1-year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study.

Background: In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge. Methods: Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium). HRQoL, assessed by the EuroQol-Five Dimensions-Five Levels utility index (EQ-5D-5L UI), pre-hospital and 1 year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient-reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. Findings: Of the 1888 participants included in the primary analysis, 1149 received corticosteroids. There was no between-group difference in EQ-5D-5L UI at 1 year (mean difference 0.004, 95% CI -0.026-0.034). A similar reduction in EQ-5D-5L UI was seen at 1 year between corticosteroid exposed and nonexposed groups (mean±sd change -0.12±0.22 versus -0.11±0.22). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a cohort of 109 318 patients admitted to hospital with COVID-19, EQ-5D-5L UI at 1 year remained similar between the two groups. Interpretation: Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL 1 year after hospital discharge. Treatments to address the persistent reduction in HRQoL are urgently needed.

Cellular and extracellular proteomic profiling of paradoxical low-flow low-gradient aortic stenosis myocardium.

Aims: Patients with severe aortic stenosis (AS), low transvalvular flow (LF) and low gradient (LG) with normal ejection fraction (EF)-are referred to as paradoxical LF-LG AS (PLF-LG). PLF-LG patients develop more advanced heart failure symptoms and have a worse prognosis than patients with normal EF and high-gradient AS (NEF-HG). Despite its clinical relevance, the mechanisms underlying PLF-LG are still poorly understood. Methods: Left ventricular (LV) myocardial biopsies of PLF-LG (n = 5) and NEF-HG patients (n = 6), obtained during transcatheter aortic valve implantation, were analyzed by LC-MS/MS after sequential extraction of cellular and extracellular matrix (ECM) proteins using a three-step extraction method. Proteomic data are available via ProteomeXchange with identifier PXD055391. Results: 73 cellular proteins were differentially abundant between the 2 groups. Among these, a network of proteins related to muscle contraction and arrhythmogenic cardiomyopathy (e.g., cTnI, FKBP1A and CACNA2D1) was found in PLF-LG. Extracellularly, upregulated proteins in PLF-LG were related to ATP synthesis and oxidative phosphorylation (e.g., ATP5PF, COX5B and UQCRB). Interestingly, we observed a 1.3-fold increase in cyclophilin A (CyPA), proinflammatory cytokine, in the extracellular extracts of PLF-LG AS patients (p < 0.05). Consistently, immunohistochemical analysis confirmed its extracellular localization in PLF-LG AS LV sections along with an increase in its receptor, CD147, compared to the NEF-HG AS patients. Levels of core ECM proteins, namely collagens and proteoglycans, were comparable between groups. Conclusion: Our study pinpointed novel candidates and processes with potential relevance in the pathophysiology of PLF-LG. The role of CyPA in particular warrants further investigation.

Impact of lesion morphology on stent elongation during bifurcation PCI: an in vivo OCT study.

BACKGROUND: Recent observations in silico and in vivo reported that, during proximal optimisation technique, drug-eluting stents (DES) elongate, challenging conventional wisdom. The interaction between plaque morphology and radial expansion is well established, but little is known about the impact of plaque morphology on elongation. AIMS: We aimed to assess the longitudinal mechanical behaviour of contemporary DES in vivo and evaluate the relationship between post-percutaneous coronary intervention (PCI) stent elongation and lesion morphology, as assessed with optical coherence tomography (OCT). METHODS: Patients treated with OCT-guided PCI to left main or left anterior descending artery bifurcations, between July 2017 and March 2022, from the King's Optical coherence Database Analysis Compendium were included. Patients were excluded if there were overlapping stents, if they had undergone prior PCI, or if there was inadequate image quality. Lesions were characterised as fibrocalcific, fibrous or lipid-rich by pre-PCI OCT. Following stent post-dilatation, stent expansion and final stent length were assessed. The primary outcome was the percentage change in stent length from baseline. RESULTS: Of 501 eligible consecutive patients from this period, 116 were included. The median age was 66 years (interquartile range [IQR] 57-76), 31% were female, and 53.4% were treated for an acute coronary syndrome. A total of 50.0% of lesions were classified as fibrocalcific, 6.9% were fibrous, and 43.1% were lipid-rich. The change in relative stent length was 4.4% (IQR 1.0-8.9), with an increase of 3.1% (IQR 0.5-6.3) in fibrocalcific lesions, 3.3% (IQR 0.5-5.9) in fibrous lesions, and 6.4% (IQR 3.1-11.1) in lipid-rich plaque (p=0.006). In multivariate regression modelling, lipid-rich plaque was an independent predictor of stent elongation (odds ratio 3.689, 95% confidence interval: 1.604-8.484). CONCLUSIONS: Contemporary DES elongate following implantation and post-dilatation, and this is significantly mediated by plaque morphology. This is an important consideration when planning a strategy for DES implantation.

