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.

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.

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.

Can Interventional Cardiologists Help Deliver the UK Mechanical Thrombectomy Interventional Programme for Patients with Acute Ischaemic Stroke? A Discussion Paper from the British Cardiovascular Interventional Society Stroke Thrombectomy Focus Group.

There is a willingness among UK interventional cardiologists to contribute to provision of a 24/7 mechanical thrombectomy (MT) service for all suitable stroke patients if given the appropriate training. This highly effective intervention remains unavailable to the majority of patients who might benefit, partly because there is a limited number of trained specialists. As demonstrated in other countries, interdisciplinary working can be the solution and an opportunity to achieve this is outlined in this article.

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.

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.

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.

Risk Stratification Guided by the Index of Microcirculatory Resistance and Left Ventricular End-Diastolic Pressure in Acute Myocardial Infarction.

BACKGROUND: The index of microcirculatory resistance (IMR) of the infarct-related artery and left ventricular end-diastolic pressure (LVEDP) are acute, prognostic biomarkers in patients undergoing primary percutaneous coronary intervention. The clinical significance of IMR and LVEDP in combination is unknown. METHODS: IMR and LVEDP were prospectively measured in a prespecified substudy of the T-TIME clinical trial (Trial of Low Dose Adjunctive Alteplase During Primary PCI). IMR was measured using a pressure- and temperature-sensing guidewire following percutaneous coronary intervention. Prognostically established thresholds for IMR (>32) and LVEDP (>18 mm Hg) were predefined. Contrast-enhanced cardiovascular magnetic resonance imaging (1.5 Tesla) was acquired 2 to 7 days and 3 months postmyocardial infarction. The primary end point was major adverse cardiac events, defined as cardiac death/nonfatal myocardial infarction/heart failure hospitalization at 1 year. RESULTS: IMR and LVEDP were both measured in 131 patients (mean age 59±10.7 years, 103 [78.6%] male, 48 [36.6%] with anterior myocardial infarction). The median IMR was 29 (interquartile range, 17-55), the median LVEDP was 17 mm Hg (interquartile range, 12-21), and the correlation between them was not statistically significant (r=0.15; P=0.087). Fifty-three patients (40%) had low IMR (≤32) and low LVEDP (≤18), 18 (14%) had low IMR and high LVEDP, 31 (24%) had high IMR and low LVEDP, while 29 (22%) had high IMR and high LVEDP. Infarct size (% LV mass), LV ejection fraction, final myocardial perfusion grade ≤1, TIMI (Thrombolysis In Myocardial Infarction) flow grade ≤2, and coronary flow reserve were associated with LVEDP/IMR group, as was hospitalization for heart failure (n=18 events; P=0.045) and major adverse cardiac events (n=21 events; P=0.051). LVEDP>18 and IMR>32 combined was associated with major adverse cardiac events, independent of age, estimated glomerular filtration rate, and infarct-related artery (odds ratio, 5.80 [95% CI, 1.60-21.22] P=0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7-98.2; P=0.033) when LVEDP>18 was added to IMR>32. CONCLUSIONS: IMR and LVEDP in combination have incremental value for risk stratification following primary percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.

Effect of coronary flow on intracoronary alteplase: a prespecified analysis from a randomised trial.

OBJECTIVES: Persistently impaired culprit artery flow (

Thermodilution-derived temperature recovery time: a novel predictor of microvascular reperfusion and prognosis after myocardial infarction.

BACKGROUND: Novel parameters that detect failed microvascular reperfusion might identify better the patients likely to benefit from adjunctive treatments during primary percutaneous coronary intervention (PCI). AIMS: The aim of this study was to test the hypothesis that a novel invasive parameter, the thermodilution-derived temperature recovery time (TRT), would be associated with microvascular obstruction (MVO) and prognosis. METHODS: TRT was derived and validated in two independent ST-elevation myocardial infarction populations and was measured immediately post PCI. TRT was defined as the duration (seconds) from the nadir of the hyperaemic thermodilution curve to 20% from baseline body temperature. MVO extent (% left ventricular mass) was assessed by cardiovascular magnetic resonance imaging at 2-7 days. RESULTS: In the retrospective derivation cohort (n=271, mean age 60±12 years, 72% male), higher TRT was associated with more MVO (coefficient: 4.09 [95% CI: 2.70-5.48], p<0.001), independently of IMR >32, CFR ≤2, hyperaemic Tmn >median, thermodilution waveform, age and ischaemic time. At five years, higher TRT was multivariably associated with all-cause death/heart failure hospitalisation (OR 4.14 [95% CI: 2.08-8.25], p<0.001) and major adverse cardiac events (OR 4.05 [95% CI: 2.00-8.21], p<0.001). In the validation population (n=144, mean age 59±11 years, 80% male), the findings were confirmed prospectively. CONCLUSIONS: TRT represents a novel diagnostic advance for predicting MVO and prognosis. ClinicalTrials.gov Identifiers: NCT02072850 & NCT02257294 Visual summary. Thermodilution-derived temperature recovery time (TRT): a novel predictor of microvascular reperfusion & prognosis after STEMI. CMR: cardiovascular magnetic resonance; MACE: major adverse cardiac events; MVO: microvascular obstruction; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction.

