Extracellular ATP inhibits excitatory synaptic input on parvalbumin positive interneurons and attenuates gamma oscillations via P2X4 receptors.

BACKGROUND AND PURPOSE: P2X4 receptors (P2X4R) are ligand gated cation channels that are activated by extracellular ATP released by neurons and glia. The receptors are widely expressed in the brain and have fractional calcium currents comparable with NMDA receptors. Although P2X4Rs have been reported to modulate synaptic transmission and plasticity, their involvement in shaping neuronal network activity remains to be elucidated. EXPERIMENTAL APPROACH: We investigated the effects of P2X receptors at network and synaptic level using local field potential electrophysiology, whole cell patch clamp recordings and calcium imaging in fast spiking parvalbumin positive interneurons (PVINs) in rat and mouse hippocampal slices. The stable ATP analogue ATPγS, selective antagonists and P2X4R knockout mice were used. KEY RESULTS: The P2XR agonist ATPγS reversibly decreased the power of gamma oscillations. This inhibition could be antagonized by the selective P2X4R antagonist PSB-12062 and was not observed in P2X4-/- mice. The phasic excitatory inputs of CA3 PVINs were one of the main regulators of the gamma power. Associational fibre compound excitatory postsynaptic currents (cEPSCs) in CA3 PVINs were inhibited by P2X4R activation. This effect was reversible, dependent on intracellular calcium and dynamin-dependent internalization of AMPA receptors. CONCLUSIONS AND IMPLICATIONS: The results indicate that P2X4Rs are an important source of dendritic calcium in CA3 PVINs, thereby regulating excitatory synaptic inputs onto the cells and presumably the state of gamma oscillations in the hippocampus. P2X4Rs represent an effective target to modulate hippocampal network activity in pathophysiological conditions such as Alzheimer's disease and schizophrenia.

Cardiac healthcare disparities and electrocardiography (ECG) differences in schizophrenia at end of life.

Schizophrenia is associated with early mortality of 15 to 20 years, and 80 % of deaths are due to cardiovascular disease with a three-times greater risk of sudden-cardiac-death. While lifestyle, medications, genetics, and healthcare disparities are contributing factors, the etiology of this complex process is not fully understood. The aim of this study is to examine cardiac-related healthcare utilization and electrocardiogram (ECG) outcomes in schizophrenia at the end of life (EOL). A cohort of individuals with schizophrenia (SG) (n = 610, ≥50 years) were identified retrospectively from a unified clinical data platform and measures of cardiovascular healthcare utilization were evaluated within a 12-month period prior to death. Similarly, a control group (n = 610) was randomly identified and matched by gender (53 % females) and age of death (72.8 ± 12.4 years). Statistical methods included Cochran-Mantel-Haenszel and mixed-effects logistic & linear regression tests with adjustments for match strata and marital status, race, age, and gender as covariates. Results indicate that SG was more likely to be unmarried, unemployed, or from minority groups (all p < 0.001), and more likely to have diabetes and/or cardiovascular disease (p < 0.001). SG was less likely to receive an ECG (p = 0.001) or cardiac catheterization procedure (p < 0.001). SG had a greater mean QTc (447.2 ms vs. 434.6 ms; p = 0.001) and were twice as likely to have "prolonged QT" on ECG report (p = 0.006). In conclusion, SG had reduced likelihood of cardiac-related healthcare interventions, and despite greater likelihood of prolonged QTc, a recognized biomarker of cardiac risk, ECG was less likely at EOL. Given greater cardiac comorbidity and risk of sudden cardiac death in schizophrenia, improved practice guidelines are needed.

Comparison of Prognostic Models for Functional Outcome in Aneurysmal Subarachnoid Hemorrhage Based on Machine Learning.

