Safety, tolerability, viral kinetics, and immune correlates of protection in healthy, seropositive UK adults inoculated with SARS-CoV-2: a single-centre, open-label, phase 1 controlled human infection study.

BACKGROUND: A SARS-CoV-2 controlled human infection model (CHIM) has been successfully established in seronegative individuals using a dose of 1×101 50% tissue culture infectious dose (TCID50) pre-alpha SARS-CoV-2 virus. Given the increasing prevalence of seropositivity to SARS-CoV-2, a CHIM that could be used for vaccine development will need to induce infection in those with pre-existing immunity. Our aim was to find a dose of pre-alpha SARS-CoV-2 virus that induced infection in previously infected individuals. METHODS: Healthy, UK volunteers aged 18-30 years, with proven (quantitative RT-PCR or lateral flow antigen test) previous SARS-CoV-2 infection (with or without vaccination) were inoculated intranasally in a stepwise dose escalation CHIM with either 1×101, 1×102, 1×10³, 1×104, or 1×105 TCID50 SARS-CoV-2/human/GBR/484861/2020, the same virus used in the seronegative CHIM. Post-inoculation, volunteers were quarantined in functionally negative pressure rooms (Oxford, UK) for 14 days and until 12-hourly combined oropharyngeal-nasal swabs were negative for viable virus by focus-forming assay. Outpatient follow-up continued for 12 months post-enrolment, with additional visits for those who developed community-acquired SARS-CoV-2 infection. The primary objective was to identify a safe, well tolerated dose that induced infection (defined as two consecutive SARS-CoV-2 positive PCRs starting 24 h after inoculation) in 50% of seropositive volunteers. This study is registered with ClinicalTrials.gov (NCT04864548); enrolment and follow-up to 12 months post-enrolment are complete. FINDINGS: Recruitment commenced on May 6, 2021, with the last volunteer enrolled into the dose escalation cohort on Nov 24, 2022. 36 volunteers were enrolled, with four to eight volunteers inoculated in each dosing group from 1×101 to 1×105 TCID50 SARS-CoV-2. All volunteers have completed quarantine, with follow-up to 12 months complete. Despite dose escalation to 1×105 TCID50, we were unable to induce sustained infection in any volunteers. Five (14%) of 36 volunteers were considered to have transient infection, based on the kinetic of their PCR-positive swabs. Transiently infected volunteers had significantly lower baseline mucosal and systemic SARS-CoV-2-specific antibody titres and significantly lower peripheral IFNγ responses against a CD8+ T-cell SARS-CoV-2 peptide pool than uninfected volunteers. 14 (39%) of 36 volunteers subsequently developed breakthrough infection with the omicron variant after discharge from quarantine. Most adverse events reported by volunteers in quarantine were mild, with fatigue (16 [44%]) and stuffy nose (16 [44%]) being the most common. There were no serious adverse events. INTERPRETATION: Our study demonstrates potent protective immunity induced by homologous vaccination and homologous or heterologous previous SARS-CoV-2 infection. The community breakthrough infections seen with the omicron variant supports the use of newer variants to establish a model with sufficient rate of infection for use in vaccine and therapeutic development. FUNDING: Wellcome Trust and Department for Health and Social Care.

The Effects of Exercise on Cardiogenic Shock with an Intra-Aortic Balloon Pump: A Case Report. / Efeitos do Exercício em Choque Cardiogênico e Balão Intra-Aórtico: Um Relato de Caso.

This case report describes the exercise program on a hospitalized 54-year-old male patient with cardiogenic shock waiting for a heart transplant assisted by an intra-aortic balloon pump, a temporary mechanical circulatory support device. The temporary mechanical circulatory support device, an intra-aortic balloon pump, was placed in the left subclavian artery, enabling the exercise protocol. Measurements and values from Swan-Ganz catheter, blood sample, brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP), as well as the six-minute walk test (6MWT) and venous oxygen saturation (SvO2) were obtained before and after an exercise protocol. The exercise training protocol involved the use of an unloaded bed cycle ergometer once a day, for a maximum of 30 minutes, to the tolerance limit. No adverse events or events related to the dislocation of the intra-aortic balloon pump were observed during the exercise protocol. The exercise program resulted in higher SvO2 levels, with an increased 6MWT with lower Borg dyspnea scores (312 meters vs. 488 meters and five points vs. three points, respectively). After completing the ten-day exercise protocol, the patient underwent a non-complicated heart transplant surgery and a full recovery in the ICU. This study showed that exercise is a feasible option for patients with cardiogenic shock who are using an intra-aortic balloon pump and that it is well-tolerated with no reported adverse events.

