Presentations, Diagnosis, and Treatment of Post-COVID Viral Myocarditis in the Inpatient Setting: A Narrative Review.

While coronavirus disease 2019 (COVID-19) infection rates have declined, and mortality outcomes have improved with vaccines, targeted antiviral therapies, and improved care practices over the course of the pandemic, post-acute sequelae of SARS CoV-2 infection (PASC, also referred to as "long COVID") has emerged as a significant concern, even among individuals who appear to have fully recovered from their initial infection. Acute COVID-19 infection is associated with myocarditis and cardiomyopathies, but the prevalence and presentation of post-infectious myocarditis are unclear. We provide a narrative review of post-COVID myocarditis, including symptoms and signs, physical exam findings, diagnosis, and treatment strategies. Post-COVID myocarditis has a wide range of presentations, from very mild symptoms to severe ones that can include sudden cardiac death. Several studies have noted what appears to be a bimodal distribution of affected patients, with individuals under age 16 (particularly males) most affected, followed by those over age 50. The gold standard of diagnosis for myocarditis is endomyocardial biopsy and cardiac magnetic resonance imaging with a confirmed diagnosis of COVID-19. However, if these are not available, other studies such as electrocardiogram, echocardiography, and inflammatory markers can guide clinicians to diagnose post-COVID myocarditis when appropriate. Treatment is largely supportive and may include oxygen therapy, intravenous hydration, diuretics, steroids, and antivirals. Post-COVID myocarditis is rare but important to recognize as more patients present with this condition in the inpatient setting.

The Feasibility and Safety of Flecainide Use Among Patients With Varying Degrees of Coronary Disease.

BACKGROUND: Class IC antiarrhythmic agents are effective for treating atrial tachyarrhythmias, but their use is restricted in patients with coronary artery disease (CAD). Data on the safety of the use of IC agents in patients with CAD in the absence of recent acute coronary syndromes are lacking. OBJECTIVES: This study sought to evaluate the safety and feasibility of treatment with IC agents in patients with varying degrees of CAD in a large serial, real-world cohort. METHODS: We retrospectively identified all patients at our institution from January 2005 to February 2021 on a IC agent (n = 3,445) and those on sotalol or dofetilide (n = 2,216) as controls, excluding those with a prior history of ventricular tachycardia, implantable cardioverter-defibrillator placement, or nonrevascularized myocardial infarction. Baseline clinical characteristics included degree of CAD (categorized as none, nonobstructive, or obstructive), other comorbid illness, and medication use. Clinical outcomes, including survival, were ascertained. We performed Cox regression analysis to evaluate the effect of IC use on event-free survival across varying degrees of CAD. RESULTS: After adjustment for baseline characteristics, there was an independent association between IC use and improved mortality. However, there was an interaction between IC use and degree of CAD (compared to sotalol) demonstrating poorer event-free survival among those with obstructive coronary disease (HR: 3.80; 95% CI: 1.67-8.67; P = 0.002). CONCLUSIONS: Among select patients with nonobstructive CAD and without a history of ventricular tachycardia, IC agents are not associated with increased mortality. Therefore, these agents may be an option for some patients in whom they are frequently restricted. Further prospective studies are warranted.

Hydrogel delivery of purinergic enzymes improves cardiac ischemia/reperfusion injury.

RATIONALE: The innate immune response contributes to cardiac injury in myocardial ischemia/reperfusion (MI/R). Neutrophils are an important early part of the innate immune response to MI/R. Adenosine, an endogenous purine, is a known innate immune modulator and inhibitor of neutrophil activation. However, its delivery to the heart is limited by its short half-life (<30 s) and off-target side effects. CD39 and CD73 are anti-inflammatory homeostatic enzymes that can generate adenosine from phosphorylated adenosine substrate such as ATP released from injured tissue. OBJECTIVE: We hypothesize that hydrogel-delivered CD39 and CD73 target the local early innate immune response, reduce neutrophil activation, and preserve cardiac function in MI/R injury. METHODS AND RESULTS: We engineered a poly(ethylene) glycol (PEG) hydrogel loaded with the adenosine-generating enzymes CD39 and CD73. We incubated the hydrogels with neutrophils in vitro and showed a reduction in hydrogen peroxide production using Amplex Red. We demonstrated availability of substrate for the enzymes in the myocardium in MI/R by LC/MS, and tested release kinetics from the hydrogel. On echocardiography, global longitudinal strain (GLS) was preserved in MI/R hearts treated with the loaded hydrogel. Delivery of purinergic enzymes via this synthetic hydrogel resulted in lower innate immune infiltration into the myocardium post-MI/R, decreased markers of macrophage and neutrophil activation (NETosis), and decreased leukocyte-platelet complexes in circulation. CONCLUSIONS: In a rat model of MI/R injury, CD39 and CD73 delivered via a hydrogel preserve cardiac function by modulating the innate immune response.