BACKGROUND: Controversy exists regarding the superiority of the performance of prognostic tools based on advanced machine learning (ML) algorithms for patients with aneurysmal subarachnoid hemorrhage (aSAH). However, it is unclear whether ML prognostic models will benefit patients due to the lack of a comprehensive assessment. We aimed to develop and evaluate ML models for predicting unfavorable functional outcomes for aSAH patients and identify the model with the greatest performance. METHODS: In this retrospective study, a dataset of 955 patients with aSAH was used to construct and validate prognostic models for functional outcomes assessed using the modified Rankin scale during a follow-up period of 3-6 months. Clinical scores and clinical and radiological features on admission and secondary complications were used to construct models based on 5 ML algorithms (i.e., logistic regression [LR], k-nearest neighbor, extreme gradient boosting, random forest, and artificial neural network). For evaluation among the models, the area under the receiver operating characteristic curve, area under the precision-recall curve, calibration curve, and decision curve analysis were used. RESULTS: Composite models had significantly higher area under the receiver operating characteristic curves than did simple models in predicting unfavorable functional outcomes. Compared with other composite models (random forest and extreme gradient boosting) with good calibration, LR had the highest area under the precision-recall score and showed the greatest benefit in decision curve analysis. CONCLUSIONS: Of the 5 studied ML models, the conventional LR model outperformed the advanced algorithms in predicting the prognosis and could be a useful tool for health care professionals.

"Quick flutter skip": midlife women's descriptions of palpitations.

OBJECTIVE: The objective of this study is to describe peri- and postmenopausal women's experiences of palpitations (quality, frequency, severity, distress, duration and temporal pattern, aura, associated symptoms, and aggravating/alleviating factors) and related healthcare experiences. METHODS: Qualitative descriptive methods were used. Semistructured interviews were conducted with women who reported palpitations and were enrolled in a larger case-control pilot study comparing electrocardiographic results between women with and without palpitations. Authors analyzed women's narratives using standard content analytic procedures. RESULTS: Fourteen participants (mean age, 54.5 y [SD = 4.8 y]; range, 46-62 y; 79% postmenopausal) completed interviews. The interviews revealed that women (a) often had difficulty describing their palpitations until prompted by the interviewer; (b) experienced noteworthy variations in the quality and other dimensions of their palpitations; (c) had a wide variety of healthcare experiences related to their palpitations, including not reporting their symptoms to providers, having providers dismiss their symptoms, and having providers be aware of their symptoms and provide diagnostic tests; and (d) at times, created worst case scenarios (downward shifts) under which they would seek treatment for their palpitations, thus enabling them to minimize their symptoms and avoid healthcare. CONCLUSION: This study advances understanding of how women describe their palpitations and related healthcare experiences. Findings could have implications for building research and clinical tools to guide assessment, communication, and/or education for patients and/or providers about palpitations and for developing and testing behavioral interventions to address this poorly understood symptom in peri- and postmenopausal women.

Piezo1 Mediates Vasodilation Induced by Acute Hyperglycemia in Mouse Renal Arteries and Microvessels.

BACKGROUND: Acute hyperglycemia is a risk factor for developing acute kidney injury and poor renal outcome in critically ill patients, whereby the role of renal vasculature remains unclear. We hypothesize that hyperglycemia-associated hyperosmolarity facilitates vasodilation through Piezo1-mediated eNOS (endothelial NO synthase) activation. METHODS: Vasoreactivity was analyzed using wire myography in isolated mouse mesenteric arteries and renal interlobar, and using microvascular perfusion in renal afferent arterioles and efferent arterioles, and vasa recta. Immunofluorescence and Western blot were used for molecular analyses of isolated mouse blood vessels and human umbilical vein endothelial cells. RESULTS: Pretreatment with hyperglycemia (44 mmol/L glucose; 4 hours) increased acetylcholine-induced relaxation in interlobar arteries and mesenteric arteries, which was prevented by eNOS inhibition using Nω-nitro-L-arginine methylester hydrochloride. Hyperosmotic mannitol solution had a similar effect. Hyperglycemia induced an immediate, Nω-nitro-L-arginine methylester hydrochloride-inhibitable dilation in afferent arterioles, efferent arterioles, and vasa recta, whereby stronger dilation in afferent arterioles compared to efferent arterioles. Hyperglycemia also increased glomerular filtration rate in mice. In human umbilical vein endothelial cells, hyperglycemia, and the Piezo1 activator Yoda-1 increased levels of Piezo1 protein, p-CaMKII (phosphorylated Ca2+/Calmodulin-dependent protein kinase type II), Akt (protein kinase B), and p-eNOS (phosphorylated eNOS). The hyperglycemia effect could be prevented by inhibiting Piezo1 using GsMTx4 (Grammostola spatulata mechanotoxin 4) and CaMKII using KN93 (N-[2-[[[3-(4-Chlorophenyl)-2-propenyl]-methylamino]-methyl]-phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide). Furthermore, in arteries and microvessels, inhibition of Piezo1 using GsMTx4 prevented the hyperglycemia -effect, while Yoda-1 caused relaxation and dilation, respectively. CONCLUSIONS: Results reveal that Piezo1 mediates renal vasodilation induced by hyperosmolarity in acute hyperglycemia. This mechanism may contribute to the pathogenesis of renal damage by acute hyperglycemia.