O presente relato de caso descreve o programa de exercícios aplicado a um paciente do sexo masculino, de 54 anos, internado com choque cardiogênico, aguardando transplante cardíaco e assistido por balão intra-aórtico, um dispositivo de suporte circulatório mecânico temporário. O dispositivo de suporte circulatório mecânico temporário, um balão intra-aórtico, foi colocado na artéria subclávia esquerda, possibilitando o protocolo de exercícios. Antes e após um protocolo de exercícios, foram obtidos dados a partir de cateter de Swan-Ganz, amostra de sangue, peptídeo natriurético cerebral (NT-proBNP), proteína C reativa de alta sensibilidade (PCR-as), teste de caminhada de seis minutos (TC6min) e medição da saturação venosa de oxigênio (SvO2). O protocolo de treinamento físico envolveu a utilização de um cicloergômetro adaptado ao leito, sem carga, uma vez ao dia, por no máximo 30 minutos, até o limite da tolerância. Não foram observados eventos adversos tampouco relacionados ao deslocamento do balão intra-aórtico durante o protocolo de exercícios. O programa de exercícios resultou em maior SvO2 com aumento do TC6min e menores escores de dispneia de Borg (312 metros vs. 488 metros e cinco pontos vs. três pontos, respectivamente). Após completar o protocolo de exercícios de dez dias, o paciente foi submetido a uma cirurgia de transplante cardíaco sem complicações e recuperação total na UTI. O presente estudo demonstrou que o exercício é uma opção viável para pacientes com choque cardiogênico em uso de balão intra-aórtico e que é bem tolerado, além de não haver relatos de eventos adversos.

Misclassification of females and males in cardiovascular magnetic resonance parametric mapping: the importance of sex-specific normal ranges for diagnosis of health vs. disease.

AIMS: Cardiovascular magnetic resonance parametric mapping enables non-invasive quantitative myocardial tissue characterization. Human myocardium has normal ranges of T1 and T2 values, deviation from which may indicate disease or change in physiology. Normal myocardial T1 and T2 values are affected by biological sex. Consequently, normal ranges created with insufficient numbers of each sex may result in sampling biases, misclassification of healthy values vs. disease, and even misdiagnoses. In this study, we investigated the impact of using male normal ranges for classifying female cases as normal or abnormal (and vice versa). METHODS AND RESULTS: One hundred and forty-two healthy volunteers (male and female) were scanned on two Siemens 3T MR systems, providing averaged global myocardial T1 and T2 values on a per-subject basis. The Monte Carlo method was used to generate simulated normal ranges from these values to estimate the statistical accuracy of classifying healthy female or male cases correctly as 'normal' when using sex-specific vs. mixed-sex normal ranges. The normal male and female T1- and T2-mapping values were significantly different by sex, after adjusting for age and heart rate. CONCLUSION: Using 15 healthy volunteers who are not sex specific to establish a normal range resulted in a typical misclassification of up to 36% of healthy females and 37% of healthy males as having abnormal T1 values and up to 16% of healthy females and 12% of healthy males as having abnormal T2 values. This paper highlights the potential adverse impact on diagnostic accuracy that can occur when local normal ranges contain insufficient numbers of both sexes. Sex-specific reference ranges should thus be routinely adopted in clinical practice.

