The coronary microvascular angina cardiovascular magnetic resonance imaging trial: Rationale and design.

BACKGROUND: Coronary microvascular dysfunction may cause myocardial ischemia with no obstructive coronary artery disease (INOCA). If functional testing is not performed INOCA may pass undetected. Stress perfusion cardiovascular MRI (CMR) quantifies myocardial blood flow (MBF) but the clinical utility of stress CMR in the management of patients with suspected angina with no obstructive coronary arteries (ANOCA) is uncertain. OBJECTIVES: First, to undertake a diagnostic study using stress CMR in patients with ANOCA following invasive coronary angiography and, second, in a nested, double-blind, randomized, controlled trial to assess the effect of disclosure on the final diagnosis and health status in the longer term. DESIGN: All-comers referred for clinically indicated coronary angiography for the investigation of suspected coronary artery disease will be screened in 3 regional centers in the United Kingdom. Following invasive coronary angiography, patients with ANOCA who provide informed consent will undergo noninvasive endotyping using stress CMR within 3 months of the angiogram. DIAGNOSTIC STUDY: Stress perfusion CMR imaging to assess the prevalence of coronary microvascular dysfunction and clinically significant incidental findings in patients with ANOCA. The primary outcome is the between-group difference in the reclassification rate of the initial diagnosis based on invasive angiography versus the final diagnosis after CMR imaging. RANDOMIZED, CONTROLLED TRIAL: Participants will be randomized to inclusion (intervention group) or exclusion (control group) of myocardial blood flow to inform the final diagnosis. The primary outcome of the clinical trial is the mean within-subject change in the Seattle Angina Questionnaire summary score (SAQSS) at 6 months. Secondary outcome assessments include the EUROQOL EQ-5D-5L questionnaire, the Brief Illness Perception Questionnaire (Brief-IPQ), the Treatment Satisfaction Questionnaire (TSQM-9), the Patient Health Questionnaire-4 (PHQ-4), the Duke Activity Status Index (DASI), the International Physical Activity Questionnaire- Short Form (IPAQ-SF), the Montreal Cognitive Assessment (MOCA) and the 8-item Productivity Cost Questionnaire (iPCQ). Health and economic outcomes will be assessed using electronic healthcare records. VALUE: To clarify if routine stress perfusion CMR imaging reclassifies the final diagnosis in patients with ANOCA and whether this strategy improves symptoms, health-related quality of life and health economic outcomes. CLINICALTRIALS: GOV: NCT04805814.

Impact of technique on bifurcation stent outcomes in the European Bifurcation Club Left Main Coronary Trial.

BACKGROUND: Techniques for provisional and dual-stent left main bifurcation stenting require optimization. AIM: To identify technical variables influencing procedural outcomes and periprocedural myocardial infarction following left main bifurcation intervention. METHODS: Procedural and outcome data were analyzed in 438 patients from the per-protocol cohort of the European Bifurcation Club Left Main Trial (EBC MAIN). These patients were randomized to the provisional strategy or a compatible dual-stent extension (T, T-and-protrude, or culotte). RESULTS: Mean age was 71 years and 37.4% presented with an acute coronary syndrome. Transient reduction of side vessel thrombolysis in myocardial infarction flow occurred after initial stent placement in 5% of procedures but was not associated with periprocedural myocardial infarction. Failure to rewire a jailed vessel during any strategy was more common when jailed wires were not used (9.5% vs. 2.5%, odds ratio [OR]: 6.4, p = 0.002). In the provisional cohort, the use of the proximal optimization technique was associated with less subsequent side vessel intervention (23.3% vs. 41.9%, OR: 0.4, p = 0.048). Side vessel stenting was predominantly required for dissection, which occurred more often following side vessel preparation (15.3% vs. 4.4%, OR: 3.1, p = 0.040). Exclusive use of noncompliant balloons for kissing balloon inflation was associated with reduced need for side vessel intervention in provisional cases (20.5% vs. 38.5%, OR: 0.4, p = 0.013), and a reduced risk of periprocedural myocardial infarction across all strategies (2.9% vs. 7.7%, OR: 0.2, p = 0.020). CONCLUSION: When performing provisional or compatible dual-stent left main bifurcation intervention, jailed wire use is associated with successful jailed vessel rewiring. Side vessel preparation in provisional patients is linked to increased side vessel dissection requiring stenting. Use of the proximal optimization technique may reduce the need for additional side vessel intervention, and noncompliant balloon use for kissing balloon inflation is associated with a reduction in both side vessel stenting and periprocedural myocardial infarction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02497014.

