Acute Cardiac Injury Research Articles

The impact of COVID-19 status and vaccine type following the first dose on acute heart disease: A nationwide retrospective cohort study in South Korea.

Recent studies have suggested an increased incidence of myocarditis and pericarditis following mRNA vaccination or COVID-19. However, the potential interaction effect between vaccine type and COVID-19 on heart disease risk remains uncertain. Our study aimed to examine the impact of COVID-19 status and vaccine type following the first dose on acute heart disease in the Korean population, using data from the National Health Insurance Service COVID-19 database (October 2018-March 2022). We sought to provide insights for public health policies and clinical decisions pertaining to COVID-19 vaccination strategies. We analysed heart disease risk, including acute cardiac injury, acute myocarditis, acute pericarditis, cardiac arrest, and cardiac arrhythmia, in relation to vaccine type and COVID-19 within 21days after the first vaccination date, employing Cox proportional hazards models with time-varying covariates. This study included 3,350,855 participants. The results revealed higher heart disease risk in individuals receiving mRNA vaccines than other types (adjusted HR, 1.48; 95% CI, 1.35-1.62). Individuals infected by SARS-CoV-2 also exhibited significantly higher heart disease risk than those uninfected (adjusted HR, 3.56; 95% CI, 1.15-11.04). We found no significant interaction effect between vaccine type and COVID-19 status on the risk of acute heart disease. Notably, however, younger individuals who received mRNA vaccines had a higher heart disease risk compared to older individuals. These results may suggest the need to consider alternative vaccine options for the younger population. Further research is needed to understand underlying mechanisms and guide vaccination strategies effectively.

Small-molecule mediated MuRF1 inhibition protects from doxorubicin-induced cardiac atrophy and contractile dysfunction

Cancer chemotherapy induces cell stress in rapidly dividing cancer cells to trigger their growth arrest and apoptosis. However, adverse effects related to cardiotoxicity underpinned by a limited regenerative potential of the heart limits clinical application: In particular, chemotherapy with doxorubicin (DOXO) causes acute heart injury that can transition to persisting cardiomyopathy (DOXO-CM). Here, we tested if MuRF1 inhibition (“MuRFi”) was able to attenuate DOXO-CM. To mimic DOXO chemotherapy, we treated mice over four weeks with five DOXO injections, resulting in a cumulative dosage of 25 mg/kg. At day 28, mice had lower body and heart weights, reduced cardiac cross-sectional myofibrillar areas (CSAs), and disturbed functional ejection fractions (EFs) and fractional shortenings (FS) as indicated by echocardiography (ECHO). In contrast, mice with a 1 g/kg Myomed#205 spiked diet, a previously described experimental MuRFi therapy, showed lower DOXO-CM at day 28, and also reduced acute DOXO cardiac injury at day 7 (single DOXO dose; 15 mg/kg). Underlying molecular signatures using Western blot (WB) assays showed at day 28 reduced phospho-AKT (AKTp) and phospo-4EBP1 (4 EBP1p) levels following DOXO that were normalized following MuRFi treatment. Taken together, our data suggest that MuRFi treatment is suitable to attenuate DOXO-CM by preserving AKTp and 4 EBP1p levels in DOXO stressed cardiomyocytes, thereby supporting de novo protein translation and cardiomyocyte survival under translational arrest stress.

Ccn2 Deletion Reduces Cardiac Dysfunction, Oxidative Markers, and Fibrosis Induced by Doxorubicin Administration in Mice.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.

Multi-Shell Nanourchin-Integrated Dual Mode Lateral Flow Immunoassay for Sensitive and Rapid Detection of Clinical Cardiac Myosin-Binding Protein C.

Cardiac myosin-binding protein C (cMyBP-C) is a novel cardiac marker of acute myocardial infarction (AMI) and acute cardiac injuries (ACI). Construction of point-of-care testing techniques capable of sensing cMyBP-C with high sensitivity and precision is urgently needed. Herein, we synthesized an Au@NGQDs@Au/Ag multi-shell nanoUrchins (MSNUs), and then applied it in a colorimetric/SERS dual-mode immunoassay for detection of cMyBP-C. The MSNUs displayed superior stability, colorimetric brightness, and SERS enhancement ability with an enhanced factor of 5.4 × 109, which were beneficial to improve the detection capability of test strips. The developed MSNU-based test strips can achieve an ultrasensitive immunochromatographic assay of cMyBP-C in both colorimetric and SERS modes with the limits of detection as low as 19.3 and 0.77 pg/mL, respectively. Strikingly, this strip was successfully applied to analyze actual plasma samples with significantly better sensitivity, negative predictive value, and accuracy than commercially available gold test strips. Notably, this method possessed a wide range of application scenarios via combining with a color recognizer application named Color Grab on the smartphone, which can meet various needs of different users. Overall, our MSNU-based test strip as a mobile health monitoring tool shows excellent sensitivity, reproducibility, and rapid detection of the cMyBP-C, which holds great potential for the early clinic diagnosis of AMI and ACI.