Efeitos do exercício em choque cardiogênico e balão intra-aórtico: um relato de caso / The Effects of Exercise on Cardiogenic Shock with an Intra-Aortic Balloon Pump: A Case Report

O presente relato de caso descreve o programa de exercícios aplicado a um paciente do sexo masculino, de 54 anos, internado com choque cardiogênico, aguardando transplante cardíaco e assistido por balão intra-aórtico, um dispositivo de suporte circulatório mecânico temporário. O dispositivo de suporte circulatório mecânico temporário, um balão intra-aórtico, foi colocado na artéria subclávia esquerda, possibilitando o protocolo de exercícios. Antes e após um protocolo de exercícios, foram obtidos dados a partir de cateter de Swan-Ganz, amostra de sangue, peptídeo natriurético cerebral (NT-proBNP), proteína C reativa de alta sensibilidade (PCR-as), teste de caminhada de seis minutos (TC6min) e medição da saturação venosa de oxigênio (SvO2). O protocolo de treinamento físico envolveu a utilização de um cicloergômetro adaptado ao leito, sem carga, uma vez ao dia, por no máximo 30 minutos, até o limite da tolerância. Não foram observados eventos adversos tampouco relacionados ao deslocamento do balão intra-aórtico durante o protocolo de exercícios. O programa de exercícios resultou em maior SvO2 com aumento do TC6min e menores escores de dispneia de Borg (312 metros vs. 488 metros e cinco pontos vs. três pontos, respectivamente). Após completar o protocolo de exercícios de dez dias, o paciente foi submetido a uma cirurgia de transplante cardíaco sem complicações e recuperação total na UTI. O presente estudo demonstrou que o exercício é uma opção viável para pacientes com choque cardiogênico em uso de balão intra-aórtico e que é bem tolerado, além de não haver relatos de eventos adversos.

Quality control-driven deep ensemble for accountable automated segmentation of cardiac magnetic resonance LGE and VNE images.

Background: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging is the gold standard for non-invasive myocardial tissue characterisation. However, accurate segmentation of the left ventricular (LV) myocardium remains a challenge due to limited training data and lack of quality control. This study addresses these issues by leveraging generative adversarial networks (GAN)-generated virtual native enhancement (VNE) images to expand the training set and incorporating an automated quality control-driven (QCD) framework to improve segmentation reliability. Methods: A dataset comprising 4,716 LGE images (from 1,363 patients with hypertrophic cardiomyopathy and myocardial infarction) was used for development. To generate additional clinically validated data, LGE data were augmented with a GAN-based generator to produce VNE images. LV was contoured on these images manually by clinical observers. To create diverse candidate segmentations, the QCD framework involved multiple U-Nets, which were combined using statistical rank filters. The framework predicted the Dice Similarity Coefficient (DSC) for each candidate segmentation, with the highest predicted DSC indicating the most accurate and reliable result. The performance of the QCD ensemble framework was evaluated on both LGE and VNE test datasets (309 LGE/VNE images from 103 patients), assessing segmentation accuracy (DSC) and quality prediction (mean absolute error (MAE) and binary classification accuracy). Results: The QCD framework effectively and rapidly segmented the LV myocardium (<1 s per image) on both LGE and VNE images, demonstrating robust performance on both test datasets with similar mean DSC (LGE: 0.845±0.075; VNE: 0.845±0.071; p=ns). Incorporating GAN-generated VNE data into the training process consistently led to enhanced performance for both individual models and the overall framework. The quality control mechanism yielded a high performance (MAE=0.043, accuracy=0.951) emphasising the accuracy of the quality control-driven strategy in predicting segmentation quality in clinical settings. Overall, no statistical difference (p=ns) was found when comparing the LGE and VNE test sets across all experiments. Conclusions: The QCD ensemble framework, leveraging GAN-generated VNE data and an automated quality control mechanism, significantly improved the accuracy and reliability of LGE segmentation, paving the way for enhanced and accountable diagnostic imaging in routine clinical use.

Myocarditis as a trigger for the expression of biventricular arrhythmogenic cardiomyopathy in desmosomal gene mutation.