Post-stenting fractional flow reserve vs coronary angiography for optimization of percutaneous coronary intervention (TARGET-FFR).

AIMS: A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90. METHODS AND RESULTS: After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR <0.90. In the PIOS group, 30.5% underwent further intervention (stent post-dilation and/or additional stenting). There was no significant difference in the primary endpoint of the proportion of patients with final post-PCI FFR ≥0.90 between groups (PIOS minus control 10%, 95% confidence interval -1.84 to 21.91, P = 0.099). The proportion of patients with a final FFR ≤0.80 was significantly reduced when compared with the angiography-guided control group (-11.2%, 95% confidence interval -21.87 to -0.35], P = 0.045). CONCLUSION: Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

Age-Stratified Outcome in Treatment of Left Main Coronary Artery Stenosis: A NOBLE Trial Substudy.

BACKGROUND: In the treatment of left main coronary artery (LMCA) disease, patients' age may affect the clinical outcome after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). This study stratified the clinical outcome according to the age of patients treated for LMCA stenosis with PCI or CABG in the Nordic-Baltic-British Left Main Revascularization (NOBLE) study. METHODS: Patients with LMCA disease were enrolled in 36 centers in northern Europe and randomized 1:1 to treatment by PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST elevation myocardial infarction. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCEs), a composite of all-cause mortality, nonprocedural myocardial infarction, any repeat coronary revascularization, and stroke. Age-stratified analysis was performed for the groups younger and older than 67 years and for patients older than 80 years. RESULTS: For patients ≥67 years, the 5-year MACCEs were 35.7 versus 22.3% (hazard ratio [HR] 1.72 [95% confidence interval [CI] 1.27-2.33], p = 0.0004) for PCI versus CABG. The difference in MACCEs was driven by more myocardial infarctions (10.8 vs. 3.8% HR 3.01 [95% CI 1.52-5.96], p = 0.0009) and more repeat revascularizations (19.5 vs. 10.0% HR 2.01 [95% CI 1.29-3.12], p = 0.002). In patients younger than 67 years, MACCE was 20.5 versus 15.3% (HR 1.38 [95% CI 0.93-2.06], p = 0.11 for PCI versus CABG. All-cause mortality was similar after PCI and CABG in both age-groups. On multivariate analysis, age was a predictor of MACCE, along with PCI, diabetes, and SYNTAX score. CONCLUSIONS: As the overall NOBLE results show revascularization of LMCA disease, age of 67 years or older was associated with lower 5-year MACCE after CABG compared to PCI. Clinical outcomes were not significantly different in the subgroup younger than 67 years, although no significant interaction was present between age and treatment. Mortality was similar for all subgroups (ClinicalTrials.gov identifier: NCT01496651).

Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. CONCLUSION: We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03193294.

Displacement Encoding With Stimulated Echoes Enables the Identification of Infarct Transmurality Early Postmyocardial Infarction.

