Publications by authors named "Paul Rocchiccioli"

32 Publications

Post-stenting fractional flow reserve vs coronary angiography for optimisation of percutaneous coronary intervention: TARGET-FFR trial.

Eur Heart J 2021 Jul 19. Epub 2021 Jul 19.

West of Scotland Regional Heart & Lung Centre, Golden Jubilee National Hospital, Agamemnon Street, Clydebank, G81 4DY, UK.

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.
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http://dx.doi.org/10.1093/eurheartj/ehab449DOI Listing
July 2021

Shockwave coronary intravascular lithotripsy system for heavily calcified de novo lesions and the need for a cost-effectiveness analysis.

Cardiovasc Revasc Med 2021 Jul 5. Epub 2021 Jul 5.

1st Cardiology Department, AHEPA General Hospital, Aristotle University of Thessaloniki, Greece.

The optimal management for severely calcified coronary artery disease is multi-adjunctive. Different strategies with dedicated devices should be available in the cardiac catheterization laboratory with their selection depending on the nature of the calcific disease and its anatomical distribution. Shockwave Intravascular Lithotripsy (S-IVL) system offers a novel option for lesion preparation of heavily calcified plaques in coronary and peripheral vessels. S-IVL is based on the fundamental principles of lithotripsy, a technology that has been used to modify renal stones for over 30 years. Pulsatile mechanical energy is used to fragment selectively amorphous calcium, sparing soft tissue. S-IVL has the potential of more widespread adoption because of its proven safety, efficacy and operational simplicity, but cost-effectiveness of such advanced technology will need to be analyzed.
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http://dx.doi.org/10.1016/j.carrev.2021.06.125DOI Listing
July 2021

Prevalence of Coronary Artery Disease and Coronary Microvascular Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction.

JAMA Cardiol 2021 Jun 23. Epub 2021 Jun 23.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.

Importance: Coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may contribute to the pathophysiologic characteristics of heart failure with preserved ejection fraction (HFpEF). However, the prevalence of CAD and CMD have not been systematically studied.

Objective: To examine the prevalence of CAD and CMD in hospitalized patients with HFpEF.

Design, Setting, And Participants: A total of 106 consecutive patients hospitalized with HFpEF were evaluated in this prospective, multicenter, cohort study conducted between January 2, 2017, and August 1, 2018; data analysis was performed from March 4 to September 6, 2019. Participants underwent coronary angiography with guidewire-based assessment of coronary flow reserve, index of microvascular resistance, and fractional flow reserve, followed by coronary vasoreactivity testing. Cardiac magnetic resonance imaging was performed with late gadolinium enhancement and assessment of extracellular volume. Myocardial perfusion was assessed qualitatively and semiquantitatively using the myocardial-perfusion reserve index.

Main Outcomes And Measures: The prevalence of obstructive epicardial CAD, CMD, and myocardial ischemia, infarction, and fibrosis.

Results: Of 106 participants enrolled (53 [50%] women; mean [SD] age, 72 [9] years), 75 had coronary angiography, 62 had assessment of coronary microvascular function, 41 underwent coronary vasoreactivity testing, and 52 received cardiac magnetic resonance imaging. Obstructive epicardial CAD was present in 38 of 75 participants (51%, 95% CI, 39%-62%); 19 of 38 (50%; 95% CI, 34%-66%) had no history of CAD. Endothelium-independent CMD (ie, coronary flow reserve <2.0 and/or index of microvascular resistance ≥25) was identified in 41 of 62 participants (66%; 95% CI, 53%-77%). Endothelium-dependent CMD (ie, abnormal coronary vasoreactivity) was identified in 10 of 41 participants (24%; 95% CI, 13%-40%). Overall, 45 of 53 participants (85%; 95% CI, 72%-92%) had evidence of CMD and 29 of 36 (81%; 95% CI, 64%-91%) of those without obstructive epicardial CAD had CMD. Cardiac magnetic resonance imaging findings included myocardial-perfusion reserve index less than or equal to 1.84 (ie, impaired global myocardial perfusion) in 29 of 41 patients (71%; 95% CI, 54%-83%), visual perfusion defect in 14 of 46 patients (30%; 95% CI, 19%-46%), ischemic late gadolinium enhancement (ie, myocardial infarction) in 14 of 52 patients (27%; 95% CI, 16%-41%), and extracellular volume greater than 30% (ie, diffuse myocardial fibrosis) in 20 of 48 patients (42%; 95% CI, 28%-56%). Patients with obstructive CAD had more adverse events during follow-up (28 [74%]) than those without obstructive CAD (17 [46%]).