A Hydrogel Strategy to Augment Tissue Adenosine to Improve Hindlimb Perfusion.

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Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.

Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

Strength-duration relationship as a tool to prioritize cardiac tissue properties that govern electrical excitability.

Engineered cardiac tissue and cardiomyocyte cell cultures offer wide opportunities for improved therapeutic intervention and laboratory heart models. Electrical field excitation is a common intervention in the production of engineered tissue and the investigation of the electrical properties of in vitro cell cultures. In this work, we use strength-duration relationships to investigate systematically factors influencing electrical excitability of two- (2D) and three-dimensional (3D) neonatal rat ventricular myocyte cultures. We find that the strength of the voltage pulse is negatively correlated with the threshold duration, as predicted by the Lapicque-Hill equation, and show that higher pacing frequencies require higher thresholds to capture paced cultures. We also study the impact of properties intrinsic to the 2D and 3D cultures on strength-duration relationships. We show that a smaller culture dimension, perpendicular anisotropic culture orientation with respect to electrical field, higher proportion of added fibroblasts, and TBX18-induced pacemaker reprogramming independently result in higher stimulation thresholds. These properties reflect the characteristics of the well-insulated endogenous pacemaking tissue in the heart (sinoatrial node) and should guide the engineering of biological pacemakers for improved outcomes. NEW & NOTEWORTHY Gaps exist in the availability of in vitro functional assessment tools that can emulate the integration of regenerative cells and tissues to the host myocardium. We use strength-duration relationships of electrically stimulated two- and three-dimensional myocardial constructs to study the effects of pacing frequency, culture dimensions, anisotropic cell alignment, fibroblast content, and pacemaker phenotype on electrical excitability. Our study delivers electrical strength-duration as a quantifiable parameter to evaluate design parameters of engineered cardiac tissue constructs.

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening.

Cells are complex systems with concurrent multi-physical responses, and cell physiological signals are often encoded with spatiotemporal dynamics and further coupled with multiple cellular activities. However, most existing electronic sensors are only single-modality and cannot capture multi-parametric cellular responses. In this paper, a 1024-pixel CMOS quad-modality cellular interfacing array that enables multi-parametric cell profiling for drug development is presented. The quad-modality CMOS array features cellular impedance characterization, optical detection, extracellular potential recording, and biphasic current stimulation. The fibroblast transparency and surface adhesion are jointly monitored by cellular impedance and optical sensing modalities for comprehensive cell growth evaluation. Simultaneous current stimulation and opto-mechanical monitoring based on cardiomyocytes are demonstrated without any stimulation/sensing dead-zone. Furthermore, drug dose-dependent multi-parametric feature extractions in cardiomyocytes from their extracellular potentials and opto-mechanical signals are presented. The CMOS array demonstrates great potential for fully automated drug screening and drug safety assessments, which may substantially reduce the drug screening time and cost in future new drug development.

Procedural outcomes and long-term survival following lead extraction in octogenarians.

BACKGROUND: Octogenarians account for a significant percentage of patients with indwelling pacemakers or defibrillators. OBJECTIVES: To determine procedural outcomes and long-term survival after lead extraction (LE) in octogenarians. METHODS: We retrospectively identified all patients who underwent defibrillator or pacemaker LE at our institution between January 1, 2007 and May 31, 2016. Patients were stratified based on age into two groups: <80 years old (Group 1, n = 674) or ≥80 (Group 2, n = 100). Outcomes were determined by medical records review and query of the Social Security Death Index. RESULTS: Patients in Group 2 were more likely to be hypertensive (77% vs 61%, P = 0.02), more like to have coronary artery disease (50% vs 39%, P = 0.049), and more likely to be extracted for infectious indications (47% vs 33%, P = .009). The number of leads extracted per procedure was 2.0 ± 0.8 and the mean dwell time of the oldest extracted lead was 5.6 ± 4.3 years, without significant differences between groups. Extraction procedure success (Group 1: 94.7%, Group 2: 96%, P = 0.808) and procedural deaths (Group 1: 0.9% vs Group 2: 0%, P = 1.0) were similar. There was no significant difference in survival up to 3 years following LE between groups. CONCLUSION: At experienced centers, LE can be performed safely in octogenarians with procedural success rates and long-term survival comparable to younger individuals.