Arrhythmogenic-cardiomyopathy (ACM) is an inherited heart disease with right, left, or biventricular (BVACM) involvement based on EKG, imaging, family history, and genetic testing. We present a 64-year-old woman with prior myocarditis and diagnosis of BVACM 29 years later. We propose myocarditis as a promoter of gene expression of plakophilin-2 mutation.

Worldwide variation in cardiovascular magnetic resonance practice models.

INTRODUCTION: The use of cardiovascular magnetic resonance (CMR) for diagnosis and management of a broad range of cardiac and vascular conditions has quickly expanded worldwide. It is essential to understand how CMR is utilized in different regions around the world and the potential practice differences between high-volume and low-volume centers. METHODS: CMR practitioners and developers from around the world were electronically surveyed by the Society for Cardiovascular Magnetic Resonance (SCMR) twice, requesting data from 2017. Both surveys were carefully merged, and the data were curated professionally by a data expert using cross-references in key questions and the specific media access control IP address. According to the United Nations classification, responses were analyzed by region and country and interpreted in the context of practice volumes and demography. RESULTS: From 70 countries and regions, 1092 individual responses were included. CMR was performed more often in academic (695/1014, 69%) and hospital settings (522/606, 86%), with adult cardiologists being the primary referring providers (680/818, 83%). Evaluation of cardiomyopathy was the top indication in high-volume and low-volume centers (p = 0.06). High-volume centers were significantly more likely to list evaluation of ischemic heart disease (e.g., stress CMR) as a primary indicator compared to low-volume centers (p < 0.001), while viability assessment was more commonly listed as a primary referral reason in low-volume centers (p = 0.001). Both developed and developing countries noted cost and competing technologies as top barriers to CMR growth. Access to scanners was listed as the most common barrier in developed countries (30% of responders), while lack of training (22% of responders) was the most common barrier in developing countries. CONCLUSION: This is the most extensive global assessment of CMR practice to date and provides insights from different regions worldwide. We identified CMR as heavily hospital-based, with referral volumes driven primarily by adult cardiology. Indications for CMR utilization varied by center volume. Efforts to improve the adoption and utilization of CMR should include growth beyond the traditional academic, hospital-based location and an emphasis on cardiomyopathy and viability assessment in community centers.

Reduced Left Atrial Rotational Flow Is Independently Associated With Embolic Brain Infarcts.

BACKGROUND: Up to 25% of embolic strokes occur in individuals without atrial fibrillation (AF) or other identifiable mechanisms. OBJECTIVES: This study aims to assess whether left atrial (LA) blood flow characteristics are associated with embolic brain infarcts, independently of AF. METHODS: The authors recruited 134 patients: 44 with a history of ischemic stroke and 90 with no history of stroke but CHA2DS2VASc score ≥1. Cardiac magnetic resonance (CMR) evaluated cardiac function and LA 4-dimensional flow parameters, including velocity and vorticity (a measure of rotational flow), and brain magnetic resonance imaging (MRI) was performed to detect large noncortical or cortical infarcts (LNCCIs) (likely embolic), or nonembolic lacunar infarcts. RESULTS: Patients (41% female; age 70 ± 9 years) had moderate stroke risk (median CHA2DS2VASc = 3, Q1-Q3: 2-4). Sixty-eight (51%) had diagnosed AF, of whom 58 (43%) were in AF during CMR. Thirty-nine (29%) had ≥1 LNCCI, 20 (15%) had ≥1 lacunar infarct without LNCCI, and 75 (56%) had no infarct. Lower LA vorticity was significantly associated with prevalent LNCCIs after adjustment for AF during CMR, history of AF, CHA2DS2VASc score, LA emptying fraction, LA indexed maximum volume, left ventricular ejection fraction, and indexed left ventricular mass (OR: 2.06 [95% CI: 1.08-3.92 per SD]; P = 0.027). By contrast, LA flow peak velocity was not significantly associated with LNCCIs (P = 0.21). No LA parameter was associated with lacunar infarcts (all P > 0.05). CONCLUSIONS: Reduced LA flow vorticity is significantly and independently associated with embolic brain infarcts. Imaging LA flow characteristics may aid identification of individuals who would benefit from anticoagulation for embolic stroke prevention, regardless of heart rhythm.

