ChaMP-CMD: A Phenotype-Blinded, Randomized Controlled, Cross-Over Trial.

BACKGROUND: Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy. METHODS: Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379). RESULTS: Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; P<0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; P=0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; P=0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; P=0.549). CONCLUSIONS: Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.

Coronary microvascular dysfunction and heart failure with preserved ejection fraction: what are the mechanistic links?

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort. RECENT FINDINGS: There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically. SUMMARY: CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.

Invasive and non-invasive assessment of ischaemia in chronic coronary syndromes: translating pathophysiology to clinical practice.

Intracoronary physiology testing has emerged as a valuable diagnostic approach in the management of patients with chronic coronary syndrome, circumventing limitations like inferring coronary function from anatomical assessment and low spatial resolution associated with angiography or non-invasive tests. The value of hyperaemic translesional pressure ratios to estimate the functional relevance of coronary stenoses is supported by a wealth of prognostic data. The continuing drive to further simplify this approach led to the development of non-hyperaemic pressure-based indices. Recent attention has focussed on estimating physiology without even measuring coronary pressure. However, the reduction in procedural time and ease of accessibility afforded by these simplifications needs to be counterbalanced against the increasing burden of physiological assumptions, which may impact on the ability to reliably identify an ischaemic substrate, the ultimate goal during catheter laboratory assessment. In that regard, measurement of both coronary pressure and flow enables comprehensive physiological evaluation of both epicardial and microcirculatory components of the vasculature, although widespread adoption has been hampered by perceived technical complexity and, in general, an underappreciation of the role of the microvasculature. In parallel, entirely non-invasive tools have matured, with the utilization of various techniques including computational fluid dynamic and quantitative perfusion analysis. This review article appraises the strengths and limitations for each test in investigating myocardial ischaemia and discusses a comprehensive algorithm that could be used to obtain a diagnosis in all patients with angina scheduled for coronary angiography, including those who are not found to have obstructive epicardial coronary disease.

Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis.

AIMS: This meta-analysis aims to quantify the association of reduced coronary flow with all-cause mortality and major adverse cardiovascular events (MACE) across a broad range of patient groups and pathologies. METHODS AND RESULTS: We systematically identified all studies between 1 January 2000 and 1 August 2020, where coronary flow was measured and clinical outcomes were reported. The endpoints were all-cause mortality and MACE. Estimates of effect were calculated from published hazard ratios (HRs) using a random-effects model. Seventy-nine studies with a total of 59 740 subjects were included. Abnormal coronary flow reserve (CFR) was associated with a higher incidence of all-cause mortality [HR: 3.78, 95% confidence interval (CI): 2.39-5.97] and a higher incidence of MACE (HR 3.42, 95% CI: 2.92-3.99). Each 0.1 unit reduction in CFR was associated with a proportional increase in mortality (per 0.1 CFR unit HR: 1.16, 95% CI: 1.04-1.29) and MACE (per 0.1 CFR unit HR: 1.08, 95% CI: 1.04-1.11). In patients with isolated coronary microvascular dysfunction, an abnormal CFR was associated with a higher incidence of mortality (HR: 5.44, 95% CI: 3.78-7.83) and MACE (HR: 3.56, 95% CI: 2.14-5.90). Abnormal CFR was also associated with a higher incidence of MACE in patients with acute coronary syndromes (HR: 3.76, 95% CI: 2.35-6.00), heart failure (HR: 6.38, 95% CI: 1.95-20.90), heart transplant (HR: 3.32, 95% CI: 2.34-4.71), and diabetes mellitus (HR: 7.47, 95% CI: 3.37-16.55). CONCLUSION: Reduced coronary flow is strongly associated with increased risk of all-cause mortality and MACE across a wide range of pathological processes. This finding supports recent recommendations that coronary flow should be measured more routinely in clinical practice, to target aggressive vascular risk modification for individuals at higher risk.

Impact of COVID-19 pandemic on the management of nonculprit lesions in patients presenting with ST-elevation myocardial infarction: Outcomes from the pan-London heart attack centers.