BACKGROUND: Segmental extent of infarction assessed by late gadolinium enhancement (LGE) imaging early post-ST-segment elevation myocardial infarction (STEMI) has utility in predicting left ventricular functional recovery. HYPOTHESIS: We hypothesized that segmental circumferential strain with displacement encoding with stimulated echoes (DENSE) would be a stronger predictor of infarct transmurality than feature-tracking strain, and noninferior to extracellular volume fraction (ECV). STUDY TYPE: Prospective. POPULATION: Fifty participants (mean ± SD, 59 ± 9 years, 40 [80%] male) underwent cardiac MRI on day 1 post-STEMI. FIELD-STRENGTH/SEQUENCES: 1.5T/cine, DENSE, T1 mapping, ECV, LGE. ASSESSMENT: Two observers assessed segmental percentage LGE extent, presence of microvascular obstruction (MVO), circumferential and radial strain with DENSE and feature-tracking, T1 relaxation times, and ECV. STATISTICAL TESTS: Normality was tested using the Shapiro-Wilk test. Skewed distributions were analyzed utilizing Mann-Whitney or Kruskal-Wallis tests and normal distributed data using independent t-tests. Diagnostic cutoff values were identified using the Youden index. The difference in area under the curve was compared using the z-statistic. RESULTS: Segmental circumferential strain with DENSE was associated with the extent of infarction ≥50% (AUC [95% CI], cutoff value = 0.9 [0.8, 0.9], -10%) similar to ECV (AUC = 0.8 [0.8, 0.9], 37%) (P = 0.117) and superior to feature-tracking circumferential strain (AUC = 0.7[0.7, 0.8], -19%) (P < 0.05). For the detection of segmental infarction ≥75%, circumferential strain with DENSE (AUC = 0.9 [0.8, 0.9], -10%) was noninferior to ECV (AUC = 0.8 [0.7, 0.9], 42%) (P = 0.132) and superior to feature-tracking (AUC = 0.7 [0.7, 0.8], -13%) (P < 0.05). For MVO detection, circumferential strain with DENSE (AUC = 0.8 [0.8, 0.9], -12%) was superior to ECV (AUC = 0.8 [0.7, 0.8] 34%) (P < 0.05) and feature-tracking (AUC = 0.7 [0.6, 0.7] -21%) (P < 0.05). DATA CONCLUSION: Circumferential strain with DENSE is a functional measure of infarct severity and may remove the need for gadolinium contrast agents in some circumstances. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 5 J. MAGN. RESON. IMAGING 2020;52:1722-1731.

Sex differences in procedural and clinical outcomes following rotational atherectomy.

AIM: Evaluate sex differences in procedural net adverse clinical events and long-term outcomes following rotational atherectomy (RA). METHODS AND RESULTS: From August 2010 to 2016, 765 consecutive patients undergoing RA PCI were followed up for a median of 4.7 years. 285 (37%) of subjects were female. Women were older (mean 76 years vs. 72 years; p < .001) and had more urgent procedures (64.6 vs. 47.3%; p < .001). Females received fewer radial procedures (75.1 vs. 85.1%; p < .001) and less intravascular imaging guidance (16.8 vs. 25.0%; p = .008). After propensity score adjustment, the primary endpoint of net adverse cardiac events (net adverse clinical events: all-cause death, myocardial infarction, stroke, target vessel revascularization plus any procedural complication) occurred more often in female patients (15.1 vs. 9.0%; adjusted OR 1.81 95% CI 1.04-3.13; p = .037). This was driven by an increased risk of procedural complications rather than procedural major adverse cardiac events (MACE). Specifically, women were more likely to experience coronary dissection (4.6 vs. 1.3%; p = .008), cardiac tamponade (2.1 vs. 0.4%; p = .046) and significant bleeding (BARC ≥2: 5.3 vs. 2.3). Despite this, overall MACE-free survival was similar between males and females (adjusted HR 1.03; 95% CI 0.80-1.34; p = .81). Procedural complications during RA were associated with almost double the incidence of MACE at long-term follow-up (HR 1.92; 95% CI 1.34-2.77; p < .001). CONCLUSION: Women may be at greater risk of procedural complications following rotational atherectomy. These include periprocedural bleeding episodes and coronary perforation leading to cardiac tamponade. Despite this, the adjusted overall long-term survival free of major adverse cardiac events was similar between males and females.

Circumferential Strain Predicts Major Adverse Cardiovascular Events Following an Acute ST-Segment-Elevation Myocardial Infarction.

