Cardiac safety after AstraZeneca COVID-19 vaccination: A cohort observational study (preprint)

Background Vaccination is a well-established part of preventive and public health medicine but is not without risk. Most of the side effects related to COVID-19 vaccines are minor including local symptoms at the injection site and some systemic symptoms, such as fatigue, headache, and fever. Some preliminary reports mentioned a more serious side effect; myocarditis seen after certain COVID-19 vaccines. The purpose of this study was to reveal any decrease in left ventricular systolic function in patients receiving the AstraZeneca COVID-19 vaccine compared to healthy individuals who did not receive the vaccine.Methods This study included 150 people divided into two equal groups; the case group included individuals who received AstraZeneca COVID-19 vaccines, and the sex- and age-matched control group included healthy individuals who did not receive any of the COVID-19 vaccines. Echocardiographic parameters for assessment of systolic function were evaluated after full vaccination.Results By the end of the study, no difference was found between the case and control groups regarding the left ventricular ejection fraction (LVEF), the S' wave of the mitral valve, or the global longitudinal strain (GLS).Conclusions AstraZeneca COVID-19 vaccination was not associated with myocardial damage, as evaluated by 2D echocardiography, tissue Doppler, and speckle tracking echocardiography.

Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure.

Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how inflammatory cells affect cardiomyocytes in the remodeling heart. Pathogenic cardiac macrophages induced an IFN response in cardiomyocytes, characterized by upregulation of the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), which posttranslationally modifies its targets through a process termed ISGylation. Cardiac ISG15 is controlled by type I IFN signaling, and ISG15 or ISGylation is upregulated in mice with transverse aortic constriction or infused with angiotensin II; rats with uninephrectomy and DOCA-salt, or pulmonary artery banding; cardiomyocytes exposed to IFNs or CD4+ T cell-conditioned medium; and ventricular tissue of humans with nonischemic cardiomyopathy. By nanoscale liquid chromatography-tandem mass spectrometry, we identified the myofibrillar protein filamin-C as an ISGylation target. ISG15 deficiency preserved cardiac function in mice with transverse aortic constriction and led to improved recovery of mouse hearts ex vivo. Metabolomics revealed that ISG15 regulates cardiac amino acid metabolism, whereas ISG15 deficiency prevented misfolded filamin-C accumulation and induced cardiomyocyte autophagy. In sum, ISG15 upregulation is a feature of pathological ventricular remodeling, and protein ISGylation is an inflammation-induced posttranslational modification that may contribute to heart failure development by altering cardiomyocyte protein turnover.

Vitamin C Regulates the Profibrotic Activity of Fibroblasts in In Vitro Replica Settings of Myocardial Infarction.

Extracellular collagen remodeling is one of the central mechanisms responsible for the structural and compositional coherence of myocardium in patients undergoing myocardial infarction (MI). Activated primary cardiac fibroblasts following myocardial infarction are extensively investigated to establish anti-fibrotic therapies to improve left ventricular remodeling. To systematically assess vitamin C functions as a potential modulator involved in collagen fibrillogenesis in an in vitro model mimicking heart tissue healing after MI. Mouse primary cardiac fibroblasts were isolated from wild-type C57BL/6 mice and cultured under normal and profibrotic (hypoxic + transforming growth factor beta 1) conditions on freshly prepared coatings mimicking extracellular matrix (ECM) remodeling during healing after an MI. At 10 µg/mL, vitamin C reprogramed the respiratory mitochondrial metabolism, which is effectively associated with a more increased accumulation of intracellular reactive oxygen species (iROS) than the number of those generated by mitochondrial reactive oxygen species (mROS). The mRNA/protein expression of subtypes I, III collagen, and fibroblasts differentiations markers were upregulated over time, particularly in the presence of vitamin C. The collagen substrate potentiated the modulator role of vitamin C in reinforcing the structure of types I and III collagen synthesis by reducing collagen V expression in a timely manner, which is important in the initiation of fibrillogenesis. Altogether, our study evidenced the synergistic function of vitamin C at an optimum dose on maintaining the equilibrium functionality of radical scavenger and gene transcription, which are important in the initial phases after healing after an MI, while modulating the synthesis of de novo collagen fibrils, which is important in the final stage of tissue healing.