Acute changes in myocardial tissue characteristics during hospitalization in patients with COVID-19.

Background: Patients with a history of COVID-19 infection are reported to have cardiac abnormalities on cardiovascular magnetic resonance (CMR) during convalescence. However, it is unclear whether these abnormalities were present during the acute COVID-19 illness and how they may evolve over time. Methods: We prospectively recruited unvaccinated patients hospitalized with acute COVID-19 (n = 23), and compared them with matched outpatient controls without COVID-19 (n = 19) between May 2020 and May 2021. Only those without a past history of cardiac disease were recruited. We performed in-hospital CMR at a median of 3 days (IQR 1-7 days) after admission, and assessed cardiac function, edema and necrosis/fibrosis, using left and right ventricular ejection fraction (LVEF, RVEF), T1-mapping, T2 signal intensity ratio (T2SI), late gadolinium enhancement (LGE) and extracellular volume (ECV). Acute COVID-19 patients were invited for follow-up CMR and blood tests at 6 months. Results: The two cohorts were well matched in baseline clinical characteristics. Both had normal LVEF (62 ± 7 vs. 65 ± 6%), RVEF (60 ± 6 vs. 58 ± 6%), ECV (31 ± 3 vs. 31 ± 4%), and similar frequency of LGE abnormalities (16 vs. 14%; all p > 0.05). However, measures of acute myocardial edema (T1 and T2SI) were significantly higher in patients with acute COVID-19 when compared to controls (T1 = 1,217 ± 41 ms vs. 1,183 ± 22 ms; p = 0.002; T2SI = 1.48 ± 0.36 vs. 1.13 ± 0.09; p < 0.001). All COVID-19 patients who returned for follow up (n = 12) at 6 months had normal biventricular function, T1 and T2SI. Conclusion: Unvaccinated patients hospitalized for acute COVID-19 demonstrated CMR imaging evidence of acute myocardial edema, which normalized at 6 months, while biventricular function and scar burden were similar when compared to controls. Acute COVID-19 appears to induce acute myocardial edema in some patients, which resolves in convalescence, without significant impact on biventricular structure and function in the acute and short-term. Further studies with larger numbers are needed to confirm these findings.

Cardiovascular magnetic resonance for evaluation of cardiac involvement in COVID-19: recommendations by the Society for Cardiovascular Magnetic Resonance.

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic that has affected nearly 600 million people to date across the world. While COVID-19 is primarily a respiratory illness, cardiac injury is also known to occur. Cardiovascular magnetic resonance (CMR) imaging is uniquely capable of characterizing myocardial tissue properties in-vivo, enabling insights into the pattern and degree of cardiac injury. The reported prevalence of myocardial involvement identified by CMR in the context of COVID-19 infection among previously hospitalized patients ranges from 26 to 60%. Variations in the reported prevalence of myocardial involvement may result from differing patient populations (e.g. differences in severity of illness) and the varying intervals between acute infection and CMR evaluation. Standardized methodologies in image acquisition, analysis, interpretation, and reporting of CMR abnormalities across would likely improve concordance between studies. This consensus document by the Society for Cardiovascular Magnetic Resonance (SCMR) provides recommendations on CMR imaging and reporting metrics towards the goal of improved standardization and uniform data acquisition and analytic approaches when performing CMR in patients with COVID-19 infection.

Imaging Methods: Magnetic Resonance Imaging.

Myocardial inflammation occurs following activation of the cardiac immune system, producing characteristic changes in the myocardial tissue. Cardiovascular magnetic resonance is the non-invasive imaging gold standard for myocardial tissue characterization, and is able to detect image signal changes that may occur resulting from inflammation, including edema, hyperemia, capillary leak, necrosis, and fibrosis. Conventional cardiovascular magnetic resonance for the detection of myocardial inflammation and its sequela include T2-weighted imaging, parametric T1- and T2-mapping, and gadolinium-based contrast-enhanced imaging. Emerging techniques seek to image several parameters simultaneously for myocardial tissue characterization, and to depict subtle immune-mediated changes, such as immune cell activity in the myocardium and cardiac cell metabolism. This review article outlines the underlying principles of current and emerging cardiovascular magnetic resonance methods for imaging myocardial inflammation.