Metabolic implications of axonal demyelination and its consequences for synchronized network activity: An in silico and in vitro study.

Myelination enhances the conduction velocity of action potentials (AP) and increases energy efficiency. Thick myelin sheaths are typically found on large-distance axonal connections or in fast-spiking interneurons, which are critical for synchronizing neuronal networks during gamma-band oscillations. Loss of myelin sheath is associated with multiple alterations in axonal architecture leading to impaired AP propagation. While numerous studies are devoted to the effects of demyelination on conduction velocity, the metabolic effects and the consequences for network synchronization have not been investigated. Here we present a unifying computational model for electrophysiology and metabolism of the myelinated axon. The computational model suggested that demyelination not only decreases the AP speed but AP propagation in demyelinated axons requires compensatory processes like mitochondrial mass increase and a switch from saltatory to continuous propagation to rescue axon functionality at the cost of reduced AP propagation speed and increased energy expenditure. Indeed, these predictions were proven to be true in a culture model of demyelination where the pharmacologically-induced loss of myelin was associated with increased oxygen consumption rates, and a significant broadening of bandwidth as well as a decrease in the power of gamma oscillations.

Effect of modernized collaborative care for depression on depressive symptoms and cardiovascular disease risk biomarkers: eIMPACT randomized controlled trial.

Although depression is a risk and prognostic factor for cardiovascular disease (CVD), clinical trials treating depression in patients with CVD have not demonstrated cardiovascular benefits. We proposed a novel explanation for the null results for CVD-related outcomes: the late timing of depression treatment in the natural history of CVD. Our objective was to determine whether successful depression treatment before, versus after, clinical CVD onset reduces CVD risk in depression. We conducted a single-center, parallel-group, assessor-blinded randomized controlled trial. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). Outcomes were depressive symptoms and CVD risk biomarkers at 12 months. Intervention participants, versus usual care participants, exhibited moderate-to-large (Hedges' g = -0.65, p < 0.01) improvements in depressive symptoms. Clinical response data yielded similar results - 43% of intervention participants, versus 17% of usual care participants, had a ≥ 50% reduction in depressive symptoms (OR = 3.73, 95% CI: 1.93-7.21, p < 0.01). However, no treatment group differences were observed for the CVD risk biomarkers - i.e., brachial flow-mediated dilation, high-frequency heart rate variability, interleukin-6, high-sensitivity C-reactive protein, ß-thromboglobulin, and platelet factor 4 (Hedges' gs = -0.23 to 0.02, ps ≥ 0.09). Our modernized collaborative care intervention - which harnessed technology to maximize access and minimize resources - produced clinically meaningful improvements in depressive symptoms. However, successful depression treatment did not lower CVD risk biomarkers. Our findings indicate that depression treatment alone may not be sufficient to reduce the excess CVD risk of people with depression and that alternative approaches are needed. In addition, our effective intervention highlights the utility of eHealth interventions and centralized, remote treatment delivery in safety net clinical settings and could inform contemporary integrated care approaches. Trial Registration:ClinicalTrials.gov Identifier: NCT02458690.