Prognostic significance of troponin in patients with malignancy (NIHR Health Informatics Collaborative TROP-MALIGNANCY study).

BACKGROUND: Cardiac troponin is commonly raised in patients presenting with malignancy. The prognostic significance of raised troponin in these patients is unclear. OBJECTIVES: We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients with a routinely measured troponin and a primary diagnosis of malignancy. METHODS: We used the National Institute for Health Research (NIHR) Health Informatics Collaborative data of 5571 patients, who had troponin levels measured at 5 UK cardiac centres between 2010 and 2017 and had a primary diagnosis of malignancy. Patients were classified into solid tumour or haematological malignancy subgroups. Peak troponin levels were standardised as a multiple of each laboratory's 99th -percentile upper limit of normal (xULN). RESULTS: 4649 patients were diagnosed with solid tumours and 922 patients with haematological malignancies. Raised troponin was an independent predictor of mortality in all patients (Troponin > 10 vs. <1 adjusted HR 2.01, 95% CI 1.73 to 2.34), in solid tumours (HR 1.84, 95% CI 1.55 to 2.19), and in haematological malignancy (HR 2.72, 95% CI 1.99 to 3.72). There was a significant trend in increasing mortality risk across troponin categories in all three subgroups (p < 0.001). CONCLUSION: Raised troponin level is associated with increased mortality in patients with a primary diagnosis of malignancy regardless of cancer subtype. Mortality risk is stable for patients with a troponin level below the ULN but increases as troponin level increases above the ULN in the absence of acute coronary syndrome.

Race- and Ethnicity-Related Differences in Heart Failure With Preserved Ejection Fraction Using Natural Language Processing.

Background: Heart failure with preserved ejection fraction (HFpEF) is the predominant form of HF in older adults. It represents a heterogenous clinical syndrome that is less well understood across different ethnicities. Objectives: This study aimed to compare the clinical presentation and assess the diagnostic performance of existing HFpEF diagnostic tools between ethnic groups. Methods: A validated Natural Language Processing (NLP) algorithm was applied to the electronic health records of a large London hospital to identify patients meeting the European Society of Cardiology criteria for a diagnosis of HFpEF. NLP extracted patient demographics (including self-reported ethnicity and socioeconomic status), comorbidities, investigation results (N-terminal pro-B-type natriuretic peptide, H2FPEF scores, and echocardiogram reports), and mortality. Analyses were stratified by ethnicity and adjusted for socioeconomic status. Results: Our cohort consisted of 1,261 (64%) White, 578 (29%) Black, and 134 (7%) Asian patients meeting the European Society of Cardiology HFpEF diagnostic criteria. Compared to White patients, Black patients were younger at diagnosis and more likely to have metabolic comorbidities (obesity, diabetes, and hypertension) but less likely to have atrial fibrillation (30% vs 13%; P < 0.001). Black patients had lower N-terminal pro-B-type natriuretic peptide levels and a lower frequency of H2FPEF scores ≥6, indicative of likely HFpEF (26% vs 44%; P < 0.0001). Conclusions: Leveraging an NLP-based artificial intelligence approach to quantify health inequities in HFpEF diagnosis, we discovered that established markers systematically underdiagnose HFpEF in Black patients, possibly due to differences in the underlying comorbidity patterns. Clinicians should be aware of these limitations and its implications for treatment and trial recruitment.

