify patients with severe CAD., Methods: We performed maximal EST in 200 patients undergoing coronary angiography for suspect of CAD. Four angiographic findings of severe CAD were considered: (1) left main (LM) disease; (2) LM or equivalent LM (LM/EQLM) disease; (3) LM or proximal left anterior descending (LAD) artery (LM/proxLAD) disease; and (4) LM or 3-vessel (LM/3V) disease., Results: LM, LM/EQLM, LM/proxLAD, and LM/3V disease were shown in 6 (3%), 13 (6.5%), 33 (16.5%), and 27 (13.5%) patients, respectively. EST-induced STE in aVR occurred in 41 patients (20.5%). ST-segment depression (STD) in ≥5 leads was the only predictor of LM stenosis (odds ratio [OR]: 6.18, 95% confidence interval [CI]: 1.19-32.2, P = 0.03) and the most significant variable associated with LM/proxLAD stenosis (OR: 4.73, 95% CI: 2.0-11.2, P = 0.0001); maximal STD ≥3 mm was the most significant variable associated with LM/EQLM (OR: 7.58, 95% CI: 2.31-24.9, P = 0.001) and LM/3V (OR: 3.86, 95% CI: 1.47-10.1, P = 0.006) CAD. EST-induced STE in aVR was associated with LM/proxLAD disease only (OR: 3.23, 95% CI: 1.44-7.24, P = 0.004). At multivariate analysis, STD in ≥5 leads was the only independent predictor of LM/proxLAD disease (OR: 3.99, 95% CI: 1.58-10.1, P = 0.003)., Conclusions: EST-induced STE in lead aVR does not significantly increase the prediction of severe CAD compared with severity and extension of STD as assessed in the other electrocardiographic leads., (© 2016 Wiley Periodicals, Inc.)

Background: Diffuse coronary artery disease treatment still remains a challenge for interventional cardiologists and cardiac surgeons. There are few data on full metal jacket (FMJ) stenting, especially with new-generation drug-eluting stents. We aimed to assess the efficacy and safety of FMJ with new-generation Zotarolimus-eluting stents (n-ZES)., Methods and Results: All patients who underwent FMJ with n-ZES (≥60mm stent length) in eleven Italian interventional centers participating in the Clinical Service® project were included in this analysis. The project population consisted of 120 patients and 122 lesions. Mean age was 67±10years and 95 (79.2%) patients were male. A chronic total occlusion was present in 34 lesions (27.9%). The number of stents implanted per lesion was 2.9±0.8, and the diameter of the stents was 3.0±0.5mm. Predilation and post-dilatation were performed in 107 (87.7%) and 92 (75.4%) patients, respectively. At 41±21month follow-up there were 2 patients with subacute definite stent thrombosis, 6 patients (5.0%) had cardiac death and 5 patients (4.2%) had non-fatal myocardial infarction. Seven patients (5.8%) underwent clinically-driven target lesion revascularization. Fourteen patients (11.7%) had at least one major adverse cardiac event., Conclusion: The treatment of diffuse coronary artery disease with FMJ stenting with n-ZES appears to be effective and safe. Late and very-late ST does not seem to be an issue and the rate of restenosis and of major cardiac adverse events after more than 3-year follow-up is rather low., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Because approximately 10% of patients with no-ST-segment elevation acute coronary syndrome (NSTE-ACS) show no obstructive coronary artery disease (NOCAD) on angiography, we assessed the spectrum of diagnoses and the predictors of outcome of these patients., Methods and results: We studied 178 patients admitted to a coronary care unit with an initial diagnosis of NSTE-ACS, based on clinical, ECG and laboratory data, but found to have NOCAD. The final diagnosis in these patients was heterogeneous; true NSTE-ACS (ie, coronary thrombosis on an unstable plaque) was ascertained in 1 patient (0.6%), whereas diagnosis at discharge was microvascular NSTE-ACS in 56.2% of patients, variant angina in 10.1%, myocarditis in 8.9%, takotsubo disease in 7.9%, tachyarrhythmia-related chest pain in 6.7%, and non-cardiac pain in 9.6%. At 24.5-month follow-up, 21 deaths (11.8%) had occurred, 9 (5.1%) from cardiovascular causes, including 2 (1.12%) coronary deaths. By multivariable Cox analysis, age only predicted global (hazard ratio [HR] 1.07 [1.02-1.12]; P=0.006) and cardiovascular (HR 1.08 [1.01-1.16]; P=0.04) mortality; non-coronary vascular disease was the main predictor of cardiovascular death or readmission for cardiovascular disease (HR 3.28 [1.75-6.14]; P<0.001) and coronary death or readmission for angina (HR 3.20 [1.26-8.14]; P=0.014)., Conclusions: Patients with an initial diagnosis of NSTE-ACS constitute a heterogeneous population with different final diagnoses. Patients have a rather high rate of fatal events, most of which, however, are not related to coronary causes. (Circ J 2016; 80: 1600-1606).