Right and Left Ventricular Cardiac Magnetic Resonance Imaging Derived Peak Systolic Strain is Abnormal in Children with Myocarditis (preprint)

Purpose: CMR derived left ventricular longitudinal and circumferential strain is known to be abnormal in myocarditis. CMR strain is an useful additional tool that can identify subclinical myocardial involvement and may help with longitudinal follow-up. Right ventricular strain derived by CMR in children has not been studied. We sought to evaluate CMR derived biventricular strain in children with acute myocarditis. Methods: Children with acute myocarditis who underwent CMR 2016 - 2022 at our center were reviewed, this group included subjects with COVID-19 myocarditis. Children with no evidence of myocarditis served as controls Those with congenital heart disease and technically limited images for CMR strain analysis were excluded from final analysis. Biventricular longitudinal, circumferential, and radial peak systolic strains were derived using Circle cvi42. Data between cases and controls were compared using an independent sample t-test. One-way ANOVA with post hoc analysis was used to compare COVID-19, non-COVID myocarditis and controls. Results: 38 myocarditis and 14 controls met inclusion criteria (14.4 ± 3 years). All CMR derived peak strain values except for RV longitudinal strain were abnormal in myocarditis group. One-way ANOVA revealed that there was a statistically significant difference with abnormal RV and LV strain in COVID-19 myocarditis when compared to non-COVID-19 myocarditis and controls. Conclusion: CMR derived right and left ventricular peak systolic strain using traditionally acquired cine images were abnormal in children with acute myocarditis. All strain measurements were significantly abnormal in children with COVID-19 even when compared to non COVID myocarditis.

Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS) - A phase II, randomized, double-blind, multi-center, placebo-controlled trial.

BACKGROUND: Activation of inflammatory pathways during acute myocardial infarction contributes to infarct size and left ventricular (LV) remodeling. The present prospective randomized clinical trial was designed to test the efficacy and safety of broad-spectrum anti-inflammatory therapy with a mammalian target of rapamycin (mTOR) inhibitor to reduce infarct size. DESIGN: Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS, clinicaltrials.gov NCT01529554) is a phase II randomized, double-blind, multi-center, placebo-controlled trial on the effects of a 5-day course of oral everolimus on infarct size, LV remodeling, and inflammation in patients with acute ST-elevation myocardial infarction (STEMI). Within 5 days of successful primary percutaneous coronary intervention (pPCI), patients are randomly assigned to everolimus (first 3 days: 7.5 mg every day; days 4 and 5: 5.0 mg every day) or placebo, respectively. The primary efficacy outcome is the change from baseline (defined as 12 hours to 5 days after pPCI) to 30-day follow-up in myocardial infarct size as measured by cardiac magnetic resonance imaging (CMRI). Secondary endpoints comprise corresponding changes in cardiac and inflammatory biomarkers as well as microvascular obstruction and LV volumes assessed by CMRI. Clinical events, laboratory parameters, and blood cell counts are reported as safety endpoints at 30 days. CONCLUSION: The CLEVER-ACS trial tests the hypothesis whether mTOR inhibition using everolimus at the time of an acute STEMI affects LV infarct size following successful pPCI.

Mechanism of Blood-Heart-Barrier Leakage: Implications for COVID-19 Induced Cardiovascular Injury.

Although blood-heart-barrier (BHB) leakage is the hallmark of congestive (cardio-pulmonary) heart failure (CHF), the primary cause of death in elderly, and during viral myocarditis resulting from the novel coronavirus variants such as the severe acute respiratory syndrome novel corona virus 2 (SARS-CoV-2) known as COVID-19, the mechanism is unclear. The goal of this project is to determine the mechanism of the BHB in CHF. Endocardial endothelium (EE) is the BHB against leakage of blood from endocardium to the interstitium; however, this BHB is broken during CHF. Previous studies from our laboratory, and others have shown a robust activation of matrix metalloproteinase-9 (MMP-9) during CHF. MMP-9 degrades the connexins leading to EE dysfunction. We demonstrated juxtacrine coupling of EE with myocyte and mitochondria (Mito) but how it works still remains at large. To test whether activation of MMP-9 causes EE barrier dysfunction, we hypothesized that if that were the case then treatment with hydroxychloroquine (HCQ) could, in fact, inhibit MMP-9, and thus preserve the EE barrier/juxtacrine signaling, and synchronous endothelial-myocyte coupling. To determine this, CHF was created by aorta-vena cava fistula (AVF) employing the mouse as a model system. The sham, and AVF mice were treated with HCQ. Cardiac hypertrophy, tissue remodeling-induced mitochondrial-myocyte, and endothelial-myocyte contractions were measured. Microvascular leakage was measured using FITC-albumin conjugate. The cardiac function was measured by echocardiography (Echo). Results suggest that MMP-9 activation, endocardial endothelial leakage, endothelial-myocyte (E-M) uncoupling, dyssynchronous mitochondrial fusion-fission (Mfn2/Drp1 ratio), and mito-myocyte uncoupling in the AVF heart failure were found to be rampant; however, treatment with HCQ successfully mitigated some of the deleterious cardiac alterations during CHF. The findings have direct relevance to the gamut of cardiac manifestations, and the resultant phenotypes arising from the ongoing complications of COVID-19 in human subjects.

