Background: Accurate evaluation of stent implantation during percutaneous coronary intervention (PCI) is essential to reduce both early and late adverse events. Conventional coronary angiography, although routinely used, has limited spatial resolution and may fail to detect subtle mechanical abnormalities in implanted stents. Enhanced stent visualization (ESV) is an X-ray-based post-processing technique that improves delineation of stent struts without additional contrast or intracoronary instrumentation. Methods: We report a retrospective case series of five patients who underwent complex PCI where ESV was used as an adjunctive imaging modality. Clinical scenarios included left main interventions, bifurcation lesions, multivessel disease, and acute coronary syndromes. The ability of ESV to detect mechanical complications not evident on angiography was assessed. The impact of ESV on procedural decision-making was also assessed. Results: ESV enabled identification of mechanical complications in all cases, including stent fracture, stent loss, stent dislodgement, stent underexpansion, and geographical miss. These findings were not clearly appreciable when using angiography alone. In each case, ESV directly influenced intraprocedural management, prompting immediate corrective actions such as additional stent implantation, stent retrieval, or further optimization with post-dilatation or intravascular lithotripsy. This resulted in improved procedural outcomes and optimized stent deployment. Conclusions: In this small retrospective case series, ESV provided incremental diagnostic value over conventional angiography by detecting otherwise unrecognized mechanical complications and guiding real-time procedural optimization. While these findings suggest a potential role for ESV in complex PCIs, larger prospective studies are required to confirm its clinical impact.

BACKGROUND:Complete coronary-artery revascularization is recommended in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease, but the preferred strategy for identifying nonculprit lesions that warrant treatment remains uncertain. METHODS:In this international, randomized trial, we assigned patients with STEMI and multivessel disease in whom the culprit lesion had been successfully treated to undergo complete coronary-artery revascularization guided by functional coronary angiography (physiology-guided group) or by conventional angiography (angiography-guided group). The primary outcome was a composite of death from any cause, myocardial infarction, cerebrovascular accident (stroke or transient ischemic attack), or ischemia-driven revascularization, assessed in a time-to-event analysis. The primary safety outcome was a composite of contrast-associated acute kidney injury or major bleeding. RESULTS:A total of 1823 patients underwent randomization; 913 were assigned to the physiology-guided group and 910 assigned to the angiography-guided group. The median age of the patients was 66 years (interquartile range, 58 to 76), and 24% were women. At a median follow-up of 17.9 months, a primary-outcome event had occurred in 81 patients (8.9%) in the physiology-guided group and in 125 patients (13.7%) in the angiography-guided group (hazard ratio, 0.62; 95% confidence interval [CI], 0.47 to 0.83; P<0.001). A primary-safety-outcome event occurred in 42 patients (4.6%) in the physiology-guided group and in 65 patients (7.1%) in the angiography-guided group (hazard ratio, 0.63; 95% CI, 0.43 to 0.93; P = 0.02). CONCLUSIONS:In patients with STEMI and multivessel coronary artery disease, a strategy of complete coronary-artery revascularization guided by functional coronary angiography resulted in a lower risk of a primary-outcome event (death, myocardial infarction, cerebrovascular accident, or ischemia-driven revascularization) than a strategy guided by conventional angiography. (Funded by the Italian Health Ministry and others; AIR-STEMI ClinicalTrials.gov number, NCT05818475.).

Accurate evaluation of stent implantation during percutaneous coronary intervention (PCI) is essential to reduce both early and late adverse events, including stent thrombosis and in-stent restenosis. Although conventional coronary angiography remains the standard imaging modality, its spatial resolution is often insufficient to detect subtle mechanical abnormalities of implanted stents. Enhanced stent visualization (ESV) is an X-ray-based post-processing technique that enhances delineation of stent struts using routine fluoroscopic images, without requiring additional contrast administration or intracoronary instrumentation. We describe a case series of five patients undergoing complex PCI in whom ESV proved crucial for the detection of mechanical complications that were not readily evident on angiography alone. The procedures involved challenging anatomical and clinical settings, including left main coronary artery treatment, bifurcation lesions, multivessel coronary disease, and acute coronary syndromes. In each case, ESV offered incremental diagnostic insight, enabling prompt identification of complications. These findings directly influenced procedural strategy and facilitated appropriate bailout interventions. This case series underscores the potential clinical utility of ESV as an adjunctive imaging tool to standard angiography and intravascular imaging techniques. Given its simplicity, broad accessibility, and negligible effect on procedure duration, ESV represents a feasible option during PCI. In selected complex interventions, its use may enhance mechanical optimization and procedural safety. Further large-scale prospective investigations are needed to corroborate the implementation of ESV in clinical practice.