Conclusions And Relevance: In this cohort study, 91% of patients with HFpEF had evidence of epicardial CAD, CMD, or both. Of those without obstructive CAD, 81% had CMD. Obstructive epicardial CAD and CMD appear to be common and often unrecognized in hospitalized patients with HFpEF and may be therapeutic targets.
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http://dx.doi.org/10.1001/jamacardio.2021.1825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223134PMC
June 2021

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

Cardiovasc Res 2021 Jun 16. Epub 2021 Jun 16.

Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, UK.

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-elevated 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 hour 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.

Translational Perspective: New therapeutic targets are urgently required to limit myocardial damage after reperfusion injury. We identified cardiac release of the protease cathepsin-L among patients following primary percutaneous coronary intervention (PPCI). Elevated serum levels of cathepsin-L were associated with reduced contractile function and increased infarct size at 24 hour and 6 months post-PPCI. Work conducted using animal models indicated that cardiac release of cathepsin-L mediated cardiac dysfunction following reperfusion injury. Specific inhibition of cathepsin-L prevented abnormal calcium handling, reduced infarct size and improved contractile function. These novel findings offer the prospect of targeting cathepsin-L-mediated cardiac dysfunction after PPCI.
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http://dx.doi.org/10.1093/cvr/cvab204DOI Listing
June 2021

Invasive versus medically managed acute coronary syndromes with prior bypass (CABG-ACS): insights into the registry versus randomised trial populations.

Open Heart 2021 02;8(1)

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Background: Coronary artery bypass graft (CABG) patients are under-represented in acute coronary syndrome (ACS) trials. We compared characteristics and outcomes for patients who did and did not participate in a randomised trial of invasive versus non-invasive management (CABG-ACS).

Methods: ACS patients with prior CABG in four hospitals were randomised to invasive or non-invasive management. Non-randomised patients entered a registry. Primary efficacy (composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction (MI), heart failure) and safety outcomes (composite of bleeding, stroke, procedure-related MI, worsening renal function) were independently adjudicated.

Results: Of 217 patients screened, 84 (39%) screenfailed, of whom 24 (29%) did not consent and 60 (71%) were ineligible. Of 133 (61%) eligible, 60 (mean±SD age, 71±9 years, 72% male) entered the trial and 73 (age, 72±10 years, 73% male) entered a registry (preferences: physician (79%), patient (38%), both (21%)).Compared with trial participants, registry patients had more valve disease, lower haemoglobin, worse New York Heart Association class and higher frailty.At baseline, invasive management was performed in 52% and 49% trial and registry patients, respectively, of whom 32% and 36% had percutaneous coronary intervention at baseline, respectively (p=0.800). After 2 years follow-up (694 (median, IQR 558-841) days), primary efficacy (43% trial vs 49% registry (HR 1.14, 95% CI 0.69 to 1.89)) and safety outcomes (28% trial vs 22% registry (HR 0.74, 95% CI 0.37 to 1.46)) were similar. EuroQol was lower in registry patients at 1 year.

Conclusions: Compared with trial participants, registry participants had excess morbidity, but longer-term outcomes were similar.

Trial Registration Number: NCT01895751.
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http://dx.doi.org/10.1136/openhrt-2020-001453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919592PMC
February 2021

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

Circ Cardiovasc Interv 2021 02 16;14(2):e009529. Epub 2021 Feb 16.

British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (A.M.M., P.J.M., K.G.O., M.M., H.E., D.C., C.B.), University of Glasgow, United Kingdom.