Incident Clinical and Mortality Associations of Myocardial Native T1 in the UK Biobank.

BACKGROUND: Cardiac magnetic resonance native T1-mapping provides noninvasive, quantitative, and contrast-free myocardial characterization. However, its predictive value in population cohorts has not been studied. OBJECTIVES: The associations of native T1 with incident events were evaluated in 42,308 UK Biobank participants over 3.17 ± 1.53 years of prospective follow-up. METHODS: Native T1-mapping was performed in 1 midventricular short-axis slice using the Shortened Modified Look-Locker Inversion recovery technique (WIP780B) in 1.5-T scanners (Siemens Healthcare). Global myocardial T1 was calculated using an automated tool. Associations of T1 with: 1) prevalent risk factors (eg, diabetes, hypertension, and high cholesterol); 2) prevalent and incident diseases (eg, any cardiovascular disease [CVD], any brain disease, valvular heart disease, heart failure, nonischemic cardiomyopathies, cardiac arrhythmias, atrial fibrillation [AF], myocardial infarction, ischemic heart disease [IHD], and stroke); and 3) mortality (eg, all-cause, CVD, and IHD) were examined. Results are reported as odds ratios (ORs) or HRs per SD increment of T1 value with 95% CIs and corrected P values, from logistic and Cox proportional hazards regression models. RESULTS: Higher myocardial T1 was associated with greater odds of a range of prevalent conditions (eg, any CVD, brain disease, heart failure, nonischemic cardiomyopathies, AF, stroke, and diabetes). The strongest relationships were with heart failure (OR: 1.41 [95% CI: 1.26-1.57]; P = 1.60 × 10-9) and nonischemic cardiomyopathies (OR: 1.40 [95% CI: 1.16-1.66]; P = 2.42 × 10-4). Native T1 was positively associated with incident AF (HR: 1.25 [95% CI: 1.10-1.43]; P = 9.19 × 10-4), incident heart failure (HR: 1.47 [95% CI: 1.31-1.65]; P = 4.79 × 10-11), all-cause mortality (HR: 1.24 [95% CI: 1.12-1.36]; P = 1.51 × 10-5), CVD mortality (HR: 1.40 [95% CI: 1.14-1.73]; P = 0.0014), and IHD mortality (HR: 1.36 [95% CI: 1.03-1.80]; P = 0.0310). CONCLUSIONS: This large population study demonstrates the utility of myocardial native T1-mapping for disease discrimination and outcome prediction.

Acute Response in the Noninfarcted Myocardium Predicts Long-Term Major Adverse Cardiac Events After STEMI.

BACKGROUND: Acute ST-segment elevation myocardial infarction (STEMI) has effects on the myocardium beyond the immediate infarcted territory. However, pathophysiologic changes in the noninfarcted myocardium and their prognostic implications remain unclear. OBJECTIVES: The purpose of this study was to evaluate the long-term prognostic value of acute changes in both infarcted and noninfarcted myocardium post-STEMI. METHODS: Patients with acute STEMI undergoing primary percutaneous coronary intervention underwent evaluation with blood biomarkers and cardiac magnetic resonance (CMR) at 2 days and 6 months, with long-term follow-up for major adverse cardiac events (MACE). A comprehensive CMR protocol included cine, T2-weighted, T2∗, T1-mapping, and late gadolinium enhancement (LGE) imaging. Areas without LGE were defined as noninfarcted myocardium. MACE was a composite of cardiac death, sustained ventricular arrhythmia, and new-onset heart failure. RESULTS: Twenty-two of 219 patients (10%) experienced an MACE at a median of 4 years (IQR: 2.5-6.0 years); 152 patients returned for the 6-month visit. High T1 (>1250 ms) in the noninfarcted myocardium was associated with lower left ventricular ejection fraction (LVEF) (51% ± 8% vs 55% ± 9%; P = 0.002) and higher NT-pro-BNP levels (290 pg/L [IQR: 103-523 pg/L] vs 170 pg/L [IQR: 61-312 pg/L]; P = 0.008) at 6 months and a 2.5-fold (IQR: 1.03-6.20) increased risk of MACE (2.53 [IQR: 1.03-6.22]), compared with patients with normal T1 in the noninfarcted myocardium (P = 0.042). A lower T1 (<1,300 ms) in the infarcted myocardium was associated with increased MACE (3.11 [IQR: 1.19-8.13]; P = 0.020). Both noninfarct and infarct T1 were independent predictors of MACE (both P = 0.001) and significantly improved risk prediction beyond LVEF, infarct size, and microvascular obstruction (C-statistic: 0.67 ± 0.07 vs 0.76 ± 0.06, net-reclassification index: 40% [IQR: 12%-64%]; P = 0.007). CONCLUSIONS: The acute responses post-STEMI in both infarcted and noninfarcted myocardium are independent incremental predictors of long-term MACE. These insights may provide new opportunities for treatment and risk stratification in STEMI.