BACKGROUND:Quantitative flow ratio (QFR) is effective in predicting mortality in patients undergoing transcatheter aortic valve replacement (TAVR). How QFR reclassifies coronary artery disease (CAD) at vessel-level compared to angiography and how this influences the risk of death, remains undetermined. METHODS:We calculated QFR from consecutive 280 TAVR patients with bystander coronary stenoses. All lesions were managed conservatively. Angiographic CAD was defined by a diameter stenosis ≥ 50%, functional CAD by a QFR ≤ 0.80. The outcome was mortality at 3 years. RESULTS:Overall, 635 lesions were included. Angiographic CAD was evident in 165 (26.0%), functional CAD in 17 (11.2%) (reclassification: p < 0.001). Angiography/QFR mismatch occurred in 22.5%, mostly in large vessels and lesions located in the proximal left anterior descending (LAD). QFR ≤ 0.80 was an independent predictor of death (HR 2.91, 95% CI 1.94-4.36; p < 0.001). The risk was progressively increased for lower QFR values and positive QFR at LAD site (vs. QFR > 0.80 HR: 3.92, 95% CI 2.78-5.53; p < 0.001; vs. QFR ≤ 0.80 at non-LAD site: HR 2.65, 95% CI 1.07-6.59; p = 0.034). CONCLUSIONS:QFR leads to a significant reclassification of CAD rates at vessel-level and shows a significant prognostic value in patients undergoing TAVR.

BACKGROUND:The pullback pressure gradient (PPG) is a novel physiological metric that quantifies coronary artery disease patterns as focal or diffuse on a scale from 0 to 1. This study assessed the relationship between PPG and residual angina at 1 year. METHODS:PPG Global is a prospective, investigator-initiated, single-arm, multicenter study that enrolled patients with at least 1 lesion with a fractional flow reserve ≤0.80 intended to be treated with percutaneous coronary intervention. After the PPG calculation, physicians could revise treatment assignment to medical therapy or coronary artery bypass graft surgery instead of percutaneous coronary intervention. Focal and diffuse disease were defined based on the median PPG value of 0.62. Patient-reported outcomes were assessed using the Seattle Angina Questionnaire at baseline and 1-year follow-up. RESULTS:The study included 947 patients with PPG and the Seattle Angina Questionnaire at 1 year. The mean age was 67.6±10.2 years, 24% were female, and 29% had diabetes. At 1 year, patients with focal coronary artery disease reported less angina than those with diffuse disease (Seattle Angina Questionnaire angina frequency score, 95.3±9.9 versus 92.5±15.0; P=0.006). PPG was independently associated with improvement in angina (P=0.017). CONCLUSIONS:In patients with flow-limiting coronary artery disease, a focal disease pattern defined by high PPG was associated with greater symptomatic relief at 1 year compared with diffuse disease (low PPG). By capturing the underlying pathophysiologic distribution of epicardial disease and its relation to post-treatment symptom relief, PPG may support a more tailored revascularization decision-making and percutaneous coronary intervention strategy.