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 (=0.15; =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; =0.045) and major adverse cardiac events (n=21 events; =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] =0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7-98.2; =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.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009529DOI Listing
February 2021

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

J Magn Reson Imaging 2020 12 27;52(6):1722-1731. Epub 2020 Jul 27.

British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

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, T 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, T 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.
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http://dx.doi.org/10.1002/jmri.27295DOI Listing
December 2020

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

Circ Cardiovasc Interv 2020 05 15;13(5):e008505. Epub 2020 May 15.

British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.M.M., K.G.O., P.J.M., M.C.P., C.B.).

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]; =0.031), myocardial hemorrhage presence (odds ratio [OR], 3.20 [95% CI, 1.25-8.24]; =0.016), and infarct size (coefficient, 5.05 [95% CI, 0.84-9.26]; =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]; =0.002), myocardial hemorrhage presence (OR, 0.34 [95% CI, 0.15-0.75]; =0.008), and infarct size (coefficient, -3.41 [95% CI, -6.76 to -0.06]; =0.046). IMR>40 was associated with heart failure hospitalization (OR, 5.34 [95% CI, 1.80-15.81] =0.002), major adverse cardiac events (OR, 4.46 [95% CI, 1.70-11.70] =0.002), and all-cause death/ heart failure hospitalization (OR, 4.08 [95% CI, 1.55-10.79] =0.005). RRR was associated with heart failure hospitalization (OR, 0.44 [95% CI, 0.19-0.99] =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.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237023PMC
May 2020

Post-operative myocardial infarction following aortic root surgery with coronary reimplantation: a case series treated with percutaneous coronary intervention.

Eur Heart J Case Rep 2019 Dec 22;3(4):1-6. Epub 2019 Oct 22.

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, G81 4DY, UK.

Background: Coronary ostial stenosis is an uncommon but potentially lethal complication following aortic root replacement with or without aortic valve replacement (including Bentall and David procedures). This manifests clinically as acute myocardial ischaemia in the early or late post-operative period. Traditionally, this might be managed with redo open-heart surgery.

Case Summary: This case series describes two presentations where urgent percutaneous coronary intervention was used to manage myocardial infarction complicating aortic root surgery with coronary reimplantation.

Discussion: This series highlights the risk of acute myocardial infarction after cardiac surgery involving coronary reimplantation. Emergency percutaneous coronary intervention is feasible and illustrates the importance of shared post-operative care involving the cardiac surgeons and the cardiology team.
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http://dx.doi.org/10.1093/ehjcr/ytz181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042144PMC
December 2019

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

Heart 2020 05 29;106(10):758-764. Epub 2020 Feb 29.

Cardiology Department, Golden Jubilee National Hospital, Glasgow, United Kingdom.

Introduction: There is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (FFR artery) values (0.75-0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia in FFR 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 FFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve <2.0 in the target FFR 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 FFR 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.
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http://dx.doi.org/10.1136/heartjnl-2019-316075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229900PMC
May 2020

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

J Am Heart Assoc 2020 02 28;9(3):e014066. Epub 2020 Jan 28.

British Heart Foundation Glasgow Cardiovascular Research Centre Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow United Kingdom.

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 (=0.013), resistive reserve ratio (=0.026), and microvascular obstruction (=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.
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http://dx.doi.org/10.1161/JAHA.119.014066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033872PMC
February 2020

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

Eur Heart J 2020 09;41(34):3239-3252

British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 9DH, UK.

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.
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http://dx.doi.org/10.1093/eurheartj/ehz915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557475PMC
September 2020

Ischemia and No Obstructive Coronary Artery Disease: Prevalence and Correlates of Coronary Vasomotion Disorders.

Circ Cardiovasc Interv 2019 12 13;12(12):e008126. Epub 2019 Dec 13.

Department of Interventional Cardiology, West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, United Kingdom (T.J.F., R.G., P.R., M.M., S.W., H.E., A.S., M.L., K.R., S.H., R.M., D. Collison., K.G.O., C.B.).

Background: Determine the prevalence and correlates of microvascular and vasospastic angina in patients with symptoms and signs of ischemia but no obstructive coronary artery disease (INOCA).