Purpose To investigate the prognostic value of circumferential left ventricular (LV) strain measured by using cardiac MRI for prediction of major adverse cardiac events (MACE) following an acute ST-segment-elevation myocardial infarction (STEMI). Materials and Methods Participants with acute STEMI were prospectively enrolled from May 11, 2011, to November 22, 2012. Cardiac MRI was performed at 1.5 T during the index hospitalization. Displacement encoding with stimulated echoes (DENSE) and feature tracking of cine cardiac MRI was used to assess circumferential LV strain. MACE that occurred after discharge were independently assessed by cardiologists blinded to the baseline observations. Results A total of 259 participants (mean age, 58 years ± 11 [standard deviation]; 198 men [mean age, 58 years ± 11] and 61 women [mean age, 58 years ± 12]) underwent cardiac MRI 2.2 days ± 1.9 after STEMI. Average infarct size was 18% ± 13 of LV mass and circumferential strain was -13% ± 3 (DENSE method) and -24% ± 7 (feature- tracking method). Fifty-one percent (131 of 259 participants) had presence of microvascular obstruction. During a median follow-up period of 4 years, 8% (21 of 259) experienced MACE. Area under the curve (AUC) for DENSE was different from that of feature tracking (AUC, 0.76 vs 0.62; P = .03). AUC for DENSE was similar to that of initial infarct size (P = .06) and extent of microvascular obstruction (P = .08). DENSE-derived strain provided incremental prognostic benefit over infarct size for prediction of MACE (hazard ratio, 1.3; P < .01). Conclusion Circumferential strain has independent prognostic importance in study participants with acute ST-segment-elevation myocardial infarction. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Kramer in this issue.

Systemic microvascular dysfunction in microvascular and vasospastic angina.

Aims: Coronary microvascular dysfunction and/or vasospasm are potential causes of ischaemia in patients with no obstructive coronary artery disease (INOCA). We tested the hypothesis that these patients also have functional abnormalities in peripheral small arteries. Methods and results: Patients were prospectively enrolled and categorised as having microvascular angina (MVA), vasospastic angina (VSA) or normal control based on invasive coronary artery function tests incorporating probes of endothelial and endothelial-independent function (acetylcholine and adenosine). Gluteal biopsies of subcutaneous fat were performed in 81 subjects (62 years, 69% female, 59 MVA, 11 VSA, and 11 controls). Resistance arteries were dissected enabling study using wire myography. Maximum relaxation to ACh (endothelial function) was reduced in MVA vs. controls [median 77.6 vs. 98.7%; 95% confidence interval (CI) of difference 2.3-38%; P = 0.0047]. Endothelium-independent relaxation [sodium nitroprusside (SNP)] was similar between all groups. The maximum contractile response to endothelin-1 (ET-1) was greater in MVA (median 121%) vs. controls (100%; 95% CI of median difference 4.7-45%, P = 0.015). Response to the thromboxane agonist, U46619, was also greater in MVA (143%) vs. controls (109%; 95% CI of difference 13-57%, P = 0.003). Patients with VSA had similar abnormal patterns of peripheral vascular reactivity including reduced maximum relaxation to ACh (median 79.0% vs. 98.7%; P = 0.03) and increased response to constrictor agonists including ET-1 (median 125% vs. 100%; P = 0.02). In all groups, resistance arteries were ≈50-fold more sensitive to the constrictor effects of ET-1 compared with U46619. Conclusions: Systemic microvascular abnormalities are common in patients with MVA and VSA. These mechanisms may involve ET-1 and were characterized by endothelial dysfunction and enhanced vasoconstriction. Clinical trial registration: ClinicalTrials.gov registration is NCT03193294.

Effect of Low-Dose Intracoronary Alteplase During Primary Percutaneous Coronary Intervention on Microvascular Obstruction in Patients With Acute Myocardial Infarction: A Randomized Clinical Trial.

Importance: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes. Objective: To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction. Design, Setting, and Participants: Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal-mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018. Interventions: Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant. Main Outcomes and Measures: The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis. Results: Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, -0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, -0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group. Conclusions and Relevance: Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02257294.