Evaluation of Post-COVID-19 Chest Pain and Dyspnea in Outpatients Using Speckle Tracking Echocardiography (preprint)

Clinicians are frequently facing patients complaining of post-COVID-19 chest pain and dyspnea. However, it remains to be seen if these symptoms indicate pathology of the cardiovascular system. We aimed to evaluate heart functions in outpatients with post-COVID-19 chest pain and dyspnea, using 2D-speckle tracking echocardiography (2D-STE). This cross-sectional study recruited consecutive patients who presented to cardiology outpatient clinics between June 15 and July 15, 2021. Subjects had recovered from COVID-19 1-2 months prior to admission. ECG, echocardiography including 2D-STE images, were obtained for all patients. Findings were compared with sex and an age-matched control group consisting of 67 healthy adults. A total of 78 patients were included. The median age was 38 (IQR, 34-45) years, and 64.1% were female. There were no significant differences between the patients and control group regarding laboratory, ECG, and echocardiography findings. Moreover, left ventricle global longitudinal strain (LVGLS) measurements in both patient and control groups were within the normal ranges and did not show a significant difference [-20.5 (-21.8- -17.9) vs. -19.8 (-21.4- -18.9), p=0.894]. Post-COVID-19 chest pain and dyspnea are unlikely signs of cardiovascular involvement in outpatient young adults who had not been hospitalized with COVID-19.

Postnatal persistence of cardiac remodeling and dysfunction in late fetal growth restriction.

Fetal growth restriction is one of the most common obstetric complications, affecting 7-10% of all pregnancies. Affected fetuses are exposed to an adverse environment in utero during a critical time of development and may face long-term health consequences such as increased cardiovascular risk in adulthood. Growth restricted fetuses develop remodeled hearts with signs of systolic and diastolic dysfunction. Cardiac adaptations are more evident in early severe cases, but also present in late onset fetal growth restriction. Cardiovascular remodeling persists into postnatal life, from the neonatal period to adolescence, encompassing an increased susceptibility to adult disease. In this review, we summarize the current evidence on cardiovascular programming associated to fetal growth restriction, its postnatal consequences and potential strategies to reduce their cardiovascular risk.

Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice. (preprint)

Cardiac injury is common in hospitalized COVID-19 patients and portends poorer prognosis and higher mortality. To better understand how SARS-CoV-2 (CoV-2) damages the heart, it is critical to elucidate the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 Spike glycoprotein (CoV-2-S) not only engages ACE2 to mediate virus infection, but also directly impairs endothelial function and can trigger innate immune responses in cultured murine macrophages. Here we tested the hypothesis that CoV-2-S damages the heart by activating cardiomyocyte (CM) innate immune responses. HCoV-NL63 is another human coronavirus with a Spike protein (NL63-S) that also engages ACE2 for virus entry but is known to only cause moderate respiratory symptoms. We found that CoV-2-S and not NL63-S interacted with Toll-like receptor 4 (TLR4), a crucial pattern recognition receptor that responsible for detecting pathogen and initiating innate immune responses. Our data show that the S1 subunit of CoV-2-S (CoV-2-S1) interacts with the extracellular leucine rich repeats-containing domain of TLR4 and activates NF-kB. To investigate the possible pathological role of CoV-2-S1 in the heart, we generated a construct that expresses membrane-localized CoV-2-S1 (S1-TM). AAV9-mediated, selective expression of the S1-TM in CMs caused heart dysfunction, induced hypertrophic remodeling, and elicited cardiac inflammation. Since CoV-2-S does not interact with murine ACE2, our study presents a novel ACE2-independent pathological role of CoV-2-S, and suggests that the circulating CoV-2-S1 is a TLR4-recognizable alarmin that may harm the CMs by triggering their innate immune responses.

COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.

A Systematic Review of COVID - 19 Induced Myocarditis - Symptomatology, Prognosis, and Clinical Findings (preprint)

Objective: With the advent of a novel coronavirus in December 2019, several case studies have reported its adversity on cardiac cells. We conducted a systematic review that describes the symptomatology, prognosis, and clinical findings of patients with COVID-19-related myocarditis. Methods: Search engines including PubMed, Google Scholar, Cochrane Central, and Web of Science were queried for SARS-CoV-2 or COVID 19 and myocarditis. PRISMA guidelines were employed, and peer-reviewed journals in English related to COVID-19 were included. Results: This systematic review included 22 studies and 37 patients. Eight patients (36%) were confirmed myocarditis, while the rest were possible myocarditis. Most patients had elevated cardiac biomarkers, including troponin, CRP, CK, CK-MB, and NT-pro BNP. Electrocardiogram results noted tachycardia (47%), left ventricular hypertrophy (50%), ST-segment alterations (41%), and T wave inversion (18%). Echocardiography presented reduced LVEF (77%), left ventricle abnormalities (34%), right ventricle aberrations (12%), and pericardial effusion (71%). Further, CMR showed reduced myocardial edema (75%), non-ischemic patterns (50%), and hypokinesis (26%). The mortality was significant at 25%. Conclusions: Mortality associated with COVID-19 myocarditis appears significant but underestimated. Further studies are warranted to evaluate and quantify patients actual prognosis and outcomes with COVID-19 myocarditis.