Methods: Three hundred ninety-one patients with angina were enrolled at 2 regional centers over 12 months from November 2016 (NCT03193294). INOCA subjects (n=185; 47%) had more limiting dyspnea (New York Heart Association classification III/IV 54% versus 37%; odds ratio [OR], 2.0 [1.3-3.0]; =0.001) and were more likely to be female (68% INOCA versus 38% in coronary artery disease; OR, 1.9 [1.5 to 2.5]; <0.001) but with lower cardiovascular risk scores (ASSIGN score median 20% versus 24%; =0.003). INOCA subjects had similar burden of angina (Seattle Angina Questionnaire) but reduced quality of life compared with coronary artery disease; subjects (EQ5D-5 L index 0.60 versus 0.65 units; =0.041).

Results: An interventional diagnostic procedure with reference invasive tests including coronary flow reserve, microvascular resistance, and vasomotor responses to intracoronary acetylcholine (vasospasm provocation) was performed in 151 INOCA subjects. Overall, 78 (52%) had isolated microvascular angina, 25 (17%) had isolated vasospastic angina, 31 (20%) had both, and 17 (11%) had noncardiac chest pain. Regression analysis showed inducible ischemia on treadmill testing (OR, 7.5 [95% CI, 1.7-33.0]; =0.008) and typical angina (OR, 2.7 [1.1-6.6]; =0.032) were independently associated with microvascular angina. Female sex tended to associate with a diagnosis of microvascular angina although this was not significant (OR, 2.7 [0.9-7.9]; =0.063). Vasospastic angina was associated with smoking (OR, 9.5 [2.8-32.7]; <0.001) and age (OR, 1.1 per year, [1.0-1.2]; =0.032].

Conclusions: Over three quarters of patients with INOCA have identifiable disorders of coronary vasomotion including microvascular and vasospastic angina. These patients have comparable angina burden but reduced quality of life compared to patients with obstructive coronary artery disease. Microvascular angina and vasospastic angina are distinct disorders that may coexist but differ in associated clinical characteristics, symptoms, and angina severity.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193294.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924940PMC
December 2019

1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CorMicA).

JACC Cardiovasc Interv 2020 01 11;13(1):33-45. Epub 2019 Nov 11.

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, United Kingdom; British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Objectives: The aim of this study was to test the hypothesis that invasive coronary function testing at time of angiography could help stratify management of angina patients without obstructive coronary artery disease.

Background: Medical therapy for angina guided by invasive coronary vascular function testing holds promise, but the longer-term effects on quality of life and clinical events are unknown among patients without obstructive disease.

Methods: A total of 151 patients with angina with symptoms and/or signs of ischemia and no obstructive coronary artery disease were randomized to stratified medical therapy guided by an interventional diagnostic procedure versus standard care (control group with blinded interventional diagnostic procedure results). The interventional diagnostic procedure-facilitated diagnosis (microvascular angina, vasospastic angina, both, or neither) was linked to guideline-based management. Pre-specified endpoints included 1-year patient-reported outcome measures (Seattle Angina Questionnaire, quality of life [EQ-5D]) and major adverse cardiac events (all-cause mortality, myocardial infarction, unstable angina hospitalization or revascularization, heart failure hospitalization, and cerebrovascular event) at subsequent follow-up.

Results: Between November 2016 and December 2017, 151 patients with ischemia and no obstructive coronary artery disease were randomized (n = 75 to the intervention group, n = 76 to the control group). At 1 year, overall angina (Seattle Angina Questionnaire summary score) improved in the intervention group by 27% (difference 13.6 units; 95% confidence interval: 7.3 to 19.9; p < 0.001). Quality of life (EQ-5D index) improved in the intervention group relative to the control group (mean difference 0.11 units [18%]; 95% confidence interval: 0.03 to 0.19; p = 0.010). After a median follow-up duration of 19 months (interquartile range: 16 to 22 months), major adverse cardiac events were similar between the groups, occurring in 9 subjects (12%) in the intervention group and 8 (11%) in the control group (p = 0.803).