BACKGROUND:Frailty is common among older patients surviving myocardial infarction, is associated with adverse outcomes, and is often perceived as a barrier to cardiac rehabilitation (CR). The aim of this study is to determine whether frailty influences prognosis after myocardial infarction, and whether frailty modifies the clinical benefit of multidomain CR. METHODS:We performed a prespecified subgroup analysis of the PIpELINe (Physical Activity Intervention in Elderly Patients With Myocardial Infarction) randomized clinical trial conducted in Italy, which enrolled 512 patients aged ≥65 years recovering from myocardial infarction and randomized them in a 2:1 ratio to CR or usual care. Frailty was assessed using the Fried Frailty Phenotype, and patients were categorized as nonfrail (robust) or prefrail/frail. Time-to-event outcomes were analyzed using Kaplan-Meier estimates and Cox proportional hazards models, including treatment-by-frailty interaction terms to evaluate effect modification of the multidomain CR. The primary outcome was a composite of cardiovascular death or unplanned hospitalization for cardiovascular causes within 1 year after randomization. RESULTS:Overall, 350 patients (68.4%) were classified as prefrail/frail, of whom 232 were randomized to intervention arm (66%). Frail patients were older (median age, 80 [75-85] years) and more frequently female (41.7% versus 24.7%). Compared with robust patients, prefrail/frail patients had a higher risk of the primary outcome (16 [9.9%] versus 62 [17.7%]; hazard ratio, 1.59 [95% CI, 0.89-2.82]; adjusted P=0.117). Among prefrail/frail patients, assignment to multidomain CR was associated with a lower risk of the primary outcome compared with usual care (hazard ratio, 0.57 [95% CI, 0.34-0.94]; P=0.028), with no statistically significant interaction in the treatment effect on the primary end point (P=0.57). CONCLUSIONS:Among older patients recovering from myocardial infarction, frailty is associated with worse prognosis but does not diminish the benefit of multidomain CR. These findings support the use of frailty assessment to guide rather than limit access to CR. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; Unique identifier: NCT03772743.

BACKGROUND:In the assessment of coronary physiology, non-hyperemic pressure ratios (NHPRs) provide an alternative to fractional flow reserve (FFR) without the need for hyperemic agents, reducing procedural time, side effects, and costs. However, it remains unclear whether NHPRs have similar diagnostic performance in the different coronary arteries. This study evaluates the diagnostic performance of NHPRs compared with FFR, stratified by coronary artery, in stable patients with coronary artery disease. METHODS:We conducted a systematic review and individual patient-level data meta-analysis from prospective studies involving patients with intermediate to severe coronary stenosis who underwent physiological assessment with NHPRs and FFR. NHPRs included resting full-cycle ratio or instantaneous wave-free ratio (iFR). The diagnostic performance of NHPRs was calculated using a threshold of ≤0.89 for NHPRs with FFR ≤0.80 as the reference and by stratifying between the left anterior descending artery (LAD) and non-LAD vessels. RESULTS:A total of 2120 paired FFR and NHPRs (1257 resting full-cycle ratio, 863 iFR) measurements were analyzed. The LAD artery was the interrogated vessel in 67% of cases, the left circumflex artery in 15%, and the right coronary artery in 17%. The mean NHPR and FFR values were 0.80±0.17 and 0.71±0.14, respectively. The overall sensitivity, specificity, and accuracy of NHPRs were 82%, 86%, and 83%. In non-LAD vessels, NHPRs had significantly lower sensitivity and accuracy, but higher specificity compared with LAD (69% versus 87%, 76% versus 86%, and 91% versus 81%, respectively, P<0.001 for all). The optimal NHPRs cutoff for detecting significant lesions differed between LAD (≤0.88) and non-LAD (≤0.92). CONCLUSIONS:NHPRs demonstrated lower diagnostic performance in non-LAD vessels compared with the LAD. These results underscore the need for vessel-specific interpretation of NHPR measurements.