BACKGROUND: The impact of COVID-19 on the diagnosis and management of nonculprit lesions remains unclear. OBJECTIVES: This study sought to evaluate the management and outcomes of patients with nonculprit lesions during the COVID-19 pandemic. METHODS: We conducted a retrospective observational analysis of consecutive primary percutaneous coronary intervention (PPCI) pathway activations across the heart attack center network in London, UK. Data from the study period in 2020 were compared with prepandemic data in 2019. The primary outcome was the rate of nonculprit lesion percutaneous coronary intervention (PCI) and secondary outcomes included major adverse cardiovascular events. RESULTS: A total of 788 patients undergoing PPCI were identified, 209 (60%) in 2020 cohort and 263 (60%) in 2019 cohort had nonculprit lesions (p = .89). There was less functional assessment of the significance of nonculprit lesions in the 2020 cohort compared to 2019 cohort; in 8% 2020 cohort versus 15% 2019 cohort (p = .01). There was no difference in rates of PCI for nonculprit disease in the 2019 and 2020 cohorts (31% vs 30%, p = .11). Patients in 2020 cohort underwent nonculprit lesion PCI sooner than the 2019 cohort (p < .001). At 6 months there was higher rates of unplanned revascularization (4% vs. 2%, p = .05) and repeat myocardial infarction (4% vs. 1%, p = .02) in the 2019 cohort compared to 2020 cohort. CONCLUSION: Changes to clinical practice during the COVID-19 pandemic were associated with reduced rates of unplanned revascularization and myocardial infarction at 6-months follow-up, and despite the pandemic, there was no difference in mortality, suggesting that it is not only safe but maybe more efficacious.

Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction.

Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD-HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD-HFpEF, as well as the clinical and research implications of the CMD-HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients.

An IoT-Enabled Information System for Smart Navigation in Museums.

The Internet of Things (IoT) is a new paradigm that connects objects to provide seamless communication and contextual information to anyone, anywhere, at any time (AAA). These Internet-of-Things-enabled automated objects interact with visitors to present a variety of information during museum navigation and exploration. In this article, a smart navigation and information system (SNIS) prototype for museum navigation and exploration is developed, which delivers an interactive and more exciting museum exploration experience based on the visitor's personal presence. The objects inside a museum share the information that assist and navigate the visitors about the different sections and objects of the museum. The system was deployed inside Chakdara Museum and experimented with 381 users to achieve the results. For results, different users marked the proposed system in terms of parameters such as interesting, reality, ease of use, satisfaction, usefulness, and user friendly. Of these 381 users, 201 marked the system as most interesting, 138 marked most realistic, 121 marked it as easy-in-use, 219 marked it useful, and 210 marked it as user friendly. These statistics prove the efficiency of SNIS and its usefulness in smart cultural heritage, including smart museums, exhibitions and cultural sites.

Coronary Microvascular Dysfunction Is Associated With Myocardial Ischemia and Abnormal Coronary Perfusion During Exercise.