Conclusions: Stratified medical therapy in patients with ischemia and no obstructive coronary artery disease leads to marked and sustained angina improvement and better quality of life at 1 year following invasive coronary angiography. (Coronary Microvascular Angina [CorMicA]; NCT03193294).
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http://dx.doi.org/10.1016/j.jcin.2019.11.001DOI Listing
January 2020

Type 1 diabetes mellitus and coronary revascularization.

Cardiovasc Endocrinol Metab 2019 Mar 13;8(1):35-38. Epub 2019 Feb 13.

Department of Cardiology, Golden Jubilee National Hospital.

Over the last three decades, trials of coronary revascularization have taken into account whether populations did or did not have diabetes. What has not been considered is whether or not patients with diabetes in these studies have type 1 or type 2 diabetes. 'Diabetes' appears to be largely used as a synonym for type 2 diabetes. The number of patients with type 1 diabetes has not been reported in most trials. Many questions remain unanswered. Do patients with type 1 diabetes have the same response to various modes of revascularization as those with type 2 diabetes? We know type 2 diabetes affects coronary endothelial function and the coronary artery wall but to what extent does type 1 diabetes affect these? Any response to revascularization does not just depend on the coronary artery but also on the myocardium. How does type 1 diabetes affect the myocardium? To what extent do patients with type 1 diabetes have viable or ischaemic myocardium or scar? What does 'diabetic cardiomyopathy' refer to in the context of type 1 diabetes? This manuscript reviews the evidence for revascularization in type 1 diabetes. We conclude that there has been a near absence of investigation of the pros and cons of revascularization in this population. Investigations to establish both the nature and extent of coronary and myocardial disease in these populations are necessary. Clinical trials of the pros and cons of revascularization in type 1 diabetes are necessary; many will declare that these will be too challenging to perform.
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http://dx.doi.org/10.1097/XCE.0000000000000166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739890PMC
March 2019

Invasive Versus Medical Management in Patients With Prior Coronary Artery Bypass Surgery With a Non-ST Segment Elevation Acute Coronary Syndrome.

Circ Cardiovasc Interv 2019 08 31;12(8):e007830. Epub 2019 Jul 31.

Department of Cardiology, West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, United Kingdom (M.M.Y.L., M.C.P., P.R., J.S., C.E.J., D.S.C., K.M., P.C., N.P.S., M.B.M., A.S., A.P.R., S.H.M.H., E.E.P., K.G.O., C.B.).

Background: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials.

Methods: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function).

Results: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years' follow-up (median [interquartile range], 744 [570-853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months.

Conclusions: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01895751.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.007830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664981PMC
August 2019

Sex differences in procedural and clinical outcomes following rotational atherectomy.

Catheter Cardiovasc Interv 2020 02 1;95(2):232-241. Epub 2019 Jul 1.

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, UK.

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.
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http://dx.doi.org/10.1002/ccd.28373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027486PMC
February 2020

Rationale and design of the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) diagnostic study: the CorMicA CMR sub-study.

Open Heart 2018;5(2):e000924. Epub 2018 Dec 30.

British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Introduction: Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs. Microvascular and vasospastic angina are relevant but may not be diagnosed without measuring coronary vascular function. The relationship between cardiovascular magnetic resonance (CMR)-derived myocardial blood flow (MBF) and reference invasive coronary function tests is uncertain. We hypothesise that multiparametric CMR assessment will be clinically useful in the ANOCA diagnostic pathway.

Methods/analysis: The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) trial is a prospective, blinded, randomised, sham-controlled study comparing two management approaches in patients with ANOCA. We aim to recruit consecutive patients with stable angina undergoing elective invasive coronary angiography. Eligible patients with ANOCA (n=150) will be randomised to invasive coronary artery function-guided diagnosis and treatment (intervention group) or not (control group). Based on these test results, patients will be stratified into disease endotypes: microvascular angina, vasospastic angina, mixed microvascular/vasospastic angina, obstructive epicardial coronary artery disease and non-cardiac chest pain. After randomisation in CorMicA, subjects will be invited to participate in the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) substudy. Patients will undergo multiparametric CMR and have assessments of MBF (using a novel pixel-wise fully quantitative method), left ventricular function and mass, and tissue characterisation (T1 mapping and late gadolinium enhancement imaging). Abnormalities of myocardial perfusion and associations between MBF and invasive coronary artery function tests will be assessed. The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests.