Comparative Prognostic Utility of Indexes of Microvascular Function Alone or in Combination in Patients With an Acute ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: Primary percutaneous coronary intervention is frequently successful at restoring coronary artery blood flow in patients with acute ST-segment-elevation myocardial infarction; however, failed myocardial reperfusion commonly passes undetected in up to half of these patients. The index of microvascular resistance (IMR) is a novel invasive measure of coronary microvascular function. We aimed to investigate the pathological and prognostic significance of an IMR>40, alone or in combination with a coronary flow reserve (CFR≤2.0), in the culprit artery after emergency percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction. METHODS: Patients with acute ST-segment-elevation myocardial infarction were prospectively enrolled during emergency percutaneous coronary intervention and categorized according to IMR (≤40 or >40) and CFR (≤2.0 or >2.0). Cardiac magnetic resonance imaging was acquired 2 days and 6 months after myocardial infarction. All-cause death or first heart failure hospitalization was a prespecified outcome (median follow-up, 845 days). RESULTS: IMR and CFR were measured in the culprit artery at the end of percutaneous coronary intervention in 283 patients with ST-segment-elevation myocardial infarction (mean±SD age, 60±12 years; 73% male). The median IMR and CFR were 25 (interquartile range, 15-48) and 1.6 (interquartile range, 1.1-2.1), respectively. An IMR>40 was a multivariable associate of myocardial hemorrhage (odds ratio, 2.10; 95% confidence interval, 1.03-4.27; P=0.042). An IMR>40 was closely associated with microvascular obstruction. Symptom-to-reperfusion time, TIMI (Thrombolysis in Myocardial Infarction) blush grade, and no (≤30%) ST-segment resolution were not associated with these pathologies. An IMR>40 was a multivariable associate of the changes in left ventricular ejection fraction (coefficient, -2.12; 95% confidence interval, -4.02 to -0.23; P=0.028) and left ventricular end-diastolic volume (coefficient, 7.85; 95% confidence interval, 0.41-15.29; P=0.039) at 6 months independently of infarct size. An IMR>40 (odds ratio, 4.36; 95% confidence interval, 2.10-9.06; P<0.001) was a multivariable associate of all-cause death or heart failure. Compared with an IMR>40, the combination of IMR>40 and CFR≤2.0 did not have incremental prognostic value. CONCLUSIONS: An IMR>40 is a multivariable associate of left ventricular and clinical outcomes after ST-segment-elevation myocardial infarction independently of the infarction size. Compared with standard clinical measures of the efficacy of myocardial reperfusion, including the ischemic time, ST-segment elevation, angiographic blush grade, and CFR, IMR has superior clinical value for risk stratification and may be considered a reference test for failed myocardial reperfusion. CLINICAL TRIAL REGISTRATION: URL: https//www.clinicaltrials.gov. Unique identifier: NCT02072850.

Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.

BACKGROUND: Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. METHODS: In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. FINDINGS: Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1·48 (95% CI 1·11-1·96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0066). As-treated estimates were 28% versus 19% (1·55, 1·18-2·04, p=0·0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1·07, 0·67-1·72, p=0·77) for all-cause mortality, 7% versus 2% (2·88, 1·40-5·90, p=0·0040) for non-procedural myocardial infarction, 16% versus 10% (1·50, 1·04-2·17, p=0·032) for any revascularisation, and 5% versus 2% (2·25, 0·93-5·48, p=0·073) for stroke. INTERPRETATION: The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease. FUNDING: Biosensors, Aarhus University Hospital, and participating sites.

Prognostic significance of infarct core pathology revealed by quantitative non-contrast in comparison with contrast cardiac magnetic resonance imaging in reperfused ST-elevation myocardial infarction survivors.

AIMS: To assess the prognostic significance of infarct core tissue characteristics using cardiac magnetic resonance (CMR) imaging in survivors of acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We performed an observational prospective single centre cohort study in 300 reperfused STEMI patients (mean ± SD age 59 ± 12 years, 74% male) who underwent CMR 2 days and 6 months post-myocardial infarction (n = 267). Native T1 was measured in myocardial regions of interest (n = 288). Adverse remodelling was defined as an increase in left ventricular (LV) end-diastolic volume ≥20% at 6 months. All-cause death or first heart failure hospitalization was a pre-specified outcome that was assessed during follow-up (median duration 845 days). One hundred and sixty (56%) patients had a hypo-intense infarct core disclosed by native T1. In multivariable regression, infarct core native T1 was inversely associated with adverse remodelling [odds ratio (95% confidence interval (CI)] per 10 ms reduction in native T1: 0.91 (0.82, 0.00); P = 0.061). Thirty (10.4%) of 288 patients died or experienced a heart failure event and 13 of these events occurred post-discharge. Native T1 values (ms) within the hypo-intense infarct core (n = 160 STEMI patients) were inversely associated with the risk of all-cause death or first hospitalization for heart failure post-discharge (for a 10 ms increase in native T1: hazard ratio 0.730, 95% CI 0.617, 0.863; P < 0.001) including after adjustment for left ventricular ejection fraction, infarct core T2 and myocardial haemorrhage. The prognostic results for microvascular obstruction were similar. CONCLUSION: Infarct core native T1 represents a novel non-contrast CMR biomarker with potential for infarct characterization and prognostication in STEMI survivors. Confirmatory studies are warranted. CLINICALTRIALS. GOV IDENTIFIER: NCT02072850.