Prophylactic supplementation with Bifidobacterium infantis or its metabolite inosine attenuates cardiac ischemia/reperfusion injury.

Emerging evidence has demonstrated the profound impact of the gut microbiome on cardiovascular diseases through the production of diverse metabolites. Using an animal model of myocardial ischemia-reperfusion (I/R) injury, we found that the prophylactic administration of a well-known probiotic, Bifidobacterium infantis (B. infantis), exhibited cardioprotective effects in terms of preserving cardiac contractile function and preventing adverse cardiac remodeling following I/Rand that these cardioprotective effects were recapitulated by its metabolite inosine. Transcriptomic analysis further revealed that inosine mitigated I/R-induced cardiac inflammation and cell death. Mechanistic investigations elucidated that inosine suppressed the production of pro-inflammatory cytokines and reduced the numbers of dendritic cellsand natural killercells, achieved through the activation of the adenosine A2A receptor (A2AR) that when inhibited abrogated the cardioprotective effects of inosine. Additionally, in vitro studies using C2C12 myoblasts revealed that inosine attenuated cell death by serving as an alternative carbon source for adenosine triphosphate (ATP) generation through the purine salvage pathway when subjected to oxygen-glucose deprivation/reoxygenationthat simulated myocardial I/R injury. Likewise, inosine reversed the I/R-induced decrease in ATP levels in mouse hearts. Taken together, our findings indicate that B. infantis or its metabolite inosine exerts cardioprotective effects against I/R by suppressing cardiac inflammation and attenuating cardiac cell death, suggesting prophylactic therapeutic options for acute ischemic cardiac injury.

Complications Linked to Acute COVID-19 Phase during its Second Wave Era

Numerous global studies have documented the multi-systemic complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there is a scarcity of research exploring SARS-CoV-2-related complications in Libya, specifically in Zawia city. Therefore, this study aimed to screen and identify complications of acute COVID-19 in 176 SARS-CoV-2 infected patients in Zawia city, Libya. As part of a past retrospective cohort study, 176 randomly selected volunteers who tested positive for SARS-CoV-2 between December 1, 2020, and February 28, 2021, in Zawia city participated in this research. Participants completed a questionnaire designed for COVID-19 patients, and the collected data were analyzed to achieve the objectives of this study. In the current study, we found that 73.9% of the COVID-19 patients were mild to moderate cases, while 26.1% were severe cases. Moreover, our recent research revealed that 90.9% of the COVID-19 patients experienced complications during the acute phase of the disease. The reported complications during this phase included psychological disorders (90%), pneumonia (35.6%), brain fog (19.4%), multi-joint pain (18.8%), hearing deficit (8.1%), acute respiratory failure (5.6%), acute cardiac injury (3.8%), thrombotic lesions (1.9%), and vision impairment (1.9%). Overall, our findings indicate that most of COVID-19 participants had mild to moderate disease, with approximately one quarter experiencing severe illness. Furthermore, the vast majority of patients had complications during the acute COVID-19 phase, with psychological disorders being the most commonly reported, followed by pneumonia. While rare, fatal complications such as acute respiratory failure, acute cardiac injury, and thrombotic lesions were observed in some participants.

Acute Myocardial Infarction in COVID-19 Patients-A Review of Literature Data and Two-Case Report Series.