Ethics/dissemination: The CorMicA trial and CorCMR substudy have UK REC approval (ref.16/WS/0192).

Trial Registration Number: NCT03193294.
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http://dx.doi.org/10.1136/openhrt-2018-000924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326326PMC
December 2018

MINOCA: Requirement for Definitive Diagnostic Work-Up.

Heart Lung Circ 2019 02;28(2):e4-e6

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, Scotland, UK; British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland, UK. Electronic address:

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http://dx.doi.org/10.1016/j.hlc.2018.04.001DOI Listing
February 2019

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

JAMA 2019 01;321(1):56-68

University of Edinburgh, Edinburgh, United Kingdom.

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.
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http://dx.doi.org/10.1001/jama.2018.19802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583564PMC
January 2019

Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial.

J Am Coll Cardiol 2018 12 25;72(23 Pt A):2841-2855. Epub 2018 Sep 25.

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, United Kingdom; British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Background: Patients with angina symptoms and/or signs of ischemia but no obstructive coronary artery disease (INOCA) pose a diagnostic and therapeutic challenge.

Objectives: The purpose of this study was to test whether an interventional diagnostic procedure (IDP) linked to stratified medicine improves health status in patients with INOCA.

Methods: The authors conducted a randomized, controlled, blinded clinical trial of stratified medical therapy versus standard care in patients with angina. Patients with angina undergoing invasive coronary angiography (standard care) were recruited. Patients without obstructive CAD were immediately randomized 1:1 to the intervention group (stratified medical therapy) or the control group (standard care, IDP sham procedure). The IDP consisted of guidewire-based assessment of coronary flow reserve, index of microcirculatory resistance, fractional flow reserve, followed by vasoreactivity testing with acetylcholine. The primary endpoint was the mean difference in angina severity at 6 months (assessed by the Seattle Angina Questionnaire summary score).

Results: A total of 391 patients were enrolled between November 25, 2016, and November 12, 2017. Coronary angiography revealed obstructive disease in 206 (53.7%). One hundred fifty-one (39%) patients without angiographically obstructive CAD were randomized (n = 76 intervention group; n = 75 blinded control group). The intervention resulted in a mean improvement of 11.7 U in the Seattle Angina Questionnaire summary score at 6 months (95% confidence interval [CI]: 5.0 to 18.4; p = 0.001). In addition, the intervention led to improvements in the mean quality-of-life score (EQ-5D index 0.10 U; 95% CI: 0.01 to 0.18; p = 0.024) and visual analogue score (14.5 U; 95% CI: 7.8 to 21.3; p < 0.001). There were no differences in major adverse cardiac events at the 6-month follow-up (2.6% controls vs. 2.6% intervention; p = 1.00).

Conclusions: Coronary angiography often fails to identify patients with vasospastic and/or microvascular angina. Stratified medical therapy, including an IDP with linked medical therapy, is routinely feasible and improves angina in patients with no obstructive CAD. (CORonary MICrovascular Angina [CorMicA]; NCT03193294).
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http://dx.doi.org/10.1016/j.jacc.2018.09.006DOI Listing
December 2018

Systemic microvascular dysfunction in microvascular and vasospastic angina.

Eur Heart J 2018 12;39(46):4086-4097

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, GJNH, Agamemnon St, Glasgow, UK.

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.
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http://dx.doi.org/10.1093/eurheartj/ehy529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284165PMC
December 2018

Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Angina (CorMicA) stratified medicine clinical trial.

Am Heart J 2018 07 3;201:86-94. Epub 2018 Apr 3.

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, United Kingdom; British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Background: Coronary angiography is performed to assess for obstructive coronary artery disease (CAD), but "nonobstructive CAD" is a common finding. Microvascular or vasospastic angina may be relevant, but routine confirmatory testing is not evidence based and thus rarely performed.