Fractional flow reserve (FFR) versus angiography in guiding management to optimise outcomes in non-ST segment elevation myocardial infarction (FAMOUS-NSTEMI) developmental trial: cost-effectiveness using a mixed trial- and model-based methods.

BACKGROUND: In the Fractional flow reserve (FFR) versus angiography in guiding management to optimise outcomes in non-ST elevation myocardial infarction (FAMOUS) clinical trial, FFR was shown to significantly reduce coronary revascularisation, compared to visual interpretation of standard coronary angiography without FFR. We estimated the cost-effectiveness from a UK National Health Service perspective, based on the results of FAMOUS. METHODS: A mixed trial- and model-based approach using decision and statistical modelling was used. Within-trial (1-year) costs and QALYs were assembled at the individual level and then modelled on subsequent management strategy [coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) or medical therapy (MT)] and major adverse coronary events (death, MI, stroke and revascularisation). One-year resource uses included: material, hospitalisation, medical, health professional service use and events. Utilities were derived from individual EQ5D responses. Unit costs were derived from the literature. Outcomes were extended to a lifetime on the basis of MACE during the 1st year. Costs and QALYs were modelled using generalized linear models whilst MACE was modelled using logistic regression. The analysis adopted a payer perspective. Costs and outcomes were discounted at 3.5 %. RESULTS: Costs were related to the subsequent management strategy and MACE whilst QALYs were not. FFR led to a modest cost increase, albeit an imprecise increase, over both the trial [£112 (-£129 to £357)] and lifetime horizons [£133 (-£199 to £499)]. FFR led to a small, albeit imprecise, increase in QALYs over both the trial [0.02 (-0.03 to 0.06)] and lifetime horizons [0.03 (-0.21 to 0.28)]. The mean ICER was £7516/QALY and £4290/QALY over the trial and lifetime horizons, respectively. Decision remained high; FFR had 64 and 59 % probability of cost-effectiveness over trial and lifetime horizons, respectively. CONCLUSIONS: FFR was cost-effective at the mean, albeit with considerable decision uncertainty. Uncertainty can be reduced with more information on long-term health events.

Fractional Flow Reserve-Guided Stent Optimisation in Focal and Diffuse Coronary Artery Disease.

Assessing coronary physiology after stent implantation facilitates the optimisation of percutaneous coronary intervention (PCI). Coronary artery disease (CAD) patterns can be characterised by the pullback pressure gradient (PPG) index. The impact of focal vs. diffuse disease on physiology-guided incremental optimisation strategy (PIOS) is unknown. This is a sub-study of the TARGET-FFR randomized clinical trial (NCT03259815). The study protocol directed that optimisation be attempted for patients in the PIOS arm when post-PCI FFR was <0.90. Overall, 114 patients (n = 61 PIOS and 53 controls) with both pre-PCI fractional flow reserve (FFR) pullbacks and post-PCI FFR were included. A PPG ≥ 0.74 defined focal CAD. The PPG correlated significantly with post-PCI FFR (r = 0.43; 95% CI 0.26 to 0.57; p-value < 0.001) and normalised delta FFR (r = 0.49; 95% CI 0.34 to 0.62; p-value < 0.001). PIOS was more frequently applied to vessels with diffuse CAD (6% focal vs. 42% diffuse; p-value = 0.006). In patients randomized to PIOS, those with focal disease achieved higher post-PCI FFR than patients with diffuse CAD (0.93 ± 0.05 vs. 0.83 ± 0.07, p < 0.001). There was a significant interaction between CAD patterns and the randomisation arm for post-PCI FFR (p-value for interaction = 0.004). Physiology-guided stent optimisation was applied more frequently to vessels with diffuse disease; however, patients with focal CAD at baseline achieved higher post-PCI FFR.