Myocardial Involvement After Hospitalization for COVID-19 Complicated by Troponin Elevation: A Prospective, Multicenter, Observational Study.

BACKGROUND: Acute myocardial injury in hospitalized patients with coronavirus disease 2019 (COVID-19) has a poor prognosis. Its associations and pathogenesis are unclear. Our aim was to assess the presence, nature, and extent of myocardial damage in hospitalized patients with troponin elevation. METHODS: Across 25 hospitals in the United Kingdom, 342 patients with COVID-19 and an elevated troponin level (COVID+/troponin+) were enrolled between June 2020 and March 2021 and had a magnetic resonance imaging scan within 28 days of discharge. Two prospective control groups were recruited, comprising 64 patients with COVID-19 and normal troponin levels (COVID+/troponin-) and 113 patients without COVID-19 or elevated troponin level matched by age and cardiovascular comorbidities (COVID-/comorbidity+). Regression modeling was performed to identify predictors of major adverse cardiovascular events at 12 months. RESULTS: Of the 519 included patients, 356 (69%) were men, with a median (interquartile range) age of 61.0 years (53.8, 68.8). The frequency of any heart abnormality, defined as left or right ventricular impairment, scar, or pericardial disease, was 2-fold greater in cases (61% [207/342]) compared with controls (36% [COVID+/troponin-] versus 31% [COVID-/comorbidity+]; P<0.001 for both). More cases than controls had ventricular impairment (17.2% versus 3.1% and 7.1%) or scar (42% versus 7% and 23%; P<0.001 for both). The myocardial injury pattern was different, with cases more likely than controls to have infarction (13% versus 2% and 7%; P<0.01) or microinfarction (9% versus 0% and 1%; P<0.001), but there was no difference in nonischemic scar (13% versus 5% and 14%; P=0.10). Using the Lake Louise magnetic resonance imaging criteria, the prevalence of probable recent myocarditis was 6.7% (23/342) in cases compared with 1.7% (2/113) in controls without COVID-19 (P=0.045). During follow-up, 4 patients died and 34 experienced a subsequent major adverse cardiovascular event (10.2%), which was similar to controls (6.1%; P=0.70). Myocardial scar, but not previous COVID-19 infection or troponin, was an independent predictor of major adverse cardiovascular events (odds ratio, 2.25 [95% CI, 1.12-4.57]; P=0.02). CONCLUSIONS: Compared with contemporary controls, patients with COVID-19 and elevated cardiac troponin level have more ventricular impairment and myocardial scar in early convalescence. However, the proportion with myocarditis was low and scar pathogenesis was diverse, including a newly described pattern of microinfarction. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: 58667920.

Artificial Intelligence for Contrast-Free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-Based Virtual Native Enhancement.