Subclinical left ventricular dysfunction in COVID-19 recovered patients using speckle tracking echocardiography (preprint)

Objectives: Myocardial injury during active coronavirus disease-2019 (COVID-19) infection is well described however, its persistence during recovery is unclear. We assessed left ventricle (LV) global longitudinal strain (GLS) using speckle tracking echocardiography (STE) in COVID-19 recovered patients and studied its correlation with various parameters. Methods: A total of 134 subjects within 30-45 days post recovery from COVID-19 infection and normal LV ejection fraction were enrolled. Routine blood investigations, inflammatory markers (on admission) and comprehensive echocardiography including STE were done for all. Results: Of the 134 subjects, 121 (90.3%) were symptomatic during COVID-19 illness and were categorized as mild: 61 (45.5%), moderate: 50 (37.3%) and severe: 10 (7.5%) COVID-19 illness. Asymptomatic COVID-19 infection was reported in 13 (9.7%) patients. Subclinical LV and right ventricle (RV) dysfunction were seen in 40 (29.9%) and 14 (10.5%) patients respectively. Impaired LVGLS was reported in 1 (7.7%), 8 (13.1%), 22 (44%) and 9 (90%) subjects with asymptomatic, mild, moderate and severe disease respectively. LVGLS was significantly lower in patients recovered from severe illness (mild: -21 ± 3.4%; moderate: -18.1 ± 6.9%; severe: -15.5 ± 3.1%; P < 0.0001). Subjects with reduced LVGLS had significantly higher interleukin-6 (P < 0.0001), C-reactive protein (P = 0.001), lactate dehydrogenase (P = 0.009) and serum ferritin (P = 0.03) levels during index admission. Conclusions: Subclinical LV dysfunction was seen in nearly a third of recovered COVID-19 patients while 10.5% had RV dysfunction. Our study suggests a need for closer follow-up among COVID-19 recovered subjects to elucidate long-term cardiovascular outcomes.

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

The soluble catalytic ectodomain of ACE2 a biomarker of cardiac remodelling: new insights for heart failure and COVID19.

The angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane that was discovered two decades ago. The ACE2 exists as a transmembrane protein and as a soluble catalytic ectodomain of ACE2, also known as the soluble ACE2 that can be found in plasma and other body fluids. ACE2 regulates the local actions of the renin-angiotensin system in cardiovascular tissues, and the ACE2/Angiotensin 1-7 axis exerts protective actions in cardiovascular disease. Increasing soluble ACE2 has been associated with heart failure, cardiovascular disease, and cardiac remodelling. This is a review of the molecular structure and biochemical functions of the ACE2, as well we provided an updated on the evidence, clinical applications, and emerging potential therapies with the ACE2 in heart failure, cardiovascular disease, lung injury, and COVID-19 infection.

COVID-19 myocarditis and prospective heart failure burden.

Introduction: COVID-19 is causing considerable morbidity and mortality worldwide. Serious respiratory complications aside, the heart is also frequently involved. The mechanisms and the extent of the myocardial injury, along with the short and long-term cardiovascular (CV) outcomes in COVID-19 survivors remain unclear. Areas covered: myocardial injury has been found in a considerable proportion of hospitalized COVID-19 patients and is associated with a worse prognosis. The late onset of CV complications with myocarditis-like changes revealed by CMR has been reported in COVID-19 survivors. Previous observational studies on viral myocarditis provide evidence of a significant incomplete recovery with residual dysfunction and remodeling of left ventricle. Incomplete recovery is thought to be the result of persistent myocardial inflammation due to a post-viral autoimmune response. Considering the significant inflammatory nature of COVID-19, COVID-19 survivors may be at risk of developing persistent residual myocardial injury, the sequelae of which are unclear. Expert commentary: COVID-19 is an emerging threat for the heart. The extent of CV injury, along with the short and long-term sequelae, requires further investigation. The early detection of residual myocardial changes in COVID-19 survivors is of utmost importance in order to identify those patients at risk of CV complication development.