BACKGROUND: Coronary microvascular dysfunction (MVD) is defined by impaired flow augmentation in response to a pharmacological vasodilator in the presence of nonobstructive coronary artery disease. It is unknown whether diminished coronary vasodilator response correlates with abnormal exercise physiology or inducible myocardial ischemia. METHODS: Patients with angina and nonobstructive coronary artery disease had simultaneous coronary pressure and flow velocity measured using a dual sensor-tipped guidewire during rest, supine bicycle exercise, and adenosine-mediated hyperemia. Microvascular resistance (MR) was calculated as coronary pressure divided by flow velocity. Wave intensity analysis quantified the proportion of accelerating wave energy (perfusion efficiency). Global myocardial blood flow and subendocardial:subepicardial perfusion ratio were quantified using 3-Tesla cardiac magnetic resonance imaging during hyperemia and rest; inducible ischemia was defined as hyperemic subendocardial:subepicardial perfusion ratio <1.0. Patients were classified as having MVD if coronary flow reserve <2.5 and controls if coronary flow reserve ≥2.5, with researchers blinded to the classification. RESULTS: Eighty-five patients were enrolled (78% female, 57±10 years), 45 (53%) were classified as having MVD. Of the MVD group, 82% had inducible ischemia compared with 22% of controls (P<0.001); global myocardial perfusion reserve was 2.01±0.41 and 2.68±0.49 (P<0.001). In controls, coronary perfusion efficiency improved from rest to exercise and was unchanged during hyperemia (59±11% vs 65±14% vs 57±18%; P=0.02 and P=0.14). In contrast, perfusion efficiency decreased during both forms of stress in MVD (61±12 vs 44±10 vs 42±11%; both P<0.001). Among patients with a coronary flow reserve <2.5, 62% had functional MVD, with normal minimal MR (hyperemic MR<2.5 mmHg/cm/s), and 38% had structural MVD with elevated hyperemic MR. Resting MR was lower in those with functional MVD (4.2±1.0 mmHg/cm/s) than in those with structural MVD (6.9±1.7 mmHg/cm/s) or controls (7.3±2.2 mmHg/cm/s; both P<0.001). During exercise, the structural group had a higher systolic blood pressure (188±25 mmHg) than did those with functional MVD (161±27 mmHg; P=0.004) and controls (156±30 mmHg; P<0.001). Functional and structural MVD had similar stress myocardial perfusion and exercise perfusion efficiency values. CONCLUSION: In patients with angina and nonobstructive coronary artery disease, diminished coronary flow reserve characterizes a cohort with inducible ischemia and a maladaptive physiological response to exercise. We have identified 2 endotypes of MVD with distinctive systemic vascular responses to exercise; whether endotypes have a different prognosis or require different treatments merits further investigation.

Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial.

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

Ischaemia without obstructive coronary artery disease: the pathophysiology of microvascular dysfunction.

PURPOSE OF REVIEW: Nearly one-third of patients presenting with angina have unobstructed epicardial coronary arteries and evidence of coronary microvascular disease. Up until recently, the pathophysiology of coronary microvascular disease has been poorly understood, resulting in limited effective therapeutic options in these patients. As a result, patients with coronary microvascular disease continue to suffer from a poor quality of life and adverse cardiovascular outcomes. RECENT FINDINGS: Recent mechanistic studies have improved our understanding of the pathophysiology underlying coronary microvascular dysfunction; these studies have implicated the nitric oxide and endothelin pathways as the main drivers. The aim of this article is to review our current understanding of the pathophysiology of ischaemia in patients with coronary microvascular disease. SUMMARY: Patients with angina who have coronary microvascular disease, but no obstructive coronary artery disease, are unable to augment their coronary blood flow in response to physiological stress, thereby predisposing them to myocardial ischaemia as a result of supply:demand mismatch in the myocardium. In addition to abnormalities of vascular resistance, perturbations in cardiac-coronary coupling also contribute to ischaemia in these patients. Although impaired flow reserve is the diagnostic hallmark, mechanistic studies have demonstrated that the underlying pathophysiology is heterogeneous. At present, two main endotypes have been identified, which can be readily differentiated on the basis of minimal microvascular resistance. A better understanding of the pathophysiology and mechanisms driving ischaemia in coronary microvascular dysfunction may stimulate the development of individualised therapies that may lead to an improvement in patients' quality of life and prognosis.

Clinical value of dark-blood late gadolinium enhancement cardiovascular magnetic resonance without additional magnetization preparation.