Angina After Percutaneous Coronary Intervention: Patient and Procedural Predictors.

BACKGROUND: Twenty percent to 40% of patients are affected by angina after percutaneous coronary intervention (PCI), which is associated with anxiety, depression, impaired physical function, and reduced quality of life. Understanding patient and procedural factors associated with post-PCI angina may inform alternative approaches to treatment. METHODS: Two hundred thirty patients undergoing PCI completed the Seattle Angina Questionnaire (SAQ-7) and European quality of life-5 dimension-5 level (EQ-5D-5L) questionnaires at baseline and 3 months post-PCI. Patients received blinded intracoronary physiology assessments before and after stenting. A post hoc analysis was performed to compare clinical and procedural characteristics among patients with and without post-PCI angina (defined by follow-up SAQ-angina frequency score <100). RESULTS: Eighty-eight of 230 patients (38.3%) reported angina 3 months post-PCI and had a higher incidence of active smoking, atrial fibrillation, and history of previous myocardial infarction or PCI. Compared with patients with no angina at follow-up, they had lower baseline SAQ summary scores (69.48±24.12 versus 50.20±22.59, P<0.001) and EQ-5D-5L health index scores (0.84±0.15 versus 0.69±0.22, P<0.001). Pre-PCI fractional flow reserve (FFR) was lower among patients who had no post-PCI angina (0.56±0.15 versus 0.62±0.13, P=0.003). Percentage change in FFR after PCI had a moderate correlation with angina frequency score at follow-up (r=0.36, P<0.0001). Patients with post-PCI angina had less improvement in FFR (43.1±33.5% versus 67.0±50.7%, P<0.001). There were no between-group differences in post-PCI FFR, coronary flow reserve, or corrected index of microcirculatory resistance. Patients with post-PCI angina had lower SAQ-summary scores (64.01±22 versus 95.16±8.72, P≤0.001) and EQ-5D-5L index scores (0.69±0.26 versus 0.91±0.17, P≤0.001) at follow-up. CONCLUSIONS: Larger improvements in FFR following PCI were associated with less angina and better quality of life at follow-up. In patients with stable symptoms, intracoronary physiology assessment can inform expectations of angina relief and quality of life improvement after stenting and thereby help to determine the appropriateness of PCI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03259815.

Comparative study of costs and resource utilization of rotational atherectomy versus intravascular lithotripsy for percutaneous coronary intervention.

BACKGROUND: Intravascular lithotripsy (IVL) is a novel alternative to rotational atherectomy (RA) for the modification of heavily calcified coronary stenoses prior to percutaneous coronary intervention (PCI). We compare the real-world resource utilization and associated costs of PCI with adjunctive RA and IVL. METHODS: We compared the resource utilization, in-lab consumable costs and procedural data of 120 patients who underwent PCI with IVL from the Disrupt-CAD II study (NCT03328949) to 60 patients who underwent PCI with RA at the Golden Jubilee National Hospital, Glasgow, UK. The RA patients were consecutive and selected on the basis of being deemed suitable for IVL by an independent interventional cardiologist experienced in the use of both techniques. RESULTS: PCI with IVL was associated with significantly lower costs than PCI with RA (mean difference £ 398 [95% CI: £ 181-615]; P<0.001). Considering between-group differences, the IVL group used 4.02 fewer balloons (P<0.001), 3.03 fewer guidewires (P<0.001), 0.52 fewer guide catheters (P=0.001), 0.22 fewer guide extensions (P=0.004) and 1.03 fewer drug eluting stents (DES) (P<0.001) per case than the RA group. The IVL group had shorter procedural duration (mean difference 13.3 min [95% CI: 3.6-23.0]; P=0.008) but longer fluoroscopy times (mean difference 4.4 min [95% CI: 1.7-7.1]; P=0.002). CONCLUSIONS: In this indirect comparison, we found that the higher initial device costs of IVL may be offset by a lower overall resource utilization. Further research is required to confirm this, and future randomized trials should include a formal health economic analysis.

Coronary Artery Perforations: Glasgow Natural History Study of Covered Stent Coronary Interventions (GNOCCI) Study.