BACKGROUND:Patients with myocardial infarction and large thrombus burden face greater infarct size and higher mortality, yet no effective therapy exists for this high-risk subgroup. OBJECTIVES:To investigate the effects of stent-retriever thrombectomy in addition to conventional percutaneous coronary intervention (PCI) versus conventional PCI alone on infarct size. METHODS:In this open-label, multicenter, superiority trial, 160 patients with ST-segment elevation myocardial infarction and large thrombus burden at angiography (TIMI thrombus grade ≥3 in infarct-related artery) were consented and 156 randomly assigned to undergo stent-retriever thrombectomy followed by conventional PCI or conventional PCI alone. Primary outcome was infarct size extension assessed by area under the curve (AUC) for creatine kinase (CK)-MB. Safety outcome was major adverse cardiovascular events (MACE; comprising cardiovascular death, nonfatal myocardial infarction, nonfatal stroke), at 3 and 30 days. RESULTS:Infarct size (CK-MB AUC) was lower in the stent-retriever group (n=78) versus the conventional group (n=76) (3965 IU/L·h; interquartile range [IQR] 2480-5092 versus 5250; IQR 3506-7449; difference -1359, 95% CI -2231 to -522; p=0.001). At exploratory cardiac magnetic resonance findings, infarct size was lower in the stent-retriever group (n=64; left ventricle, 17%; IQR 11-28) versus the conventional PCI group (n=59; 28.0%; IQR 18-33; difference -7.0, 95% CI -12 to -2.0), whereas left ventricular volumes and ejection fraction did not differ. There was no MACE at 3 days and 1 at 30 days in the stent-retriever group versus 2 and 3, respectively, in the conventional PCI group. CONCLUSIONS:Stent-retriever thrombectomy followed by conventional PCI in patients with large thrombus burden undergoing primary PCI ≤8 hours of symptom onset was associated with reduced infarct size versus conventional PCI alone.

BACKGROUND:The number of older patients admitted with myocardial infarction (MI) is increasing, and their clinical profiles range from very fit to frail and functionally impaired. OBJECTIVES:To evaluate whether the benefits of complete revascularization are consistent across subpopulations of older MI patients stratified by the Clinical Frailty Scale (CFS). METHODS:In the FIRE trial, 1445 patients aged ≥75 years with MI and multivessel disease were randomized to either complete or culprit-only revascularization. Overall, 1010 patients (70%) were stratified according to CFS (scores 1-3 non-frail, 4 pre-frail, 5-9 frail). The primary endpoint was a 3-year composite of death, MI, stroke, or ischemia-driven revascularization. RESULTS:Of the stratified cohort, 523 (52%) were non-frail, 304 (30%) pre-frail, and 183 (18%) frail. Increasing frailty was significantly associated with a higher risk of the primary endpoint (HR 1.62, 95% CI 1.19-2.20; P = .002). Complete revascularization reduced the primary endpoint with no significant interaction between revascularization strategy and CFS category (p for interaction = 0.769). The benefit of complete versus culprit-only revascularization remained consistent across the full range of CFS scores. Similar findings were observed for secondary endpoints, and no significant interaction emerged for safety outcomes. CONCLUSIONS:Frailty, as assessed by the CFS, was independently associated with adverse outcomes. Complete revascularization was effective regardless of frailty status and should be considered in all older MI patients with multivessel disease undergoing an invasive strategy. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03772743.

BACKGROUND:Invasive coronary functional testing enables the classification of angina with non-obstructive coronary arteries (ANOCA) into distinct endotypes. However, real-world data linking endotype identification to subsequent pharmacological management and patient-reported symptom outcomes remain limited. AIMS:We sought to evaluate the association between coronary endotypes, post-testing pharmacological treatment patterns, and changes in angina-related quality of life in patients with ANOCA in a multicentre real-world registry. METHODS:Consecutive ANOCA patients undergoing invasive coronary functional testing were included. Patients were classified into six endotypes using adenosine- and acetylcholine-based testing. Pharmacological therapy was adjusted at the discretion of the treating physician based on the functional test results. The primary endpoint was a clinically meaningful improvement in angina-related health status, defined as a ≥5-point increase in the 7-item Seattle Angina Questionnaire (SAQ-7) summary score, assessed within each endotype. RESULTS:Among 525 patients, endotype distribution was as follows: normal physiology 10.5%, elevated resting coronary blood flow 8.8%, high resistance 13.9%, compensated high resistance 14.9%, epicardial spasm 33.3%, and microvascular spasm 18.7%. After testing, prescription patterns differed across the endotypes, with increased use of beta blockers, ranolazine, and renin-angiotensin-aldosterone system blockers in coronary microvascular dysfunction endotypes and greater use of non-dihydropyridine calcium channel blockers in vasospastic endotypes. At follow-up, a ΔSAQ-7 summary score ≥5 points was observed in elevated resting flow, high-resistance, compensated high-resistance, and epicardial spasm endotypes (all p<0.001) but not in microvascular spasm or normal physiology. CONCLUSIONS:In this multicentre real-world registry, invasive coronary endotyping was associated with distinct pharmacological management patterns and differential changes in angina-related quality of life across ANOCA endotypes.