Background/Objectives: The newly emergent COVID-19 pandemic involved primarily the respiratory system and had also major cardiovascular system (CVS) implications, revealed by acute myocardial infarction (AMI), arrhythmias, myocardial injury, and thromboembolism. CVS involvement is done through main mechanisms-direct and indirect heart muscle injury, with high mortality rates, worse short-term outcomes, and severe complications. AMI is the echo of myocardial injury (revealed by increases in CK, CK-MB, and troponin serum markers-which are taken into consideration as possible COVID-19 risk stratification markers). When studying myocardial injury, physicians can make use of imaging studies, such as cardiac MRI, transthoracic (or transesophageal) echocardiography, coronary angiography, cardiac computed tomography, and nuclear imaging (which have been used in cases where angiography was not possible), or even endomyocardial biopsy (which is not always available or feasible). Two-case-series presentations: We present the cases of two COVID-19 positive male patients who were admitted into the Clinical Department of Cardiology in "Sfântul Apostol Andrei" Emergency Clinical Hospital of Galați (Romania), who presented with acute cardiac distress symptoms and have been diagnosed with ST elevation AMI. The patients were 82 and 57 years old, respectively, with moderate and severe forms of COVID-19, and were diagnosed with anteroseptal left ventricular AMI and extensive anterior transmural left ventricular AMI (with ventricular fibrillation at presentation), respectively. The first patient was a non-smoker and non-drinker with no associated comorbidities, and was later discharged, while the second one died due to AMI complications. Conclusions: From this two-case series, we extract the following: old age alone is not a significant risk factor for adverse outcomes in COVID-19-related CVS events, and that the cumulative effects of several patient-associated risk factors (be it either for severe forms of COVID-19 and/or acute cardiac injury) will most probably lead to poor patient prognosis (death). At the same time, serum cardiac enzymes, dynamic ECG changes, along with newly developed echocardiographic modifications are indicators for poor prognosis in acute cardiac injury in COVID-19 patients with acute myocardial injury, regardless of the presence of right ventricular dysfunction (due to pulmonary hypertension).

Comparison between acute and chronic refractory cardiogenic shock: is prognosis different?

Abstract Funding Acknowledgements None. Background Short-term mechanical circulatory support (ST-MCS) is essential to reverse refractory cardiogenic shock (RCS). Since compensatory mechanisms are differently activated depending on whether the cause of CS is acute injury or decompensation of advanced chronic heart failure, hypothetically, the prognosis could also be different. Purposes The aim of our study was to compare the prognosis of patients with RCS supported with ST-MCS (venoarterial-extracorporeal membrane oxygenation (VA-ECMO), Centrimag, Impella CP and Impella 5.0) according to whether the cause of cardiogenic shock was an acute myocardial injury (acute myocardial infarction, myocarditis...) or a worsening of advanced cardiomyopathy. Methods Consecutive patients ≥ 18 years with RCS requiring ST-MCS at a tertiary center from January 2020 to August 2023 were prospectively included. They were stratified according to whether the cause of shock was acute or chronic. Demographic, clinical characteristics before insertion, and outcomes were included in the analysis. Results A total of 86 patients with RCS were supported with ST-MCS in that period, 55 of them (64%) for acute injury and the rest (n=31; 36%) as decompensation of chronic heart failure, with a significantly higher Charlson Comorbidity Index in the chronic group (2(0-3) vs 3(2-4); p=0.01). Acute shock was predominantly supported with VA-ECMO (49.1%) and Impella CP (41.8%), while Impella 5.0 was the most commonly used device in chronic patients (32.2%). The severity of CS was significantly higher in the acute shock group, assessed by SCAI (p=0.005), VIS Score (55.1 (26.19-90.5) vs 8 (3.1-30); p=0.005) and lactate level (5.3 (3-10.3) vs 1.2 (1-2.2) mmol/l; p<0.005) and a higher but non-significant SOFA score (8 (6-10) vs 6 (4-9); p=0,06). However, no differences were found in prognosis, both in-hospital mortality, mortality during support and 30-day and 1-year mortality (Figure 1). Most patients with chronic shock were referred to cardiac transplantation (54.8%) while most patients with acute shock were weaned by myocardial recovery(30.9%), but there were no differences in the final destination of these patients (p=0.089). There were no differences in systemic and local complications between the three groups, except for the rate of device-related ischemia (21.8% vs. 6.4%, p=0.015). Conclusions In our center, most patients in CS who required short-term mechanical circulatory support debut after an acute cardiac injury. Percutaneous ST-MCS is preferentially selected in the acute group, probably because of its easy accessibility in emergency situations. Although patients with acute CS present a more severe overall situation than patients worsening due to advanced heart failure, there were no differences in the short- and long-term prognosis or in the destination treatment of these patients.Table of resultsFigure 1.Mortality in RCS