Background The objective of the GNOCCI (Glasgow Natural History Study of Covered Stent Coronary Interventions) Study was to report the incidence and outcomes of coronary artery perforations over an 18-year period at a single, high-volume percutaneous coronary intervention center. We considered both the temporal trends and long-term outcomes of covered stent deployment. Methods and Results We evaluated procedural and long-term clinical outcomes following coronary perforation in a cohort of 43,343 consecutive percutaneous coronary intervention procedures. Procedural major adverse cardiac events were defined as a composite of death, myocardial infarction, stroke, target vessel revascularization, or cardiac surgery within 24 hours. A total of 161 (0.37%) procedures were complicated by coronary perforation of which 57 (35%) were Ellis grade III. Incidence increased with time over the study period (r=0.73; P<0.001). Perforation severity was linearly associated with procedural mortality (median 2.9-year follow-up): Ellis I (0%), Ellis II (1.7%), Ellis III/IIIB (21%), P<0.001. Procedural major adverse cardiac events occurred in 47% of patients with Ellis III/IIIB versus 13.5% of those with Ellis I/II perforations (odds ratio, 5.8; 95% CI, 2.7-12.5; P<0.001). Covered stents were associated with an increased risk of stent thrombosis at 2.9-year follow-up (Academic Research Consortium definite or probable; 9.1% versus 0.9%; risk ratio, 10.5; 95% CI, 1.1-97; P=0.04). Conclusions The incidence of coronary perforation increased between 2001 and 2019. Severe perforation was associated with higher procedural major adverse cardiac events and was an independent predictor of long-term mortality. Although covered stents are a potentially lifesaving treatment, the generation of devices used during the study period was limited by their efficacy and high risk of stent thrombosis. Registration Information Clinicaltrials.gov. Identifier: NCT03862352.

A Noncontrast CMR Risk Score for Long-Term Risk Stratification in Reperfused ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: This study compared the prognostic value of a noncontrast CMR risk score for the composite of all-cause death, nonfatal myocardial infarction, and new congestive heart failure. BACKGROUND: A cardiovascular magnetic resonance (CMR) risk score including left ventricular ejection fraction (LVEF), myocardial infarct (MI) size, and microvascular obstruction (MVO) was recently proposed to risk-stratify patients with ST-segment elevation myocardial infarction (STEMI). METHODS: The Eitel CMR risk score and GRACE (Global Registry of Acute Coronary Events) score were used as a reference (Score 1: acute MI size ≥19% LV, LVEF ≤47%, MVO >1.4% LV and GRACE score). MVO was replaced by intramyocardial hemorrhage (IMH) in Score 2 (acute MI size ≥19% LV, LVEF ≤47%, IMH, and GRACE score). Score 3 included only LVEF ≤45%, IMH, and GRACE score. RESULTS: There were 370 patients in the derivation cohort and 234 patients in the validation cohort. In the derivation cohort, the 3 scores performed similarly and better than GRACE score to predict the 1-year composite endpoint with C-statistics of 0.83, 0.83, 0.82, and 0.74, respectively. In the validation cohort, there was good discrimination and calibration of score 3, with a C-statistic of 0.87 and P = 0.71 in a Hosmer-Lemeshow test for goodness of fit, on the 1-year composite outcome. Kaplan-Meier curves for 5-year composite outcome showed that those with LVEF ≤45% (high-risk) and LVEF >45% and IMH (intermediate-risk) had significantly higher cumulative events than those with LVEF >45% and no IMH (low-risk), log-rank tests: P = 0.02 and P = 0.03, respectively. The HR for the high-risk group was 2.3 (95% CI: 1.1-4.7) and for the intermediate-risk group was 2.0 (95% CI: 1.0-3.8), and these remained significant after adjusting for the GRACE score. CONCLUSIONS: This noncontrast CMR risk score has performance comparable to an established risk score, and patients with STEMI could be stratified into low risk (LVEF >45% and no IMH), intermediate risk (LVEF >45% and IMH), and high risk (LVEF ≤45%). (A Trial of Low-dose Adjunctive alTeplase During prIMary PCI [T-TIME]; NCT02257294) (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850).

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size.

AIMS: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. METHODS AND RESULTS: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. CONCLUSION: Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.