The assessment of myocardial ischaemia is entering a new computational era. Beyond the traditional boundaries of anatomical imaging and invasive fractional flow reserve (FFR), emerging techniques based on coronary computed tomography (CT) angiography and invasive coronary artery angiography now allow the derivation of physiological information without pressure wires, hyperaemic agents, or additional procedures. These image-based indices, commonly referred to as FFR-CT and angiography-derived FFR, are reshaping both diagnostic and interventional cardiology. This review provides an updated synthesis of the latest evidence on their clinical integration. FFR-CT has demonstrated its ability to refine diagnostic pathways, reduce unnecessary invasive angiography, and safely guide management decisions within precision diagnostic strategies. In parallel, angiography-derived FFR has matured into a real-time wire-free solution within the catheterisation laboratory. Randomised studies confirm that physiology-guided revascularisation improves procedural efficiency and optimises outcomes compared with angiography alone. Beyond ischaemia detection, these technologies now extend to virtual stenting, procedural simulation, and the identification of vulnerable plaques through haemodynamic indices such as endothelial shear stress and perivascular inflammation mapping. Together, these developments mark a paradigm shift: from anatomy-based to physiology-driven and, ultimately, prediction-guided coronary intervention. By merging artificial intelligence, computational modelling, and advanced imaging, CT- and angiography-derived physiology offer the prospect of fully integrated real-time functional assessment. This convergence defines a new frontier in coronary medicine, where precision, automation, and clinical impact coalesce to transform everyday cardiovascular practice.

Abstract Background In patients with myocardial infarction (MI) and multivessel disease, diabetes mellitus is associated with more diffuse coronary atherosclerosis and worse clinical outcomes, often influencing revascularization decisions. The Functional Assessment in Elderly MI Patients with Multivessel Disease (FIRE) trial demonstrated the superiority of physiology-guided complete revascularization in older patients with MI. Whether this benefit is preserved in patients with diabetes remains uncertain. Methods In FIRE, 1445 patients aged ≥ 75 years with MI and multivessel disease were randomized to culprit-only or physiology-guided complete revascularization. In this prespecified analysis, outcomes were assessed according to diabetes status. The primary endpoint was a composite of death, MI, stroke, or revascularization at 3 years. The key secondary endpoint was cardiovascular death or MI. The safety endpoint included contrast-associated acute kidney injury, stroke, or Bleeding Academic Research Consortium type 3–5 bleeding. Results Among 1445 patients, 463 (32%) had diabetes. After adjustment for baseline characteristics, diabetes was independently associated with a higher risk of the primary endpoint (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.02–1.56) and heart failure (HR 1.35, 95% CI 1.01–1.83) at 3 years. Physiology-guided complete revascularization reduced the primary outcome in both patients with diabetes (HR 0.70, 95% CI 0.50–0.97) and without diabetes (HR 0.75, 95% CI 0.58–0.97), with no evidence of effect modification by diabetes status (p for interaction = 0.712). Similar consistency was observed for the key secondary and safety endpoints. Conclusions In older patients with MI and multivessel disease, physiology-guided complete revascularization reduces ischemic events irrespective of diabetes status, supporting its use in elderly diabetic patients. Trial registration ClinicalTrials.gov Identifier NCT03772743.