BACKGROUND: Myocardial scars are assessed noninvasively using cardiovascular magnetic resonance late gadolinium enhancement (LGE) as an imaging gold standard. A contrast-free approach would provide many advantages, including a faster and cheaper scan without contrast-associated problems. METHODS: Virtual native enhancement (VNE) is a novel technology that can produce virtual LGE-like images without the need for contrast. VNE combines cine imaging and native T1 maps to produce LGE-like images using artificial intelligence. VNE was developed for patients with previous myocardial infarction from 4271 data sets (912 patients); each data set comprises slice position-matched cine, T1 maps, and LGE images. After quality control, 3002 data sets (775 patients) were used for development and 291 data sets (68 patients) for testing. The VNE generator was trained using generative adversarial networks, using 2 adversarial discriminators to improve the image quality. The left ventricle was contoured semiautomatically. Myocardial scar volume was quantified using the full width at half maximum method. Scar transmurality was measured using the centerline chord method and visualized on bull's-eye plots. Lesion quantification by VNE and LGE was compared using linear regression, Pearson correlation (R), and intraclass correlation coefficients. Proof-of-principle histopathologic comparison of VNE in a porcine model of myocardial infarction also was performed. RESULTS: VNE provided significantly better image quality than LGE on blinded analysis by 5 independent operators on 291 data sets (all P<0.001). VNE correlated strongly with LGE in quantifying scar size (R, 0.89; intraclass correlation coefficient, 0.94) and transmurality (R, 0.84; intraclass correlation coefficient, 0.90) in 66 patients (277 test data sets). Two cardiovascular magnetic resonance experts reviewed all test image slices and reported an overall accuracy of 84% for VNE in detecting scars when compared with LGE, with specificity of 100% and sensitivity of 77%. VNE also showed excellent visuospatial agreement with histopathology in 2 cases of a porcine model of myocardial infarction. CONCLUSIONS: VNE demonstrated high agreement with LGE cardiovascular magnetic resonance for myocardial scar assessment in patients with previous myocardial infarction in visuospatial distribution and lesion quantification with superior image quality. VNE is a potentially transformative artificial intelligence-based technology with promise in reducing scan times and costs, increasing clinical throughput, and improving the accessibility of cardiovascular magnetic resonance in the near future.

Neutrophils incite and macrophages avert electrical storm after myocardial infarction.

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2 -/- mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36 -/- and Mertk -/- mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

Neuropeptide-Y Levels in ST-Segment-Elevation Myocardial Infarction: Relationship With Coronary Microvascular Function, Heart Failure, and Mortality.

Background The sympathetic cotransmitter, neuropeptide Y (NPY), is released into the coronary sinus during ST-segment-elevation myocardial infarction and can constrict the coronary microvasculature. We sought to establish whether peripheral venous (PV) NPY levels, which are easy to obtain and measure, are associated with microvascular obstruction, myocardial recovery, and prognosis. Methods and Results NPY levels were measured immediately after primary percutaneous coronary intervention and compared with angiographic and cardiovascular magnetic resonance indexes of microvascular function. Patients were prospectively followed up for 6.4 (interquartile range, 4.1-8.0) years. PV (n=163) and coronary sinus (n=68) NPY levels were significantly correlated (r=0.92; P<0.001) and associated with multiple coronary and imaging parameters of microvascular function and infarct size (such as coronary flow reserve, acute myocardial edema, left ventricular ejection fraction, and late gadolinium enhancement 6 months later). We therefore assessed the prognostic value of PV NPY during follow-up, where 34 patients (20.7%) developed heart failure or died. Kaplan-Meier survival analysis demonstrated that high PV NPY levels (>21.4 pg/mL by binary recursive partitioning) were associated with increased incidence of heart failure and mortality (hazard ratio, 3.49 [95% CI, 1.65-7.4]; P<0.001). This relationship was maintained after adjustment for age, cardiovascular risk factors, and previous myocardial infarction. Conclusions Both PV and coronary sinus NPY levels correlate with microvascular function and infarct size after ST-segment-elevation myocardial infarction. PV NPY levels are associated with the subsequent development of heart failure or mortality and may therefore be a useful prognostic marker. Further research is required to validate these findings.