A series of scientific evidence supports the concept that provisional side-branch stenting should be the preferred strategy for percutaneous coronary intervention of bifurcation coronary lesions. However, to date, many interventional cardiologists still consider this technique unsuitable for complex bifurcation lesions. This is mainly due to the fact that provisional stenting may be performed in different ways and several technical refinements may influence the procedural outcome. We here systematically overviewed the arguments which should be considered during the following steps of the provisional strategy: branch wiring, side-branch predilation, "crossover" stenting, proximal optimization, kissing balloon and the side-branch rescue techniques. We suggest that provisional stenting should be regarded as a highly flexible technique which, with specific technical tricks, may allow us to safely treat patients with wide spectrum of bifurcated lesion complexity.

Aims: The need of adenosine administration for the achievement of maximal hyperaemia limits the widespread application of fractional flow reserve (FFR) in the real world. We hypothesised that Pd/Pa ratio registered during submaximal reactive hyperaemia induced by conventional non-ionic radiographic contrast medium (contrast medium induced Pd/Pa ratio: CMR) can be sufficient for the assessment of physiological severity of stenosis in the vast majority of cases. The aim of the present study was to test the accuracy of CMR in comparison to FFR., Methods and Results: Eighty patients with 104 intermediate coronary stenoses were prospectively and consecutively enrolled. CMR was obtained after intracoronary injection of 6 ml of radiographic contrast medium, while FFR was measured after administration of adenosine. Despite the fact that CMR values were significantly higher than FFR values (0.88 [IR 0.80-0.92] vs. 0.87 [IR 0.83-0.94], p<0.001), a strong correlation between CMR and FFR values was observed (r=0.94, p<0.001) with a close agreement at Bland-Altman analysis (95% CI of disagreement: -0.029 to 0.072). ROC curve analysis showed an excellent accuracy of CMR cut-off of ≤0.83 in predicting FFR value ≤0.80 (AUC 0.97 [95% CI: 0.91-0.99, specificity 96.1, sensitivity 85.7]). Moreover, no FFR value ≤0.80 corresponded to a CMR ≥0.88., Conclusions: CMR is accurate in predicting the functional significance of coronary stenosis. This could allow limiting the use of adenosine to obtain FFR to doubtful cases. In particular, we suggest considering a CMR value ≤0.83 to be significant, a CMR value ≥0.88 as not significant, and inducing maximal hyperaemia using adenosine for FFR assessment when CMR is between 0.84 and 0.87.