BACKGROUND:Coronary microvascular dysfunction (CMD) has been proposed as a mechanism underlying residual angina after percutaneous coronary intervention (PCI). OBJECTIVES:The objective of the study was to investigate the impact of CMD on symptoms in patients undergoing PCI. METHODS:Patients with hemodynamically significant coronary artery disease (CAD) (fractional flow reserve ≤0.80) were included. CAD was classified as focal or diffuse using the pull back pressure gradient (PPG) (diffuse CAD defined as PPG <0.62). CMD was defined as microvascular resistance reserve <3.0. The Seattle Angina Questionnaire (SAQ) was administered at baseline and 1 year. RESULTS:Among 201 patients (mean age 68.5 ± 10.1 years; 71% male), CMD was present in 75 (37.3%), with no difference between focal and diffuse CAD (41% vs 34%; P = 0.35). At baseline, CMD was associated with more severe symptoms without reaching statistical significance (SAQ summary score 64.0 ± 25.3 vs 69.6 ± 21.0; P = 0.09). At 1 year, symptoms were similar between groups (SAQ summary score 87.6 ± 16.0 vs 89.4 ± 16.4; P = 0.47). A significant interaction between PPG and microvascular resistance reserve was observed for residual angina (P for interaction = 0.015); patients with focal CAD and concomitant CMD had the highest burden of residual symptoms. CONCLUSIONS:CMD is present in approximately one-third of patients undergoing PCI and occurs with similar frequency in focal and diffuse CAD. CMD alone was not associated with residual angina. However, its clinical relevance varied according to the epicardial disease pattern: in focal CAD, concomitant CMD was associated with less symptomatic improvement after PCI, whereas in diffuse CAD, residual symptoms appeared to be driven predominantly by persistent epicardial disease.

BACKGROUND:Current society guidelines recommend physiological assessment of intermediate coronary lesions to guide revascularization. Data regarding revascularization guided by vessel fractional flow reserve (vFFR), derived from three-dimensional quantitative coronary angiography without the need for a pressure wire or hyperemic agent, as compared with pressure-wire-based fractional flow reserve (FFR), are lacking. METHODS:We conducted an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients with intermediate coronary-artery lesions (diameter stenosis of 30 to 80%) who presented with chronic or acute coronary syndromes were randomly assigned in a 1:1 ratio to undergo either vFFR-guided or FFR-guided revascularization of the intermediate coronary-artery lesions. The primary end point was a composite of death from any cause, any myocardial infarction, or any revascularization at 1 year. The noninferiority margin was 3.0 percentage points. RESULTS:The primary end point was assessed in 1116 patients in the vFFR group and 1095 in the FFR group. The mean age of the patients was 67 years, 24.3% were women, 18.7% presented with an acute coronary syndrome, and 26.6% had diabetes mellitus. At 1 year, a primary end-point event had occurred in 80 patients (Kaplan-Meier estimate, 7.5%) in the vFFR group and in 79 patients (Kaplan-Meier estimate, 7.5%) in the FFR group (risk difference, -0.02 percentage points; 95% confidence interval, -2.25 to 2.21; P = 0.004 for noninferiority). The incidence of serious adverse events appeared to be similar in the two groups. CONCLUSIONS:Among patients with intermediate coronary lesions, vFFR-guided revascularization was noninferior to FFR-guided revascularization with respect to a composite of death, myocardial infarction, or revascularization at 1 year. (Funded by Pie Medical Imaging and Siemens Healthineers; FAST III ClinicalTrials.gov number, NCT04931771.).

BACKGROUND:Angina with no obstructive coronary artery disease (ANOCA) is associated with persistent symptoms and impaired quality of life. Although guidelines advocate a patient-centered, multidisciplinary approach, randomized evidence is lacking. OBJECTIVES:The aim of this study was to determine whether a multidomain lifestyle intervention improves patient-reported health status and quality of life in patients with ANOCA. METHODS:SAMCRO was a prospective, multicenter, randomized trial with blinded endpoint assessment. Patients with angina and invasive evidence of coronary microvascular dysfunction and/or coronary vasomotor disorder were randomized 1:1 to endotype-guided therapy plus a structured multidomain lifestyle intervention (intervention group) or endotype-guided therapy alone (control group). The intervention integrated exercise training, Mediterranean dietary counseling, and psychological support. The primary endpoint was the change in Seattle Angina Questionnaire summary score. RESULTS:A total of 123 patients were randomized (62 to intervention and 61 to control), with follow-up completed at 12 months for the primary endpoint. The mean age was 65.8 ± 9 years, and 46% were women. The adjusted mean improvement in Seattle Angina Questionnaire summary score was significantly greater in the intervention group (between-group difference: 13.12 points; 95% CI: 9.68-16.56; P < 0.001). A clinically meaningful improvement (≥10-point increase) was achieved in 48 (77%) versus 23 (38%) of patients, respectively (adjusted risk ratio: 1.98; 95% CI: 1.20-3.26; P < 0.001). Significant improvements were also observed in the EuroQol 5-Dimension 5-Level index and Beck Depression Inventory scores. CONCLUSIONS:In patients with invasively confirmed ANOCA, a structured multidomain lifestyle intervention provided clinically meaningful improvements in patient-reported health status on top of endotype-guided medical therapy. REGISTRATION:(Standardizing the Management of Patients With Coronary Microvascular Dysfunction [SAMCRO]; NCT06025994).