Measures of social deprivation and outcomes after percutaneous coronary intervention.

BACKGROUND: Disparities in socioeconomic status are a frequently cited factor associated with worse cardiovascular outcomes. The social deprivation index (SDI) can be used to quantify socioeconomic resources at the population level. OBJECTIVES: The aim of this study was to assess the association of SDI with clinical outcomes following percutaneous coronary interventions (PCI). METHODS: This was a retrospective observational analysis of patients who underwent PCI and were included in a multicenter cardiac catheterization registry study. Baseline characteristics, congestive heart failure (CHF) readmission rates and survival were compared between patients with the highest and lower SDI. SDI was calculated based on the US community survey census tract-level data. RESULTS: Patients within the highest SDI quintile (n = 1843) had more comorbidities and a higher risk of death [hazard ratio (HR): 1.22 (95% confidence interval, CI: 1.1-1.39, p = 0.004); log rank: p = 0.009] and CHF readmission [HR: 1.56 (1.39-1.75, p < 0.001); log rank: p < 0.001) as compared with those in the lower quintiles (n = 10,201) during mean follow-up of 3 years. Increased risk of highest SDI for all-cause mortality and CHF remained significant after adjustment in multivariable analysis for factors associated with highest SDI. CONCLUSIONS: Patients within the highest SDI quintile had a greater proportion of comorbidities as well as higher risk for adverse outcomes as compared with patients with a lower SDI following PCI.

Deep Isoflurane Anesthesia Is Associated with Alterations in Ion Homeostasis and Specific Na+/K+-ATPase Impairment in the Rat Brain.

BACKGROUND: Maintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase. METHODS: Using ion-selective microelectrodes, this study assessed isoflurane-induced extracellular ion dynamics in cortical slices of male and female Wistar rats in the absence of synaptic activity, in the presence of two-pore-domain potassium channel antagonists, during seizures, and during spreading depolarizations. The specific isoflurane effects on Na+/K+-ATPase function were measured using a coupled enzyme assay and studied the relevance of the findings in vivo and in silico. RESULTS: Isoflurane concentrations clinically relevant for burst suppression anesthesia increased baseline extracellular potassium (mean ± SD, 3.0 ± 0.0 vs. 3.9 ± 0.5 mM; P < 0.001; n = 39) and lowered extracellular sodium (153.4 ± 0.8 vs. 145.2 ± 6.0 mM; P < 0.001; n = 28). Similar changes in extracellular potassium and extracellular sodium and a substantial drop in extracellular calcium (1.5 ± 0.0 vs. 1.2 ± 0.1 mM; P = 0.001; n = 16) during inhibition of synaptic activity and two-pore-domain potassium suggested a different underlying mechanism. After seizure-like events and spreading depolarization, isoflurane greatly slowed extracellular potassium clearance (63.4 ± 18.2 vs. 196.2 ± 82.4 s; P < 0.001; n = 14). Na+/K+-ATPase activity was markedly reduced after isoflurane exposure (greater than 25%), affecting specifically the α2/3 activity fraction. In vivo, isoflurane-induced burst suppression resulted in impaired extracellular potassium clearance and interstitial potassium accumulation. A computational biophysical model reproduced the observed effects on extracellular potassium and displayed intensified bursting when Na+/K+-ATPase activity was reduced by 35%. Finally, Na+/K+-ATPase inhibition with ouabain induced burst-like activity during light anesthesia in vivo. CONCLUSIONS: The results demonstrate cortical ion homeostasis perturbation and specific Na+/K+-ATPase impairment during deep isoflurane anesthesia. Slowed potassium clearance and extracellular accumulation might modulate cortical excitability during burst suppression generation, while prolonged Na+/K+-ATPase impairment could contribute to neuronal dysfunction after deep anesthesia.

Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose.