Aim: The aim was to assess the effect of stratified medicine guided by coronary function testing on the diagnosis, treatment, and well-being of patients with angina and nonobstructive CAD.

Design: The BHF CorMicA trial is a prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03193294). All-comers referred for elective coronary angiography for investigation of suspected CAD will be screened. Following informed consent, eligible patients with angina and nonobstructive CAD will be randomized 1:1 immediately in the catheter laboratory to either coronary artery function-guided diagnosis and treatment (intervention group) or not (control group). Coronary function will be assessed using a pressure-temperature-sensitive guidewire and adenosine followed by pharmacological testing with intracoronary acetylcholine. Patients will be stratified into endotypes with linked therapy. The primary outcome is change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and diagnostic certainty), and clinical utility (impact on treatment and investigations). Health status is a key secondary outcome assessed according to the following domains: quality of life, treatment satisfaction, illness perception, physical activity, and anxiety-depression score. Patients with obstructive disease who are not randomized will form a registry group who will be followed up as a comparator for secondary outcomes including health status. Health and economic outcomes will be evaluated in the longer term using electronic health record linkage.

Value: CorMicA is a proof-of-concept clinical trial of a disruptive stratified intervention with potential benefits to patients and health care providers.
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http://dx.doi.org/10.1016/j.ahj.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018570PMC
July 2018

A keen eye for risk.

BMJ 2018 02 1;360:j5884. Epub 2018 Feb 1.

British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

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http://dx.doi.org/10.1136/bmj.j5884DOI Listing
February 2018

Coronary angiography in heart failure: when and why? Uncertainty reigns.

Heart 2018 04 5;104(7):548-549. Epub 2017 Oct 5.

West of Scotland Heart & Lung Centre, Golden Jubilee National Hospital, Glasgow, UK.

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http://dx.doi.org/10.1136/heartjnl-2017-312200DOI Listing
April 2018

Discordance Between Resting and Hyperemic Indices of Coronary Stenosis Severity: The VERIFY 2 Study (A Comparative Study of Resting Coronary Pressure Gradient, Instantaneous Wave-Free Ratio and Fractional Flow Reserve in an Unselected Population Referred for Invasive Angiography).

Circ Cardiovasc Interv 2016 11;9(11)

From the University of Glasgow, United Kingdom (B.H., K.G.O., C.B., P.M., M.B.M., H.E., M.C.P., P.R., R.G., M.M.L., S.H., S.W.); Cardiology Department, Golden Jubilee National Hospital, Clydebank, Glasgow, United Kingdom (B.H., K.G.O., C.B., J.M.); and The Weatherhead PET Imaging Center, Houston, TX (N.J.).

Background: Distal coronary to aortic pressure ratio (Pd/Pa) and instantaneous wave-free ratio (iFR) are indices of functional significance of a coronary stenosis measured without hyperemia. It has been suggested that iFR has superior diagnostic accuracy to Pd/Pa when compared with fractional flow reserve (FFR).We hypothesized that in comparison with FFR, revascularization decisions based on either binary cutoff values for iFR and Pd/Pa or hybrid strategies incorporating iFR or Pd/Pa will result in similar levels of disagreement.

Methods And Results: This is a prospective study in consecutive patients undergoing FFR for clinical indications using proprietary software to calculate iFR. We measured Pd/Pa, iFR, FFR, and hyperemic iFR. Diagnostic accuracy versus FFR ≤0.80 was calculated using binary cutoff values of ≤0.90 for iFR and ≤0.92 for Pd/Pa, and adenosine zones for iFR of 0.86 to 0.93 and Pd/Pa of 0.87 to 0.94 in the hybrid strategy. One hundred ninety-seven patients with 257 stenoses (mean diameter stenosis 48%) were studied. Using binary cutoffs, diagnostic accuracy was similar for iFR and resting Pd/Pa with misclassification rates of 21% versus 20.2% (P=0.85). In the hybrid analysis, 54% of iFR cases and 53% of Pd/Pa cases were outside the adenosine zone and rates of misclassification were 9.4% versus 11.9% (P=0.55).