Risk factors and early prediction of cardiorenal syndrome type 3 among acute kidney injury patients: a cohort study

Background Type 3 cardiorenal syndrome (CRS type 3) triggers acute cardiac injury from acute kidney injury (AKI), raising mortality in AKI patients. We aimed to identify risk factors for CRS type 3 and develop a predictive nomogram. Methods In this retrospective study, 805 AKI patients admitted at the Department of Nephrology, Second Hospital of Shanxi Medical University from 1 January 2017, to 31 December 2021, were categorized into a study cohort (406 patients from 2017.1.1-2021.6.30, with 63 CRS type 3 cases) and a validation cohort (126 patients from 1 July 2021 to 31 Dec 2021, with 22 CRS type 3 cases). Risk factors for CRS type 3, identified by logistic regression, informed the construction of a predictive nomogram. Its performance and accuracy were evaluated by the area under the curve (AUC), calibration curve and decision curve analysis, with further validation through a validation cohort. Results The nomogram included 6 risk factors: age (OR = 1.03; 95%CI = 1.009–1.052; p = 0.006), cardiovascular disease (CVD) history (OR = 2.802; 95%CI = 1.193–6.582; p = 0.018), mean artery pressure (MAP) (OR = 1.033; 95%CI = 1.012–1.054; p = 0.002), hemoglobin (OR = 0.973; 95%CI = 0.96-–0.987; p < 0.001), homocysteine (OR = 1.05; 95%CI = 1.03–1.069; p < 0.001), AKI stage [(stage 1: reference), (stage 2: OR = 5.427; 95%CI = 1.781–16.534; p = 0.003), (stage 3: OR = 5.554; 95%CI = 2.234–13.805; p < 0.001)]. The nomogram exhibited excellent predictive performance with an AUC of 0.907 in the study cohort and 0.892 in the validation cohort. Calibration and decision curve analyses upheld its accuracy and clinical utility. Conclusions We developed a nomogram predicting CRS type 3 in AKI patients, incorporating 6 risk factors: age, CVD history, MAP, hemoglobin, homocysteine, and AKI stage, enhancing early risk identification and patient management.

Elevated Troponins after COVID-19 Hospitalization and Long-Term COVID-19 Symptoms: Incidence, Prognosis, and Clinical Outcomes-Results from a Multi-Center International Prospective Registry (HOPE-2).

Background: Acute cardiac injury (ACI) after COVID-19 has been linked with unfavorable clinical outcomes, but data on the clinical impact of elevated cardiac troponin on discharge during follow-up are scarce. Our objective is to elucidate the clinical outcome of patients with elevated troponin on discharge after surviving a COVID-19 hospitalization. Methods: We conducted an analysis in the prospective registry HOPE-2 (NCT04778020). Only patients discharged alive were selected for analysis, and all-cause death on follow-up was considered as the primary endpoint. As a secondary endpoint, we established any long-term COVID-19 symptoms. HOPE-2 stopped enrolling patients on 31 December 2021, with 9299 patients hospitalized with COVID-19, of which 1805 were deceased during the acute phase. Finally, 2382 patients alive on discharge underwent propensity score matching by relevant baseline variables in a 1:3 fashion, from 56 centers in 8 countries. Results: Patients with elevated troponin experienced significantly higher all-cause death during follow-up (log-rank = 27.23, p < 0.001), and had a higher chance of experiencing long-term COVID-19 cardiovascular symptoms. Specifically, fatigue and dyspnea (57.7% and 62.8%, with p-values of 0.009 and <0.001, respectively) are among the most common. Conclusions: After surviving the acute phase, patients with elevated troponin on discharge present increased mortality and long-term COVID-19 symptoms over time, which is clinically relevant in follow-up visits.

Isthmin-1 alleviates cardiac ischaemia/reperfusion injury through cGMP-PKG signalling pathway.