Aims: Despite the fact that fractional flow reserve (FFR) is better than angiography in guiding PCI, in the real world the choice to perform PCI is generally based on angiography. Three-dimensional quantitative coronary angiography (3D-QCA) may increase the accuracy of angiography, especially in intermediate coronary artery stenosis (ICAS). The aim of the study was to assess the best cut-off values of area stenosis % (AS%) and the extent of jeopardised myocardium for predicting FFR and for excluding the need to perform FFR., Methods and Results: FFR, AS% and Myocardial Jeopardy Index (MJI) were assessed in 211 ICAS. MJI (=-0.36; p=0.001), AS% (=-0.35; p=0.001) and presence of a chronic total occlusion (CTO) (=-0.15; p=0.01) were independent predictors of FFR. In patients without CTO (174 lesions), the best cut-offs for the detection of FFR ≤0.80 for AS% and MJI were 61% (AUC=0.76; p<0.001) and 30% (AUC=0.71; p<0.001), respectively. More importantly, the cut-offs of AS% safely to exclude (100% sensitivity) an FFR ≤0.80 were 40% (AUC=0.85, p<0.001) for an MJI ≥30% and 50% (AUC=0.70, p<0.04) for an MJI <30%, respectively., Conclusions: AS%, MJI and the presence of a CTO predicted FFR values. 3D-QCA in addition to MJI allows the safe exclusion of FFR ≤0.80, limiting FFR assessment to doubtful cases with considerable reduction of costs.

Percutaneous coronary intervention (PCI) on distal left main (LM) remains an independent predictor of poor outcome. The strategy of implanting one stent on the main branch (MB), with provisional stenting on the side-branch (SB) only when required (provisional T-stenting), has become the default approach to most bifurcation lesions. This prospective registry sought to investigate the long-term safety and efficacy of provisional SB T-stenting for the treatment of unprotected distal LM disease in patients undergoing PCI. From January 2006 to May 2009, 107 consecutive patients affected by unprotected distal LM disease underwent PCI at our center with the intent to use a provisional SB-stenting technique. We evaluated the rate of major adverse cardiac events (MACE) at long-term follow-up (up to 12-41 months). Procedural success was obtained in 98% of patients. A final kissing balloon inflation was performed in 95% and intravascular ultrasound in 83% of patients. Additional stenting on the SB after provisional stenting on MB was required in 29% of lesions. Long-term follow-up (3.5 years; 25-75th percentile and 1.1-4.5 years) was completed in 97% of patients. The cumulative incidence of MACE was 32.7%: all-cause death was 15.8%, nonfatal myocardial infarction 8.4%, and target vessel revascularization 21.5%. At multivariable analysis, age (hazard ratio, 2.08; 95% confidence interval: 2.01-3.32, P = 0.03), European System for Cardiac Operative Risk Evaluation (HR 1.20, 95% CI: 1.04-1.33, P = 0.02), and diabetes mellitus (HR 3.48, 95% CI: 1.12-6.87, P = 0.01) were identified as independent predictors of MACE. In patients with unprotected distal LM disease undergoing PCI, a provisional strategy of stenting the MB only is associated with good long-term clinical outcomes., (Copyright © 2011 Wiley-Liss, Inc.)

Objective: Previous studies have shown that exercise increases platelet reactivity in patients with coronary artery disease (CAD). However, the response of platelet reactivity to exercise is considerably variable and its predictors are poorly known., Methods: We studied 214 consecutive patients (age 61.9 +/- 9 years, 167 men) with stable angina and obstructive coronary artery disease. All patients underwent a symptom-limited treadmill exercise stress test. Venous blood samples were collected before and at peak exercise. Platelet reactivity was assessed by the platelet function analyzer system as the time for flowing whole blood to occlude a collagen-adenosine diphosphate ring (closure time: shorter times = higher reactivity). Both closure time at peak exercise and the exercise-induced change in closure time from rest were assessed as an expression of exercise-related platelet reactivity., Results: Closure time decreased significantly with exercise in the whole population (from 95.9 +/- 22 to 81.2 +/- 18 s, P < 0.001). The only variable significantly associated with closure time at peak exercise was hematocrit (P = 0.003). Basal systolic blood pressure (P = 0.023) and lack of nitrate use (P = 0.03), on the contrary, were the only variables significantly associated with increased exercise-induced closure time change. Peak hematocrit maintained an independent association with peak closure time in multivariable analysis, although the correlation was mild. No variable, on the contrary, was associated with exercise-induced platelet reactivity after correction for basal closure time values at multivariable analyses., Conclusion: Among stable coronary artery disease patients, platelet reactivity after exercise cannot be reliably predicted by several common clinical and laboratory variables.