Phenogrouping heart failure with preserved or mildly reduced ejection fraction using electronic health record data.

BACKGROUND: Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. METHODS: 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. RESULTS: Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF. CONCLUSIONS: Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles.

Changes in the investigation and management of suspected myocardial infarction and injury during COVID-19: a multi-centre study using routinely collected healthcare data.

Objective: The COVID-19 pandemic was associated with a reduction in the incidence of myocardial infarction (MI) diagnosis, in part because patients were less likely to present to hospital. Whether changes in clinical decision making with respect to the investigation and management of patients with suspected MI also contributed to this phenomenon is unknown. Methods: Multicentre retrospective cohort study in three UK centres contributing data to the National Institute for Health Research Health Informatics Collaborative. Patients presenting to the Emergency Department (ED) of these centres between 1st January 2020 and 1st September 2020 were included. Three time epochs within this period were defined based on the course of the first wave of the COVID-19 pandemic: pre-pandemic (epoch 1), lockdown (epoch 2), post-lockdown (epoch 3). Results: During the study period, 10,670 unique patients attended the ED with chest pain or dyspnoea, of whom 6,928 were admitted. Despite fewer total ED attendances in epoch 2, patient presentations with dyspnoea were increased (p < 0.001), with greater likelihood of troponin testing in both chest pain (p = 0.001) and dyspnoea (p < 0.001). There was a dramatic reduction in elective and emergency cardiac procedures (both p < 0.001), and greater overall mortality of patients (p < 0.001), compared to the pre-pandemic period. Positive COVID-19 and/or troponin test results were associated with increased mortality (p < 0.001), though the temporal risk profile differed. Conclusions: The first wave of the COVID-19 pandemic was associated with significant changes not just in presentation, but also the investigation, management, and outcomes of patients presenting with suspected myocardial injury or MI.

Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension.

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.

Disrupting Na+ ion homeostasis and Na+/K+ ATPase activity in breast cancer cells directly modulates glycolysis in vitro and in vivo.

BACKGROUND: Glycolytic flux is regulated by the energy demands of the cell. Upregulated glycolysis in cancer cells may therefore result from increased demand for adenosine triphosphate (ATP), however it is unknown what this extra ATP turnover is used for. We hypothesise that an important contribution to the increased glycolytic flux in cancer cells results from the ATP demand of Na+/K+-ATPase (NKA) due to altered sodium ion homeostasis in cancer cells. METHODS: Live whole-cell measurements of intracellular sodium [Na+]i were performed in three human breast cancer cells (MDA-MB-231, HCC1954, MCF-7), in murine breast cancer cells (4T1), and control human epithelial cells MCF-10A using triple quantum filtered 23Na nuclear magnetic resonance (NMR) spectroscopy. Glycolytic flux was measured by 2H NMR to monitor conversion of [6,6-2H2]D-glucose to [2H]-labelled L-lactate at baseline and in response to NKA inhibition with ouabain. Intracellular [Na+]i was titrated using isotonic buffers with varying [Na+] and [K+] and introducing an artificial Na+ plasma membrane leak using the ionophore gramicidin-A. Experiments were carried out in parallel with cell viability assays, 1H NMR metabolomics of intracellular and extracellular metabolites, extracellular flux analyses and in vivo measurements in a MDA-MB-231 human-xenograft mouse model using 2-deoxy-2-[18F]fluoroglucose (18F-FDG) positron emission tomography (PET). RESULTS: Intracellular [Na+]i was elevated in human and murine breast cancer cells compared to control MCF-10A cells. Acute inhibition of NKA by ouabain resulted in elevated [Na+]i and inhibition of glycolytic flux in all three human cancer cells which are ouabain sensitive, but not in the murine cells which are ouabain resistant. Permeabilization of cell membranes with gramicidin-A led to a titratable increase of [Na+]i in MDA-MB-231 and 4T1 cells and a Na+-dependent increase in glycolytic flux. This was attenuated with ouabain in the human cells but not in the murine cells. 18FDG PET imaging in an MDA-MB-231 human-xenograft mouse model recorded lower 18FDG tumour uptake when treated with ouabain while murine tissue uptake was unaffected. CONCLUSIONS: Glycolytic flux correlates with Na+-driven NKA activity in breast cancer cells, providing evidence for the 'centrality of the [Na+]i-NKA nexus' in the mechanistic basis of the Warburg effect.