Outcomes of lead extraction in young adults.

BACKGROUND: Extraction of pacemaker and defibrillator leads in young adults may be technically challenging because of more extensive fibrosis and calcification in this patient population. OBJECTIVE: The purpose of this study was to examine outcomes of lead extraction (LE) in young adults at our institution. METHODS: We retrospectively identified all patients who underwent LE at our institution between January 1, 2007, and May 31, 2016. Patients were divided by age into 2 groups: <40 years (group 1, n = 84) or ≥40 years (group 2, n = 690). Outcomes were determined by medical records review. RESULTS: Patients in group 2 had a higher overall average number of leads extracted per procedure compared to group 1 (1.64 ± 0.80 vs 1.45 ± 0.64; P <.001). Lead dwell time was similar in the 2 groups (5.7 ± 5 years vs 5.6 ± 4.3 years; P = .95). The younger cohort tended to require femoral extraction techniques more frequently (9.5% vs 4.4%; P = .055). Extraction procedural success (group 1: 94.1%, group 2: 94.9%; P = .792), major complications (group 1: 0%, group 2: 1.3%; P = 1), and periprocedural mortality (group 1: 0%, group 2: 0.86%; P = 1) were similar in the 2 groups. CONCLUSION: LE can be performed safely and effectively in young adults. Despite the lower number of leads extracted per procedure and the similar lead dwell time, younger adults more frequently required the use of femoral extraction tools, thus highlighting the importance of performing these procedures in centers with advanced expertise in extraction techniques.

Predictors and outcomes of lead extraction requiring a bailout femoral approach: Data from 2 high-volume centers.

BACKGROUND: Lead extraction (LE) infrequently requires the use of the "bailout" femoral approach. Predictors and outcomes of femoral extraction are not well characterized. OBJECTIVE: The aim of this study was to determine the predictors of need for femoral LE and its outcomes. METHODS: Consecutive patients who underwent LE at our centers were identified. Baseline demographic characteristics, procedural outcomes, and clinical outcomes were ascertained by medical record review. Patients were stratified into 2 groups on the basis of the need for femoral extraction. RESULTS: A total of 1080 patients underwent LE, of whom 50 (4.63%) required femoral extraction. Patients requiring femoral extraction were more likely to have leads with longer dwell time (9.5 ± 6.0 years vs 5.7 ± 4.3 years; P < .001), to have more leads extracted per procedure (2.0 ± 1.0 vs 1.7 ± 0.9; P = .003), and to have infection as an indication for extraction (72% vs 37.2%; P < .001). Procedural and clinical success was lower in the femoral extraction group than in the nonfemoral group (58% and 76% vs 94.7% and 97.9 %, respectively; P < .001). Major periprocedural complications (0% vs 1.3%; P = 1.0) and periprocedural mortality (0% vs 0.8%; P = 1.0) were similar between the 2 groups. CONCLUSION: In this study, femoral extraction was needed in ~5% of LEs. Longer lead dwell time, higher number of leads extracted per procedure, and the presence of infection predicted the need for femoral extraction. Procedural success of femoral extraction was low, highlighting the fact that this approach is mostly used as a bailout strategy and thus selects for more challenging cases.

Adaptive remodelling by FliN in the bacterial rotary motor.

Sensory adaptation in the Escherichia coli chemosensory pathway has been the subject of interest for decades, with investigation focusing on the receptors that process extracellular inputs. Recent studies demonstrate that the flagellar motors responsible for cell locomotion also play a role, adding or subtracting FliM subunits to maximise sensitivity to pathway signals. It is difficult to reconcile this FliM remodelling with the observation that partner FliN subunits are relatively static fixtures in the motor. By fusing a fluorescent protein internally to FliN, we show that there is in fact significant FliN remodelling. The kinetics and stoichiometry of FliN in steady state and in adapting motors are investigated and found to match the behaviour of FliM in all respects except for timescale where FliN rates are about 4 times slower. We notice that motor adaptation is slower in the presence of the fluorescent protein, indicating a possible source for the difference. The behaviour of FliM and FliN is consistent with a kinetic and stoichiometric model that contradicts the traditional view of a packed, rigid motor architecture.