Introduction: In previous studies we have consistently shown a significant increase of platelet reactivity after exercise in patients with obstructive coronary artery disease (CAD). We also observed a significant individual variability in the response to exercise of platelet reactivity in these patients. Whether exercise-induced changes in platelet reactivity correlate with changes in platelet membrane receptors in patients with CAD is unknown., Methods: We studied 26 patients with stable CAD and 10 matched healthy controls who underwent a symptom-limited treadmill exercise stress test. Venous blood samples were collected at rest and within 5 min of peak exercise. Platelet reactivity was measured by the PFA-100 method as time to occlude (closure time, CT) a ring coated with collagen/adenosine diphosphate (C/ADP). Platelet expression of glycoprotein (GP) IIb/IIIa, in both global (CD41) and active form (PAC-1), and P-selectin (CD62P) and formation of leukocyte-platelet aggregates were assessed by flow cytometry., Results: After exercise CT did not change in controls (85.4+/-12 to 84.0+/-9 s, p=0.37), whereas it decreased in CAD patients (98.8+/-24 to 91.4+/-25 s, p<0.001). After exercise, CD41 and PAC-1 platelet expression increased significantly in CAD patients (p=0.04 for both), but not in controls (p=0.39 and p=0.98, respectively). To evaluate the relationship between the response to exercise of platelet reactivity and of platelet receptor expression, CAD patients were divided into two groups: CAD group 1 (16 patients, decrease in CT >5 s after exercise) and CAD group 2 (10 patients no increase in platelet reactivity after exercise). CD41 and PAC-1 expression increased in CAD group 1 (p=0.008 and p=0.026, respectively) but not in CAD group 2 (p=0.39 and p=0.50, respectively). No significant differences were observed between the 2 groups for changes in CD62P and leukocyte-platelet aggregates., Conclusions: Our data show that, in patients with stable CAD, an increased platelet reactivity to C/ADP stimulation after exercise, as assessed by the PFA-100 method, is specifically associated with an increased expression of platelet GP IIb/IIIa receptor.

Introduction: Previous studies showed differences in platelet reactivity in response to exercise in patients with syndrome X (SX) and those with obstructive coronary artery disease (CAD). In this study, we investigated whether similar differences could be detectable in response to a mental stressful stimulus., Materials and Methods: We studied 30 SX patients (60+/-8 years, 8 men), 20 patients with stable angina and angiographically documented CAD (SA, 66+/-8 years, 14 men), and 11 patients with unstable angina (UA, 67+/-8 years, 6 men). A control group of 22 healthy controls (50+/-7 years, 5 men) was also studied. All subjects underwent a mathematical mental stress test (MST) consisting of rapid consecutive subtractions of number 7 for a period of 5 min. A venous blood sample was collected at baseline and immediately after MST. Platelet reactivity was measured on flowing blood as time necessary to occlude a ring coated with collagen-adenosine diphosphate (ADP; closure time, CT), using the platelet function analyzer (PFA-100) system., Results: At rest, CT was lower in UA patients (87+/-19 s) compared to controls (109+/-24 s, p=0.02) and SA patients (105+/-37 s, p=0.055), and also tended to be lower in SX patients (96+/-18 s) compared to controls (p=0.07). The CT response to MST differed significantly among groups (p=0.0009). At peak MST, CT did not change in controls (110+/-27 s, p=0.88), whereas it decreased in SA patients (96+/-29 s, p=0.003) and tended to decrease in UA patients (82+/-15 s, p=0.25). In contrast, a significant increase in CT with MST was shown in SX patients (103+/-21 s, p=0.007)., Conclusions: Platelet reactivity is increased by MST in patients with CAD, whereas it paradoxically decreases in SX patients, which may constitute a protective effect against stress-induced events in these patients.