BACKGROUND: For two decades, bright-blood late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) has been considered the reference standard for the non-invasive assessment of myocardial viability. While bright-blood LGE can clearly distinguish areas of myocardial infarction from viable myocardium, it often suffers from poor scar-to-blood contrast, making subendocardial scar difficult to detect. Recently, we proposed a novel dark-blood LGE approach that increases scar-to-blood contrast and thereby improves subendocardial scar conspicuity. In the present study we sought to assess the clinical value of this novel approach in a large patient cohort with various non-congenital ischemic and non-ischemic cardiomyopathies on both 1.5 T and 3 T CMR scanners of different vendors. METHODS: Three hundred consecutive patients referred for clinical CMR were randomly assigned to a 1.5 T or 3 T scanner. An entire short-axis stack and multiple long-axis views were acquired using conventional phase sensitive inversion recovery (PSIR) LGE with TI set to null myocardium (bright-blood) and proposed PSIR LGE with TI set to null blood (dark-blood), in a randomized order. The bright-blood LGE and dark-blood LGE images were separated, anonymized, and interpreted in a random order at different time points by one of five independent observers. Each case was analyzed for the type of scar, per-segment transmurality, papillary muscle enhancement, overall image quality, observer confidence, and presence of right ventricular scar and intraventricular thrombus. RESULTS: Dark-blood LGE detected significantly more cases with ischemic scar compared to conventional bright-blood LGE (97 vs 89, p = 0.008), on both 1.5 T and 3 T, and led to a significantly increased total scar burden (3.3 ± 2.4 vs 3.0 ± 2.3 standard AHA segments, p = 0.015). Overall image quality significantly improved using dark-blood LGE compared to bright-blood LGE (81.3% vs 74.0% of all segments were of highest diagnostic quality, p = 0.006). Furthermore, dark-blood LGE led to significantly higher observer confidence (confident in 84.2% vs 78.4%, p = 0.033). CONCLUSIONS: The improved detection of ischemic scar makes the proposed dark-blood LGE method a valuable diagnostic tool in the non-invasive assessment of myocardial scar. The applicability in routine clinical practice is further strengthened, as the present approach, in contrast to other recently proposed dark- and black-blood LGE techniques, is readily available without the need for scanner adjustments, extensive optimizations, or additional training.

Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer.

The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Hemicraniectomy versus Conservative Treatment in Large Hemispheric Ischemic Stroke Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Several small trials have inconclusively evaluated the effect of hemicraniectomy in reducing death and disability in acute ischemic stroke patients with large hemispheric infarctions. We compared the effects of hemicraniectomy on death and disability with conservative treatment in patients with large hemispheric infarctions. METHODS: We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using random-effects models from 7 randomized trials that compared hemicraniectomy with conservative treatment in acute ischemic stroke patients. The primary end point was a favorable outcome defined by modified Rankin Scale grades of 0 (no symptoms), 1 (no significant disability), 2 (slight disability), and 3 (moderate disability) at 6-12 months post randomization. RESULTS: Of the 341 total subjects randomized, the proportion of subjects who achieved a favorable outcome was significantly greater among those randomized to hemicraniectomy than among those randomized to conservative treatment (OR 2.04, 95% CI 1.03-4.03, P = .04). Survival was also significantly greater among those randomized to hemicraniectomy (OR 5.56, 95% CI 3.40-9.08, P < .001) than among those randomized to conservative treatment. There was a trend toward higher odds of favorable outcome among those randomized to hemicraniectomy than among those randomized to conservative treatment in trials that permitted recruitment of patients aged 60 years or older (303 subjects analyzed; OR 1.87, 95% CI .91-3.86, P = .09). CONCLUSIONS: Compared with conservative treatment, the odds of achieving a favorable outcome at 6 months is approximately 2-folds higher with hemicraniectomy in patients with large hemispheric infarctions.

The role of coronary microvascular dysfunction in the pathogenesis of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common condition with few effective therapies and hence represents a major healthcare burden. The clinical syndrome of HFpEF can be caused by varying pathophysiological processes, with coronary microvascular dysfunction (CMD) proposed as one of the aetiologies, although confirming causality has been challenging. CMD is characterised by the inability of the coronary vasculature to augment blood flow in response to a physiological stressor and has been established as the driver of angina in patients with non-obstructed coronaries (ANOCA), and this has subsequently led to efficacious endotype-directed therapies. CMD is also highly prevalent among sufferers of HFpEF and may represent a novel treatment target for this particular endotype of this condition. This review aims to discuss the role of the microcirculation in the healthy heart how it's dysfunction may precipitate HFpEF and explore the current diagnostic tools available. We also discuss the gaps in evidence and where we believe future research should be focussed.

Characterizing Mechanisms of Ischemia in Patients With Myocardial Bridges.