Ischaemia/reperfusion (I/R) injury is an important complication of reperfusion therapy for acute myocardial infarction, extremely compromising the cardiac benefits of revascularization; however, specific and efficient treatment for cardiac I/R injury is still lacking. Isthmin-1 (ISM1) is a novel adipokine and plays indispensable roles in regulating glycolipid metabolism and cell survival. The present study aims to investigate the potential role and molecular mechanism of ISM1 in cardiac I/R injury using gain- and loss-of-function approaches. Cardiac-specific ISM1 overexpression and silence were achieved using an adeno-associated virus serotype 9 system, and then these mice were subjected to I/R surgery, followed by biochemical test, echocardiography and histopathologic examinations, etc. Meanwhile, neonatal rat cardiomyocytes (NRCMs) with ISM1 silence or overexpression also received simulated I/R (sI/R) injury to further verify its role in vitro. The potential downstream pathways and molecular targets of ISM1 were screened by RNA sequencing. We also treated injured mice and NRCMs with recombinant ISM1 (rISM1) to explore whether supplementation with ISM1 was sufficient to protect against I/R injury. Furthermore, acute myocardial infarction patients with percutaneous coronary intervention (PCI) and paired healthy controls were included to reveal the clinical relevance of circulating ISM1. Cardiac-specific ISM1 silencing aggravated while ISM1 overexpression alleviated I/R-induced acute cardiac injury and cardiac remodelling and dysfunction. Mechanistically, ISM1 targeted αvβ5 integrin to facilitate the nuclear accumulation of nuclear transcription factor Y subunit alpha, transcriptionally increased soluble guanylyl cyclase beta subunit expression, and eventually enhanced cGMP generation. Besides, we confirmed that treatment with rISM1 before or after reperfusion could confer cardioprotective effects in mice. Clinically, lower ISM1 levels post-PCI was associated with worse outcome in patients. ISM1 can protect against cardiac I/R injury through cGMP-PKG signalling pathway, and it is a promising therapeutic and predictive target of cardiac I/R injury.

Factors Associated with Mortality Among Severe Omicron Patients for COVID-19.

The purpose of the study was to explore the potential risk factors of mortality in patients with severe pneumonia during the omicron pandemic in South China in 2022. Clinical data was collected from patients hospitalized with omicron COVID-19. Then, patients were categorized into the non-survival and survival groups. A comprehensive analysis was conducted to analyze the factors associated with negative outcome in individuals suffering from severe omicron COVID-19. In this study, 155 severe COVID-19 patients were included, comprising 55 non-survivors and 100 survivors. Non-survivors, in comparison to survivors, exhibited elevated levels of various biomarkers including neutrophil count, hypersensitive troponin T, urea, creatinine, C-reactive protein, procalcitonin, interleukin-6, plasma D-dimer, and derived neutrophil-to-lymphocyte ratio (dNLR) (P < 0.05). They also displayed reduced lymphocyte count, platelet count, and albumin levels (P < 0.05) and were more prone to developing comorbidities, including shock, acute cardiac and renal injury, acute respiratory distress syndrome, coagulation disorders, and secondary infections. Platelet count (PLT) <100 × 10^/L, interleukin-6 (IL-6) >100 pg/mL, and dNLR >5.0 independently contributed to the risk of death in patients suffering from severe COVID-19. PLT, IL-6, and dNRL independently contributed to the risk of mortality in patients with severe pneumonia during the 2022 omicron pandemic in South China.

Prophylactic Supplementation with Lactobacillus Reuteri or Its Metabolite GABA Protects Against Acute Ischemic Cardiac Injury.

The gut microbiome has emerged as a potential target for the treatment of cardiovascular disease. Ischemia/reperfusion (I/R) after myocardial infarction is a serious complication and whether certain gut bacteria can serve as a treatment option remains unclear. Lactobacillus reuteri (L. reuteri) is a well-studied probiotic that can colonize mammals including humans with known cholesterol-lowering properties and anti-inflammatory effects. Here, the prophylactic cardioprotective effects of L. reuteri or its metabolite γ-aminobutyric acid (GABA) against acute ischemic cardiac injury caused by I/R surgery are demonstrated. The prophylactic gavage of L. reuteri or GABA confers cardioprotection mainly by suppressingcardiac inflammation upon I/R. Mechanistically, GABA gavage results in a decreased number of proinflammatory macrophages in I/R hearts and GABA gavage no longer confers any cardioprotection in I/R hearts upon the clearance of macrophages. In vitro studies with LPS-stimulated bone marrow-derived macrophages (BMDM) further reveal that GABA inhibits the polarization of macrophages toward the proinflammatory M1 phenotype by inhibiting lysosomal leakage and NLRP3 inflammasome activation. Together, this study demonstrates that the prophylactic oral administration of L. reuteri or its metabolite GABA attenuates macrophage-mediated cardiac inflammation and therefore alleviates cardiac dysfunction after I/R, thus providing a new prophylactic strategy to mitigate acute ischemic cardiac injury.