INTRODUCTION: Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine's activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45 mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine's effect on the QT interval and investigated its cardiac safety profile. METHODS: C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD). RESULTS: A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90% confidence interval (CI), 0.0109-0.0127). At the therapeutic dose of 45 mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6 ms (upper bound 90% CI, 8.0 ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45 mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500 ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. CONCLUSIONS: At the 45 mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant. TRIAL REGISTRATION: PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22.

Determinants of Early and Late In-Hospital Mortality After Acute Myocardial Infarction: A Subanalysis of the OBTAIN Registry.

BACKGROUND: Predictors of in-hospital mortality after myocardial infarction (MI) have been reported dichotomously: survival vs death. Predictors of time from admission to death have not been reported. METHODS: A total of 7335 patients were enrolled in a prospective multicentre registry of acute MI. In-hospital mortality was classified by time from admission as acute (≤ 2 days), subacute (3 to 7 days), late (8 to 14 days), and very late (≥ 15 days) to identify factors associated with time to death in patients who died before discharge. Patient and MI characteristics, in-hospital interventions, and electrocardiographic findings were screened for differences in time to in-hospital death. RESULTS: In-hospital death affected 351 patients (4.8%). Mean age was 72.0 ± 12.4 years, and 40.5% were female patients. Median survival was 5 days (interquartile range: 2-12), and 41% of in-hospital deaths occurred after 1 week. Cardiac biomarkers and ejection fraction were not related to time to in-hospital death. Previous MI, systolic blood pressure, pharmacologic therapy, and interventional treatments were different among the 4 groups. The factors associated with late in-hospital death were coronary artery bypass graft surgery (CABG), new-onset atrial fibrillation or flutter, heart failure or pulmonary edema, bleeding, and lung disease. Acute and subacute in-hospital death was associated with ST-elevation MI, lower systolic blood pressure, and cardiac arrest on admission. CABG was performed in 12% of post-MI patients who died in hospital. CONCLUSIONS: Clinical risk factors for in-hospital mortality evolve over time immediately after acute MI. Understanding the time-dependent risk factors may allow for the development of new approaches to curtail the "later" in-hospital mortality.

Social deprivation index and ischemic events after percutaneous coronary intervention in patients with diabetes mellitus.

The aim of this study was to assess neighborhood-based differences in outcomes of diabetics versus non-diabetics undergoing percutaneous coronary interventions. Disparities in healthcare access impact long-term outcomes in safety net populations. Diabetes mellitus (DM) is associated with worse clinical outcomes in patients with coronary artery disease (CAD) and may disproportionately impact patients with CAD from underserved populations. We created a geocoded retrospective cohort of patients who underwent percutaneous coronary intervention (PCI) at an urban safety net hospital in this single-center cohort analysis. We evaluated long-term ischemic events in diabetics versus nondiabetics through review of electronic medical records. Social deprivation index (SDI) was calculated based on US-census tract level and stratified according to quintiles. Among 1002 patients, 46% (n = 463) were diabetic and among those 48% (n = 222) were in the highest quintile of SDI. Baseline and angiographic characteristics were similar among diabetic and nondiabetic subjects. Among diabetic patients, those in the highest SDI quintile had significantly higher risk of cardiovascular death and myocardial infarction as compared to those in the remaining quintiles (log rank: p = 0.029) (adjusted hazard's ratio: 1.72 [95% CI: 1.01-2.92], p = 0.04). There was no association of the SDI with outcomes in nondiabetic patients (log rank: p = 0.39). In an underserved population, patients with diabetes and high SDI demonstrate higher rates of adverse ischemic events and cardiovascular death during long-term follow up after PCI. Further research examining the impact of disparities in healthcare access on outcomes after PCI in patients with diabetes is warranted.

Athlete ECG T-wave abnormality interpretation patterns by non-experts.

Background: The presence of T-wave abnormalities (TWA) on an athlete's electrocardiogram (ECG) presents as a diagnostic challenge for physicians. Types of TWA patterns classified as abnormal by inexperienced readers have not been systematically analyzed. Methods: ECGs from the 2011-2015 National Football League Scouting Combine (initially interpreted by general cardiologists) were retrospectively reviewed by expert sports cardiologists with strict application of the 2017 International Criteria. Patterns of TWA that were altered from the original interpretation were analyzed. Results: The study included 1643 athletes (mean age 22 years). There was a 67 % reduction in the number of athletes with any TWA (p < 0.001) with 111 ECGs changed to normal. Inferior TWA was the most common interpreted initial ECG abnormality altered followed by anterior and lateral. Discussion: This analysis revealed an initial high rate of TWA by non-expert readers. Tailored education programs to physicians who interpret athlete ECGs should highlight these specific T-wave patterns. We see this as an opportunity to make more clinicians aware of ECG interpretation guidelines as sports trained cardiologists are mostly self-taught.

American College of Rheumatology White Paper on Antimalarial Cardiac Toxicity.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well-established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)-prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID-19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus-based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long-term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk-benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases.

Right Ventricular Infarction Presenting With Refractory Hypoxia Due to Shunting Across a Patent Foramen Ovale.

Right ventricular infarction is often associated with significant morbidity and mortality. Here, we report a case of right ventricular infarction associated with persistent hypoxia due to acute right-to-left shunting through a patent foramen ovale. (Level of Difficulty: Intermediate.).

Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry.

Importance: Myocarditis is a leading cause of sudden death in competitive athletes. Myocardial inflammation is known to occur with SARS-CoV-2. Different screening approaches for detection of myocarditis have been reported. The Big Ten Conference requires comprehensive cardiac testing including cardiac magnetic resonance (CMR) imaging for all athletes with COVID-19, allowing comparison of screening approaches. Objective: To determine the prevalence of myocarditis in athletes with COVID-19 and compare screening strategies for safe return to play. Design, Setting, and Participants: Big Ten COVID-19 Cardiac Registry principal investigators were surveyed for aggregate observational data from March 1, 2020, through December 15, 2020, on athletes with COVID-19. For athletes with myocarditis, presence of cardiac symptoms and details of cardiac testing were recorded. Myocarditis was categorized as clinical or subclinical based on the presence of cardiac symptoms and CMR findings. Subclinical myocarditis classified as probable or possible myocarditis based on other testing abnormalities. Myocarditis prevalence across universities was determined. The utility of different screening strategies was evaluated. Exposures: SARS-CoV-2 by polymerase chain reaction testing. Main Outcome and Measure: Myocarditis via cardiovascular diagnostic testing. Results: Representing 13 universities, cardiovascular testing was performed in 1597 athletes (964 men [60.4%]). Thirty-seven (including 27 men) were diagnosed with COVID-19 myocarditis (overall 2.3%; range per program, 0%-7.6%); 9 had clinical myocarditis and 28 had subclinical myocarditis. If cardiac testing was based on cardiac symptoms alone, only 5 athletes would have been detected (detected prevalence, 0.31%). Cardiac magnetic resonance imaging for all athletes yielded a 7.4-fold increase in detection of myocarditis (clinical and subclinical). Follow-up CMR imaging performed in 27 (73.0%) demonstrated resolution of T2 elevation in all (100%) and late gadolinium enhancement in 11 (40.7%). Conclusions and Relevance: In this cohort study of 1597 US competitive athletes with CMR screening after COVID-19 infection, 37 athletes (2.3%) were diagnosed with clinical and subclinical myocarditis. Variability was observed in prevalence across universities, and testing protocols were closely tied to the detection of myocarditis. Variable ascertainment and unknown implications of CMR findings underscore the need for standardized timing and interpretation of cardiac testing. These unique CMR imaging data provide a more complete understanding of the prevalence of clinical and subclinical myocarditis in college athletes after COVID-19 infection. The role of CMR in routine screening for athletes safe return to play should be explored further.

Calcium/Calmodulin-Dependent Protein Kinase II Delta Inhibition and Ventricular Remodeling After Myocardial Infarction: A Randomized Clinical Trial.

Importance: After anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling. Objective: To determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018. Interventions: Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo. Main Outcomes and Measures: The primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed. Results: A total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P = .03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P = .78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period. Conclusions and Relevance: Three months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02557217.