BACKGROUND: Myocardial bridges (MBs) are prevalent and can be associated with acute and chronic ischemic syndromes. We sought to determine the substrates for ischemia in patients with angina with nonobstructive coronary arteries and a MB in the left anterior descending artery. METHODS: Patients with angina with nonobstructive coronary arteries underwent the acquisition of intracoronary pressure and flow during rest, supine bicycle exercise, and adenosine infusion. Coronary wave intensity analysis was performed, with perfusion efficiency defined as accelerating wave energy/total wave energy (%). Epicardial endothelial dysfunction was defined as a reduction in epicardial vessel diameter ≥20% in response to intracoronary acetylcholine infusion. Patients with angina with nonobstructive coronary arteries and a MB were compared with 2 angina with nonobstructive coronary arteries groups with no MB: 1 with coronary microvascular disease (CMD: coronary flow reserve, <2.5) and 1 with normal coronary flow reserve (reference: coronary flow reserve, ≥2.5). RESULTS: Ninety-two patients were enrolled in the study (30 MB, 33 CMD, and 29 reference). Fractional flow reserve in these 3 groups was 0.86±0.05, 0.92±0.04, and 0.94±0.05; coronary flow reserve was 2.5±0.5, 2.0±0.3, and 3.2±0.6. Perfusion efficiency increased numerically during exercise in the reference group (65±9%-69±13%; P=0.063) but decreased in the CMD (68±10%-50±10%; P<0.001) and MB (66±9%-55±9%; P<0.001) groups. The reduction in perfusion efficiency had distinct causes: in CMD, this was driven by microcirculation-derived energy in early diastole, whereas in MB, this was driven by diminished accelerating wave energy, due to the upstream bridge, in early systole. Epicardial endothelial dysfunction was more common in the MB group (54% versus 29% reference and 38% CMD). Overall, 93% of patients with a MB had an identifiable ischemic substrate. CONCLUSIONS: MBs led to impaired coronary perfusion efficiency during exercise, which was due to diminished accelerating wave energy in early systole compared with the reference group. Additionally, there was a high prevalence of endothelial and microvascular dysfunction. These ischemic mechanisms may represent distinct treatment targets.

Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function.

BACKGROUND: Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease. OBJECTIVES: The aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA). METHODS: Patients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%. RESULTS: A total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%. CONCLUSIONS: In patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

Percutaneous Left Ventricular Unloading During High-Risk Coronary Intervention: Rationale and Design of the CHIP-BCIS3 Randomized Controlled Trial.

INTRODUCTION: Percutaneous coronary intervention for complex coronary disease is associated with a high risk of cardiogenic shock. This can cause harm and limit the quality of revascularization achieved, especially when left ventricular function is impaired at the outset. Elective percutaneous left ventricular unloading is increasingly used to mitigate adverse events in patients undergoing high-risk percutaneous coronary intervention, but this strategy has fiscal and clinical costs and is not supported by robust evidence. METHODS: CHIP-BCIS3 (Controlled Trial of High-Risk Coronary Intervention With Percutaneous Left Ventricular Unloading) is a prospective, multicenter, open-label randomized controlled trial that aims to determine whether a strategy of elective percutaneous left ventricular unloading is superior to standard care (no planned mechanical circulatory support) in patients undergoing nonemergent high-risk percutaneous coronary intervention. Patients are eligible for recruitment if they have severe left ventricular systolic dysfunction, extensive coronary artery disease, and are due to undergo complex percutaneous coronary intervention (to the left main stem with calcium modification or to a chronic total occlusion with a retrograde approach). Cardiogenic shock and acute ST-segment-elevation myocardial infarction are exclusions. The primary outcome is a hierarchical composite of all-cause death, stroke, spontaneous myocardial infarction, cardiovascular hospitalization, and periprocedural myocardial infarction, analyzed using the win ratio. Secondary outcomes include completeness of revascularization, major bleeding, vascular complications, health economic analyses, and health-related quality of life. A sample size of 250 patients will have in excess of 80% power to detect a hazard ratio of 0.62 at a minimum of 12 months, assuming 150 patients experience an event across all follow-up. CONCLUSIONS: To date, 169 patients have been recruited from 21 National Health Service hospitals in the United Kingdom, with recruitment expected to complete in 2024. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05003817.