BACKGROUND AND AIMS:Angina with non-obstructive coronary arteries (ANOCA) is a prevalent myocardial ischaemic syndrome, and women are disproportionately affected. Mechanisms of ischaemia are challenging to diagnose and treatment is empirical. METHODS:Consecutive patients with angina (or equivalent symptoms), no angiographically severe stenosis and fractional flow reserve > 0.80 undergoing coronary functional testing were prospectively enrolled in nine centres in Europe and North America. Haemodynamic endotypes were assessed measuring coronary flow reserve and resistance using an intracoronary pressure- and temperature-sensitive sensor and bolus thermodilution. Measurements were obtained during resting conditions and following adenosine and acetylcholine. Chest pain and electrocardiographic ischaemic changes were recorded. The participant characteristics of each haemodynamic endotype were investigated using regression analysis. A three-step Delphi consensus method was applied to identify endotype-specific therapies. RESULTS:Overall, 1001 participants (mean age 62 ± 11years, 56% female) were enrolled and eight distinct endotypes were defined by adenosine testing (n = 3) and acetylcholine testing (n = 5), respectively: high resting coronary blood flow (n = 195, 19%); high resistance (n = 125, 13%); compensated high resistance (n = 112, 11%); epicardial coronary spasm (n = 162, 17%); microvascular spasm (n = 75, 8%); endothelial dysfunction (n = 96, 10%); ischaemia w/o haemodynamic changes (n = 68, 7%); and enhanced cardiac nociception (n = 79, 8%). More than one endotype occurred in 119 (12%) individuals and normal responses occurred in 234 (23%) individuals. Each endotype was associated with distinct clinical correlates. The Delphi consensus (100% 'agree' or 'strongly agree') identified endotype-specific medical therapy with a Likert scale score ≥ 6 for all endotypes. CONCLUSIONS:In patients with suspected ANOCA, assessment of the symptomatic, electrocardiographic, and haemodynamic responses to adenosine and acetylcholine identifies distinct endotypes and enables mechanism-guided stratified medicine.

The optimal management of patients with ST-segment elevation myocardial infarction (STEMI) with large thrombus burden (LTB) undergoing primary percutaneous coronary intervention (PCI) remains unsettled. The NATURE (clinicaltrials.gov, NCT04969471) study is a prospective, multicenter, two-arm randomized clinical trial designed to assess the safety and effectiveness of the enVast stent retriever as an adjunctive reperfusion strategy in STEMI patients with LTB undergoing primary PCI. Eligible patients consenting for trial participation are randomly allocated (1:1) to enVast-assisted mechanical thrombectomy followed by conventional PCI (experimental arm) versus standard of care (control arm). Randomization is stratified by site, time from symptom onset (≤ 3 versus >3 h) and intended use of parenteral antiplatelet agents (i.e. glycoprotein IIb/IIIa inhibitors or cangrelor). Scheduled follow-up visits take place at 30 (±7) days, 150 (±60) days, and 365 (±30) days post-randomization. The primary endpoint is the infarct size assessed by the area under the curve for creatin kinase myocardial band (CK-MB) activity. Clinical events will be adjudicated by an independent Clinical Events Committee. A central core-lab will analyse 12‑lead ECG, coronary angiography examinations, cardiac magnetic resonance imaging and echocardiography examinations. A sample size of 148 (74 per arm) STEMI patients with complete primary endpoint assessment will provide a 90% power with a two-sided 5% significance level to detect a decrease in the AUC for CK-MB by 30%. The NATURE trial is the first randomized clinical trial aimed at investigating if enVast-assisted mechanical thrombectomy as adjunctive reperfusion strategy is safe and may reduce infarct size in STEMI patients with LTB undergoing primary PCI. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT04969471.