Serum metabolomics improves risk stratification for incident heart failure.

AIMS: Prediction and early detection of heart failure (HF) is crucial to mitigate its impact on quality of life, survival, and healthcare expenditure. Here, we explored the predictive value of serum metabolomics (168 metabolites detected by proton nuclear magnetic resonance [1H-NMR] spectroscopy) for incident HF. METHODS AND RESULTS: Leveraging data of 68 311 individuals and >0.8 million person-years of follow-up from the UK Biobank cohort, we (i) fitted per-metabolite Cox proportional hazards models to assess individual metabolite associations, and (ii) trained and validated elastic net models to predict incident HF using the serum metabolome. We benchmarked discriminative performance against a comprehensive, well-validated clinical risk score (Pooled Cohort Equations to Prevent HF [PCP-HF]). During a median follow-up of ≈12.3 years, several metabolites showed independent association with incident HF (90/168 adjusting for age and sex, 48/168 adjusting for PCP-HF). Performance-optimized risk models effectively retained key predictors representing highly correlated clusters (≈80% feature reduction). Adding metabolomics to PCP-HF improved predictive performance (Harrel's C: 0.768 vs. 0.755, ΔC = 0.013, [95% confidence interval [CI] 0.004-0.022], continuous net reclassification improvement [NRI]: 0.287 [95% CI 0.200-0.367], relative integrated discrimination improvement [IDI]: 17.47% [95% CI 9.463-27.825]). Models including age, sex and metabolomics performed almost as well as PCP-HF (Harrel's C: 0.745 vs. 0.755, ΔC = 0.010 [95% CI -0.004 to 0.027], continuous NRI: 0.097 [95% CI -0.025 to 0.217], relative IDI: 13.445% [95% CI -10.608 to 41.454]). Risk and survival stratification was improved by integrating metabolomics. CONCLUSION: Serum metabolomics improves incident HF risk prediction over PCP-HF. Scores based on age, sex and metabolomics exhibit similar predictive power to clinically-based models, potentially offering a cost-effective, standardizable, and scalable single-domain alternative.

Cellular host response sepsis test for risk stratification of patients in the emergency department: A pooled analysis.

OBJECTIVES: Sepsis is one of the most common, costly, and misdiagnosed conditions in U.S. emergency departments (EDs). ED providers often treat on nonspecific signs, subjective suspicion, or presumption of infection, resulting in over- and undertreatment. An increased understanding of host response has opened a new direction for sepsis diagnostics. The IntelliSep test is a U.S. Food and Drug Administration-cleared cellular host response diagnostic that could help distinguish sepsis in ED settings. Our objective was to evaluate the potential of the cellular host response test to expedite appropriate care for patients who present with signs of infection. METHODS: We performed a pooled analysis of five adult (≥18 years) cohorts enrolled at seven geographically diverse U.S. sites in separate studies. Structured blinded adjudication was used to classify presence or absence of sepsis, and only patients with high confidence in the adjudicated label were included (n = 1002), defined as patients for whom there was consensus in the determination of sepsis per the Sepsis-3 and severe sepsis per the Sepsis-2 definitions between both the independent adjudication panel and the site-level physician. RESULTS: Among patients with signs or suspicion of infection, the test achieved similar or better performance compared to other indicators in identifying patients at high risk for sepsis (specificity > 83%) and significantly superior performance in identifying those at low risk (sensitivity > 92%; 0% sepsis-associated mortality). The test also stratified severity of illness, as shown by 30-day in-hospital mortality (p < 0.001), hospital length of stay (p < 0.01), and use of hospital resources (p < 0.001). CONCLUSIONS: Our data suggest that the cellular host response test provides clinically actionable results for patients at both high and low risk for sepsis and provides a rapid, objective means for risk stratification of patients with signs of infection. If integrated into standard of care, the test may help improve outcomes and reduce unnecessary antibiotic use.