Conclusions: Binary cutoff values for iFR and Pd/Pa result in misclassification of 1 in 5 lesions. Using a hybrid strategy, approximately half of the patients do not receive adenosine, but 1 in 10 lesions are still misclassified. The use of nonhyperemic indices of stenosis severity cannot be recommended for decision making in the catheterization laboratory.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02377310.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.116.004016DOI Listing
November 2016

Non-invasive versus invasive management in patients with prior coronary artery bypass surgery with a non-ST segment elevation acute coronary syndrome: study design of the pilot randomised controlled trial and registry (CABG-ACS).

Open Heart 2016;3(1):e000371. Epub 2016 Apr 20.

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, UK; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; Western Infirmary, Glasgow, UK.

Introduction: There is an evidence gap about how to best treat patients with prior coronary artery bypass grafts (CABGs) presenting with non-ST segment elevation acute coronary syndromes (NSTE-ACS) because historically, these patients were excluded from pivotal randomised trials. We aim to undertake a pilot trial of routine non-invasive management versus routine invasive management in patients with NSTE-ACS with prior CABG and optimal medical therapy during routine clinical care. Our trial is a proof-of-concept study for feasibility, safety, potential efficacy and health economic modelling. We hypothesise that a routine invasive approach in patients with NSTE-ACS with prior CABG is not superior to a non-invasive approach with optimal medical therapy.

Methods And Analysis: 60 patients will be enrolled in a randomised clinical trial in 4 hospitals. A screening log will be prospectively completed. Patients not randomised due to lack of eligibility criteria and/or patient or physician preference and who give consent will be included in a registry. We will gather information about screening, enrolment, eligibility, randomisation, patient characteristics and adverse events (including post-discharge). The primary efficacy outcome is the composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction and hospitalisation for heart failure. The primary safety outcome is the composite of bleeding, stroke, procedure-related myocardial infarction and worsening renal function. Health status will be assessed using EuroQol 5 Dimensions (EQ-5D) assessed at baseline and 6 monthly intervals, for at least 18 months.

Trial Registration Number: NCT01895751 (ClinicalTrials.gov).
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http://dx.doi.org/10.1136/openhrt-2015-000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838768PMC
April 2016

Spectral microvolt T-wave alternans testing has no prognostic value in patients recently hospitalized with decompensated heart failure.

Eur J Heart Fail 2013 Nov 22;15(11):1253-61. Epub 2013 May 22.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: Microvolt T-wave alternans (MTWA) testing identifies beat-to-beat fluctuations in T-wave morphology, which have been linked to ventricular arrhythmias. However, clinical studies have produced conflicting results and data in heart failure (HF) have been limited. The aim of this study was to determine the prevalence and incremental prognostic value of spectral MTWA testing in an unselected cohort of patients recently hospitalized with HF.

Methods And Results: Consecutive admissions with confirmed HF were recruited, and survivors were invited to attend 1 month post-discharge for MTWA testing. A total of 648 of 1003 enrolled patients returned for MTWA testing (58% male, mean age 71 years). Forty-nine per cent were ineligible due to AF, pacemaker dependency, or inability to exercise. Of the 330 MTWA test results, 30% were positive, 24% negative, and 46% indeterminate. Overall, 268 deaths occurred during a median follow-up of 3.1 (interquartile range 1.9-3.9) years. Of the ineligible patients, 48% died vs. 35% of eligible patients (P < 0.001). Of those patients with positive, negative, and indeterminate tests, 27, 35, and 40%, respectively, died (P = 0.12). Even when analysed as non-negative (positive/indeterminate) vs. negative, there was still no between-group difference in mortality (P = 0.95). MTWA results categorized as positive, negative, or indeterminate showed no incremental prognostic value in a multivariable model, which included BNP. Paradoxically, when compared in a binary fashion with a non-negative result, a negative test was an independent predictor of death, as was ineligibility for MTWA testing.

Conclusion: Spectral MTWA testing was not widely applicable and failed to predict mortality, and so cannot be endorsed as a risk stratification tool in HF.
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http://dx.doi.org/10.1093/eurjhf/hft085DOI Listing
November 2013
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