Decoding HiPSC-CM’s Response to SARS-CoV-2: mapping the molecular landscape of cardiac injury

BackgroundAcute cardiac injury caused by coronavirus disease 2019 (COVID-19) increases mortality. Acute cardiac injury caused by COVID-19 requires understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly infects cardiomyocytes. This study provides a solid foundation for related studies by using a model of SARS-CoV-2 infection in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) at the transcriptome level, highlighting the relevance of this study to related studies. SARS-CoV-2 infection in hiPSC-CMs has previously been studied by bioinformatics without presenting the full molecular biological process. We present a unique bioinformatics view of the complete molecular biological process of SARS-CoV-2 infection in hiPSC-CMs.MethodsTo validate the RNA-seq datasets, we used GSE184715 and GSE150392 for the analytical studies, GSE193722 for validation at the cellular level, and GSE169241 for validation in heart tissue samples. GeneCards and MsigDB databases were used to find genes associated with the phenotype. In addition to differential expression analysis and principal component analysis (PCA), we also performed protein-protein interaction (PPI) analysis, functional enrichment analysis, hub gene analysis, upstream transcription factor prediction, and drug prediction.ResultsDifferentially expressed genes (DEGs) were classified into four categories: cardiomyocyte cytoskeletal protein inhibition, proto-oncogene activation and inflammation, mitochondrial dysfunction, and intracellular cytoplasmic physiological function. Each of the hub genes showed good diagnostic prediction, which was well validated in other datasets. Inhibited biological functions included cardiomyocyte cytoskeletal proteins, adenosine triphosphate (ATP) synthesis and electron transport chain (ETC), glucose metabolism, amino acid metabolism, fatty acid metabolism, pyruvate metabolism, citric acid cycle, nucleic acid metabolism, replication, transcription, translation, ubiquitination, autophagy, and cellular transport. Proto-oncogenes, inflammation, nuclear factor-kappaB (NF-κB) pathways, and interferon signaling were activated, as well as inflammatory factors. Viral infection activates multiple pathways, including the interferon pathway, proto-oncogenes and mitochondrial oxidative stress, while inhibiting cardiomyocyte backbone proteins and energy metabolism. Infection limits intracellular synthesis and metabolism, as well as the raw materials for mitochondrial energy synthesis. Mitochondrial dysfunction and energy abnormalities are ultimately caused by proto-oncogene activation and SARS-CoV-2 infection. Activation of the interferon pathway, proto-oncogene up-regulation, and mitochondrial oxidative stress cause the inflammatory response and lead to diminished cardiomyocyte contraction. Replication, transcription, translation, ubiquitination, autophagy, and cellular transport are among the functions that decline physiologically.ConclusionSARS-CoV-2 infection in hiPSC-CMs is fundamentally mediated via mitochondrial dysfunction. Therapeutic interventions targeting mitochondrial dysfunction may alleviate the cardiovascular complications associated with SARS-CoV-2 infection.

Mechanical Circulatory Support Systems in Fulminant Myocarditis: Recent Advances and Outlook.

Background: Fulminant myocarditis (FM) constitutes a severe and life-threatening form of acute cardiac injury associated with cardiogenic shock. The condition is characterised by rapidly progressing myocardial inflammation, leading to significant impairment of cardiac function. Due to the acute and severe nature of the disease, affected patients require urgent medical attention to mitigate adverse outcomes. Besides symptom-oriented treatment in specialised intensive care units (ICUs), the necessity for temporary mechanical cardiac support (MCS) may arise. Numerous patients depend on these treatment methods as a bridge to recovery or heart transplantation, while, in certain situations, permanent MCS systems can also be utilised as a long-term treatment option. Methods: This review consolidates the existing evidence concerning the currently available MCS options. Notably, data on venoarterial extracorporeal membrane oxygenation (VA-ECMO), microaxial flow pump, and ventricular assist device (VAD) implantation are highlighted within the landscape of FM. Results: Indications for the use of MCS, strategies for ventricular unloading, and suggested weaning approaches are assessed and systematically reviewed. Conclusions: Besides general recommendations, emphasis is put on the differences in underlying pathomechanisms in FM. Focusing on specific aetiologies, such as lymphocytic-, giant cell-, eosinophilic-, and COVID-19-associated myocarditis, this review delineates the indications and efficacy of MCS strategies in this context.

Validity of Routine Health Data To Identify Safety Outcomes of Interest For Covid-19 Vaccines and Therapeutics in the Context of the Emerging Pandemic: A Comprehensive Literature Review.

Regulatory guidance encourages transparent reporting of information on the quality and validity of electronic health record data being used to generate real-world benefit-risk evidence for vaccines and therapeutics. We aimed to provide an overview of the availability of validated diagnostic algorithms for selected safety endpoints for Coronavirus disease 2019 (COVID-19) vaccines and therapeutics in the context of the emerging pandemic prior to December 2020. We reviewed the literature up to December 2020 to identify validation studies for various safety events of interest, including myocardial infarction, arrhythmia, myocarditis, acute cardiac injury, vasculitis/vasculopathy, venous thromboembolism, stroke, respiratory distress syndrome (RDS), pneumonitis, cytokine release syndrome (CRS), multiple organ dysfunction syndrome, and renal failure. We included studies published between 2015 and 2020 that were considered high quality assessed with QUADAS and that reported positive predictive values (PPVs). Out of 43 identified studies, we found that diagnostic algorithms for cardiovascular outcomes were supported by the highest number of validation studies (n=17). Accurate algorithms are available for myocardial infarction (median PPV 80%; IQR 22%), arrhythmia (PPV range >70%), venous thromboembolism (median PPV: 73%) and ischaemic stroke (PPV range ≥85%). We found a lack of validation studies for less common respiratory and cardiac safety outcomes of interest (eg, pneumonitis and myocarditis), as well as for COVID-specific complications (CRS, RDS). There is a need for better understanding of barriers to conducting validation studies, including data governance restrictions. Regulatory guidance should promote embedding validation within real-world EHR research used for decision-making.

Off-Target Effects of P2Y12 Receptor Inhibitors: Focus on Early Myocardial Fibrosis Modulation.

Several studies have demonstrated that, beyond their antithrombotic effects, P2Y12 receptor inhibitors may provide additional off-target effects through different mechanisms. These effects range from the preservation of endothelial barrier function to the modulation of inflammation or stabilization of atherosclerotic plaques, with an impact on different cell types, including endothelial and immune cells. Many P2Y12 inhibitors have been developed, from ticlopidine, the first thienopyridine, to the more potent non-thienopyridine derivatives such as ticagrelor which may promote cardioprotective effects following myocardial infarction (MI) by inhibiting adenosine reuptake through sodium-independent equilibrative nucleoside transporter 1 (ENT1). Adenosine may affect different molecular pathways involved in cardiac fibrosis, such as the Wnt (wingless-type)/beta (β)-catenin signaling. An early pro-fibrotic response of the epicardium and activation of cardiac fibroblasts with the involvement of Wnt1 (wingless-type family member 1)/β-catenin, are critically required for preserving cardiac function after acute ischemic cardiac injury. This review discusses molecular signaling pathways involved in cardiac fibrosis post MI, focusing on the Wnt/β-catenin pathway, and the off-target effect of P2Y12 receptor inhibition. A potential role of ticagrelor was speculated in the early modulation of cardiac fibrosis, thanks to its off-target effect.

Comparative safety analysis of mRNA and adenoviral vector COVID-19 vaccines: a nationwide cohort study using an emulated target trial approach

ObjectiveThis nationwide cohort study compared the incidence of adverse events of special interest (AESIs) between adenoviral vector-based (ChAdOx1) and mRNA-based (BNT162b2 or mRNA-1273) coronavirus disease 2019 (COVID-19) vaccines. MethodsA targeted trial emulation study was conducted using data from the National Health Insurance Service database. Vaccinees aged 18–85 years who had received at least one dose of ChAdOx1 or an mRNA-based vaccine were identified. The 42-day risks of AESIs were calculated. ResultsA total of 1 767 539 ChAdOx1 vaccinees were matched exactly with mRNA vaccinees according to their risk factors. The 42-day risks of adverse events were low (∼0 to 176 events per 100 000 persons in both vaccine groups), and the incidence rates of AESIs were comparable between the two platforms, except for a higher occurrence of acute cardiac injury (incidence rate ratio [IRR], 1.22; 95% CI, 1.10–1.35), myocarditis or pericarditis (IRR, 2.14; 95% CI, 1.14–4.04), and arrhythmia (IRR, 1.46; 95% CI, 1.24–1.71) in mRNA vaccinees. The incidence of Guillain–Barré syndrome (IRR, 0.20; 95% CI, 0.06–0.69), vasovagal syncope (IRR, 0.77; 95% CI, 0.62–0.97), radiculopathy (IRR = 0.59, 95% CI, 0.41–0.84), and aseptic arthritis (IRR, 0.81; 95% CI, 0.70–0.93) was significantly lower in mRNA-based vaccinees compared with ChAdOx1 vaccinees. DiscussionA remarkable platform-dependent difference was observed in the safety profiles of COVID-19 vaccines, particularly for myocarditis or pericarditis and Guillain–Barré syndrome. However, the overall risk of AESIs was low for both vaccine platforms.

Urolithin A protects severe acute pancreatitis-associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes.

Severe acute pancreatitis (SAP) often develops into acute cardiac injury (ACI), contributing to the high mortality of SAP. Urolithin A (UA; 3,8-dihydroxy-6H-dibenzopyran-6-one), a natural polyphenolic compound, has been extensively studied and shown to possess significant anti-inflammatory effects. Nevertheless, the specific effects of UA in SAP-associated acute cardiac injury (SACI) have not been definitively elucidated. Here, we investigated the therapeutic role and mechanisms of UA in SACI using transcriptomics and untargeted metabolomics analyses in a mouse model of SACI and in vitro studies. SACI resulted in severely damaged pancreatic and cardiac tissues with myocardial mitochondrial dysfunction and mitochondrial metabolism disorders. UA significantly reduced the levels of lipase, amylase and inflammatory factors, attenuated pathological damage to pancreatic and cardiac tissues, and reduced myocardial cell apoptosis and oxidative stress in SACI. Moreover, UA increased mitochondrial membrane potential and adenosine triphosphate production and restored mitochondrial metabolism, but the efficacy of UA was weakened by the inhibition of CPT1. Therefore, UA can attenuate cardiac mitochondrial dysfunction and reduce myocardial apoptosis by restoring the balance of mitochondrial fatty acid oxidation metabolism. CPT1 may be a potential target. This study has substantial implications for advancing our understanding of the pathogenesis and drug development of SACI.

The Association between Acute Cardiac Injury and Outcomes of Hospitalized Patients with COVID-19: Long-Term Follow-up Results from the Sina Hospital COVID-19 Registry, Iran.

The present study aimed to investigate the association between acute cardiac injury (ACI) and outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19) in Iran. The current cohort study enrolled all consecutive hospitalized patients with COVID-19 (≥ 18 y) who had serum high-sensitivity cardiac troponin-I (hs-cTnT) measurements on admission between March 2020 and March 2021. ACI was determined as hs-cTnT levels exceeding the 99th percentile of normal values. Data on demographics, comorbidities, clinical and laboratory characteristics, and outcomes were collected from Web-based electronic health records. The study population consisted of 1413 hospitalized patients with COVID-19, of whom 319 patients (22.58%) presented with ACI. The patients with ACI had a significantly higher mortality rate than those without ACI (48.28% vs 15.63%; P<0.001) within a mean follow-up of 218.86 days from symptom onset. ACI on admission was independently associated with mortality (HR, 1.44; P=0.018). In multivariable logistic regression, age (OR, 1.034; P<0.001), preexisting cardiac disease (OR, 1.49; P=0.035), preexisting malignancy (OR, 2.01; P=0.030), oxygen saturation reduced to less than 90% (OR, 2.15; P<0.001), leukocytosis (OR, 1.45; P=0.043), lymphopenia (OR, 1.49; P=0.020), reduced estimated glomerular filtration rates (eGFRs) (OR, 0.99; P=0.008), and treatment with intravenous immunoglobulin during hospitalization (OR, 4.03; P=0.006) were independently associated with ACI development. ACI occurrence on admission was associated with long-term mortality in our hospitalized patients with COVID-19. The finding further underscores the significance of evaluating ACI occurrence on admission, particularly in individuals more prone to ACI, including older individuals and those with preexisting comorbidities, reduced oxygen saturation, and increased inflammatory responses.