Validation of a Novel, Rapid Sepsis Diagnostic for Emergency Department Use.

OBJECTIVES: To assess the in vitro IntelliSep test, a microfluidic assay that quantifies the state of immune activation by evaluating the biophysical properties of leukocytes, as a rapid diagnostic for sepsis. DESIGN: Prospective cohort study. SETTING: Five emergency departments (EDs) in Louisiana, Missouri, North Carolina, and Washington. PATIENTS: Adult patients presenting to the ED with signs (two of four Systemic Inflammatory Response Syndrome criteria, where one must be temperature or WBC count) or suspicion (provider-ordered culture) of infection. INTERVENTIONS: All patients underwent testing with the IntelliSep using ethylene diamine tetraacetic acid-anticoagulated whole blood followed by retrospective adjudication for sepsis by sepsis-3 criteria by a blinded panel of physicians. MEASUREMENTS AND MAIN RESULTS: Of 599 patients enrolled, 572 patients were included in the final analysis. The result of the IntelliSep test is reported as the IntelliSep Index (ISI), ranging from 0.1 to 10.0, divided into three interpretation bands for the risk of sepsis: band 1 (low) to band 3 (high). The median turnaround time for ISI results was 7.2 minutes. The ISI resulted band 1 in 252 (44.1%), band 2 in 160 (28.0%), and band 3 in 160 (28.0%). Sepsis occurred in 26.6% (152 of 572 patients). Sepsis prevalence was 11.1% (95% CI, 7.5-15.7%) in band 1, 28.1% (95% CI, 21.3-35.8%) in band 2, and 49.4% (95% CI, 41.4-57.4%) in band 3. The Positive Percent Agreement of band 1 was 81.6% and the Negative Percent Agreement of band 3 was 80.7%, with an area under the receiver operating characteristic curve of 0.74. Compared with band 1, band 3 correlated with adverse clinical outcomes, including mortality, and resource utilization. CONCLUSIONS: Increasing ISI interpretation band is associated with increasing probability of sepsis in patients presenting to the ED with suspected infection.

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.

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.

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.

Artificial intelligence methods for improved detection of undiagnosed heart failure with preserved ejection fraction.

AIM: Heart failure with preserved ejection fraction (HFpEF) remains under-diagnosed in clinical practice despite accounting for nearly half of all heart failure (HF) cases. Accurate and timely diagnosis of HFpEF is crucial for proper patient management and treatment. In this study, we explored the potential of natural language processing (NLP) to improve the detection and diagnosis of HFpEF according to the European Society of Cardiology (ESC) diagnostic criteria. METHODS AND RESULTS: In a retrospective cohort study, we used an NLP pipeline applied to the electronic health record (EHR) to identify patients with a clinical diagnosis of HF between 2010 and 2022. We collected demographic, clinical, echocardiographic and outcome data from the EHR. Patients were categorized according to the left ventricular ejection fraction (LVEF). Those with LVEF ≥50% were further categorized based on whether they had a clinician-assigned diagnosis of HFpEF and if not, whether they met the ESC diagnostic criteria. Results were validated in a second, independent centre. We identified 8606 patients with HF. Of 3727 consecutive patients with HF and LVEF ≥50% on echocardiogram, only 8.3% had a clinician-assigned diagnosis of HFpEF, while 75.4% met ESC criteria but did not have a formal diagnosis of HFpEF. Patients with confirmed HFpEF were hospitalized more frequently; however the ESC criteria group had a higher 5-year mortality, despite being less comorbid and experiencing fewer acute cardiovascular events. CONCLUSIONS: This study demonstrates that patients with undiagnosed HFpEF are an at-risk group with high mortality. It is possible to use NLP methods to identify likely HFpEF patients from EHR data who would likely then benefit from expert clinical review and complement the use of diagnostic algorithms.