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.

Redefining Adverse and Reverse Left Ventricular Remodeling by Cardiovascular Magnetic Resonance Following ST-Segment-Elevation Myocardial Infarction and Their Implications on Long-Term Prognosis.

BACKGROUND: Cut off values for change in left ventricular end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) by cardiovascular magnetic resonance following ST-segment-elevation myocardial infarction have recently been proposed and 4 patterns of LV remodeling were described. We aimed to assess their long-term prognostic significance. METHODS: A prospective cohort of unselected patients with ST-segment-elevation myocardial infarction with paired acute and 6-month cardiovascular magnetic resonance, with the 5-year composite end point of all-cause death and hospitalization for heart failure was included. The prognosis of the following groups (group 1: reverse LV remodeling [≥12% decrease in LVESV]; group 2: no LV remodeling [changes in LVEDV and LVESV <12%]; group 3: adverse LV remodeling with compensation [≥12% increase in LVEDV only]; and group 4: adverse LV remodeling [≥12% increase in both LVESV and LVEDV]) was compared. RESULTS: Two hundred eighty-five patients were included with a median follow-up was 5.8 years. The composite end point occurred in 9.5% in group 1, 12.3% in group 2, 7.1% in group 3, and 24.2% in group 4. Group 4 had significantly higher cumulative event rates of the composite end point (log-rank test, P=0.03) with the other 3 groups showing similar cumulative event rates (log-rank test, P=0.51). Cox proportional hazard for group 2 (hazard ratio, 1.3 [95% CI, 0.6-3.1], P=0.53) and group 3 (hazard ratio, 0.6 [95% CI, 0.2-2.3], P=0.49) were not significantly different but was significantly higher in group 4 (hazard ratio, 3.0 [95% CI, 1.2-7.1], P=0.015) when compared with group 1. CONCLUSIONS: Patients with ST-segment-elevation myocardial infarction developing adverse LV remodeling at 6 months, defined as ≥12% increase in both LVESV and LVEDV by cardiovascular magnetic resonance, was associated with worse long-term clinical outcomes than those with adverse LV remodeling with compensation, reverse LV remodeling, and no LV remodeling, with the latter 3 groups having similar outcomes in a cohort of stable reperfused patients with ST-segment-elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850.

Comparative Significance of Invasive Measures of Microvascular Injury in Acute Myocardial Infarction.

BACKGROUND: The resistive reserve ratio (RRR) expresses the ratio between basal and hyperemic microvascular resistance. RRR measures the vasodilatory capacity of the microcirculation. We compared RRR, index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) for predicting microvascular obstruction (MVO), myocardial hemorrhage, infarct size, and clinical outcomes, after ST-segment-elevation myocardial infarction. METHODS: In the T-TIME trial (Trial of Low-Dose Adjunctive Alteplase During Primary PCI), 440 patients with acute ST-segment-elevation myocardial infarction from 11 UK hospitals were prospectively enrolled. In a subset of 144 patients, IMR, CFR, and RRR were measured post-primary percutaneous coronary intervention. MVO extent (% left ventricular mass) was determined by cardiovascular magnetic resonance imaging at 2 to 7 days. Infarct size was determined at 3 months. One-year major adverse cardiac events, heart failure hospitalizations, and all-cause death/heart failure hospitalizations were assessed. RESULTS: In these 144 patients (mean age, 59±11 years, 80% male), median IMR was 29.5 (interquartile range: 17.0-55.0), CFR was 1.4 (1.1-2.0), and RRR was 1.7 (1.3-2.3). MVO occurred in 41% of patients. IMR>40 was multivariably associated with more MVO (coefficient, 0.53 [95% CI, 0.05-1.02]; P=0.031), myocardial hemorrhage presence (odds ratio [OR], 3.20 [95% CI, 1.25-8.24]; P=0.016), and infarct size (coefficient, 5.05 [95% CI, 0.84-9.26]; P=0.019), independently of CFR≤2.0, RRR≤1.7, myocardial perfusion grade≤1, and Thrombolysis in Myocardial Infarction frame count. RRR was multivariably associated with MVO extent (coefficient, -0.60 [95% CI, -0.97 to -0.23]; P=0.002), myocardial hemorrhage presence (OR, 0.34 [95% CI, 0.15-0.75]; P=0.008), and infarct size (coefficient, -3.41 [95% CI, -6.76 to -0.06]; P=0.046). IMR>40 was associated with heart failure hospitalization (OR, 5.34 [95% CI, 1.80-15.81] P=0.002), major adverse cardiac events (OR, 4.46 [95% CI, 1.70-11.70] P=0.002), and all-cause death/ heart failure hospitalization (OR, 4.08 [95% CI, 1.55-10.79] P=0.005). RRR was associated with heart failure hospitalization (OR, 0.44 [95% CI, 0.19-0.99] P=0.047). CFR was not associated with infarct characteristics or clinical outcomes. CONCLUSIONS: In acute ST-segment-elevationl infarction, IMR and RRR, but not CFR, were associated with MVO, myocardial hemorrhage, infarct size, and clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02257294.

Low-Dose Alteplase During Primary Percutaneous Coronary Intervention According to Ischemic Time.

BACKGROUND: Microvascular obstruction affects one-half of patients with ST-segment elevation myocardial infarction and confers an adverse prognosis. OBJECTIVES: This study aimed to determine whether the efficacy and safety of a therapeutic strategy involving low-dose intracoronary alteplase infused early after coronary reperfusion associates with ischemic time. METHODS: This study was conducted in a prospective, multicenter, parallel group, 1:1:1 randomized, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischemic time, defined as the time from symptom onset to coronary reperfusion, was a pre-specified subgroup of interest. Between March 17, 2016, and December 21, 2017, 440 patients, presenting with ST-segment elevation myocardial infarction within 6 h of symptom onset (<2 h, n = 107; ≥2 h but <4 h, n = 235; ≥4 h to 6 h, n = 98), were enrolled at 11 U.K. hospitals. Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145). The primary outcome was the amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days (available for 396 of 440). RESULTS: Overall, there was no association between alteplase dose and the extent of MVO (p for trend = 0.128). However, in patients with an ischemic time ≥4 to 6 h, alteplase increased the mean extent of MVO compared with placebo: 1.14% (placebo) versus 3.11% (10 mg) versus 5.20% (20 mg); p = 0.009 for the trend. The interaction between ischemic time and alteplase dose was statistically significant (p = 0.018). CONCLUSION: In patients presenting with ST-segment elevation myocardial infarction and an ischemic time ≥4 to 6 h, adjunctive treatment with low-dose intracoronary alteplase during primary percutaneous coronary intervention was associated with increased MVO. Intracoronary alteplase may be harmful for this subgroup. (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI [T-TIME]; NCT02257294).

Percutaneous coronary intervention versus medical therapy in patients with angina and grey-zone fractional flow reserve values: a randomised clinical trial.

INTRODUCTION: There is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75-0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia in GZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control. METHODS: We enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ). RESULTS: 104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the target GZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve <2.0 in the target GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months. CONCLUSIONS: Non-invasive evidence of major ischaemia is uncommon in patients with GZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months. TRIAL REGISTRATION NUMBER: NCT02425969.

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.

Effects of Intracoronary Alteplase on Microvascular Function in Acute Myocardial Infarction.

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST-segment-elevation myocardial infarction. In the T-TIME (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low-dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T-TIME trial. From 2016 to 2017, patients with ST-segment-elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double-blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (<2, 2-4, and ≥4 hours) were prespecified. One hundred forty-four patients (mean age, 59±11 years; 80% male) were prospectively enrolled, representing 33% of the overall population (n=440). Overall, index of microcirculatory resistance (median, 29.5; interquartile range, 17.0-55.0), coronary flow reserve(1.4 [1.1-2.0]), and resistive reserve ratio (1.7 [1.3-2.3]) at the end of percutaneous coronary intervention did not differ between treatment groups. Interactions were observed between ischemic time and alteplase for coronary flow reserve (P=0.013), resistive reserve ratio (P=0.026), and microvascular obstruction (P=0.022), but not index of microcirculatory resistance. Conclusions In ST-segment-elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.