Diagnostic accuracy, clinical characteristics, and prognostic differences of patients with acute myocarditis according to inclusion criteria.

INTRODUCTION: The diagnosis of acute myocarditis (AM) is complex due to its heterogeneity and typically is defined by either Electronic Healthcare Records (EHRs) or advanced imaging and endomyocardial biopsy, but there is no consensus. We aimed to investigate the diagnostic accuracy of these approaches for AM. METHODS: Data on ICD 10th Revision(ICD-10) codes corresponding to AM were collected from two hospitals and compared to CMR-confirmed or clinically suspected(CS) AM cases with respect to diagnostic accuracy, clinical characteristics, and all-cause mortality. Next, we performed a review of published AM studies according to inclusion criteria. RESULTS: We identified 291 unique admissions with ICD-10 codes corresponding to AM in the first three diagnostic positions. The positive predictive value(PPV) of ICD-10 codes for CMR-confirmed or CS-AM was 36%, and patients with CMR-confirmed or CS AM had a lower all-cause mortality than those with a refuted diagnosis (P = 0.019). Using an unstructured approach, patients with CMR-confirmed and CS AM had similar demographics, comorbidity profiles and survival over a median follow-up of 52 months (P = 0.72). Our review of the literature confirmed our findings. Outcomes for patients included in studies using CMR-confirmed criteria were favourable compared to studies with EMB-confirmed AM cases. CONCLUSION: ICD-10 codes have poor accuracy in identification of AM cases and should be used with caution in clinical research. There are important differences in management and outcomes of patients according to the selection criteria used to diagnose AM. Potential selection biases must be considered when interpreting AM cohorts and requires standardisation of inclusion criteria for AM studies.

The Relationship Between Cardiac Troponin in People Hospitalised for Exacerbation of COPD and Major Adverse Cardiac Events (MACE) and COPD Readmissions.

Background: No single biomarker currently risk stratifies chronic obstructive pulmonary disease (COPD) patients at the time of an exacerbation, though previous studies have suggested that patients with elevated troponin at exacerbation have worse outcomes. This study evaluated the relationship between peak cardiac troponin and subsequent major adverse cardiac events (MACE) including all-cause mortality and COPD hospital readmission, among patients admitted with COPD exacerbation. Methods: Data from five cross-regional hospitals in England were analysed using the National Institute of Health Research Health Informatics Collaborative (NIHR-HIC) acute coronary syndrome database (2008-2017). People hospitalised with a COPD exacerbation were included, and peak troponin levels were standardised relative to the 99th percentile (upper limit of normal). We used Cox Proportional Hazard models adjusting for age, sex, laboratory results and clinical risk factors, and implemented logarithmic transformation (base-10 logarithm). The primary outcome was risk of MACE within 90 days from peak troponin measurement. Secondary outcome was risk of COPD readmission within 90 days from peak troponin measurement. Results: There were 2487 patients included. Of these, 377 (15.2%) patients had a MACE event and 203 (8.2%) were readmitted within 90 days from peak troponin measurement. A total of 1107 (44.5%) patients had an elevated troponin level. Of 1107 patients with elevated troponin at exacerbation, 256 (22.8%) had a MACE event and 101 (9.0%) a COPD readmission within 90 days from peak troponin measurement. Patients with troponin above the upper limit of normal had a higher risk of MACE (adjusted HR 2.20, 95% CI 1.75-2.77) and COPD hospital readmission (adjusted HR 1.37, 95% CI 1.02-1.83) when compared with patients without elevated troponin. Conclusion: An elevated troponin level at the time of COPD exacerbation may be a useful tool for predicting MACE in COPD patients. The relationship between degree of troponin elevation and risk of future events is complex and requires further investigation.

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection.

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal.