Spike Protein Impairs Mitochondrial Function in Human Cardiomyocytes: Mechanisms Underlying Cardiac Injury in COVID-19.

BACKGROUND: COVID-19 has a major impact on cardiovascular diseases and may lead to myocarditis or cardiac failure. The clove-like spike (S) protein of SARS-CoV-2 facilitates its transmission and pathogenesis. Cardiac mitochondria produce energy for key heart functions. We hypothesized that S1 would directly impair the functions of cardiomyocyte mitochondria, thus causing cardiac dysfunction. METHODS: Through the Seahorse Mito Stress Test and real-time ATP rate assays, we explored the mitochondrial bioenergetics in human cardiomyocytes (AC16). The cells were treated without (control) or with S1 (1 nM) for 24, 48, and 72 h and we observed the mitochondrial morphology using transmission electron microscopy and confocal fluorescence microscopy. Western blotting, XRhod-1, and MitoSOX Red staining were performed to evaluate the expression of proteins related to energetic metabolism and relevant signaling cascades, mitochondrial Ca2+ levels, and ROS production. RESULTS: The 24 h S1 treatment increased ATP production and mitochondrial respiration by increasing the expression of fatty-acid-transporting regulators and inducing more negative mitochondrial membrane potential (Δψm). The 72 h S1 treatment decreased mitochondrial respiration rates and Δψm, but increased levels of reactive oxygen species (ROS), mCa2+, and intracellular Ca2+. Electron microscopy revealed increased mitochondrial fragmentation/fission in AC16 cells treated for 72 h. The effects of S1 on ATP production were completely blocked by neutralizing ACE2 but not CD147 antibodies, and were partly attenuated by Mitotempo (1 µM). CONCLUSION: S1 might impair mitochondrial function in human cardiomyocytes by altering Δψm, mCa2+ overload, ROS accumulation, and mitochondrial dynamics via ACE2.

Update on the treatment of multisystem inflammatory syndrome in children associated with COVID-19.

In late 2019, SARS-CoV-2 was detected in China and spread worldwide. In rare cases, children who were infected with COVID-19 may develop multisystem inflammatory syndrome (MIS-C), which could have higher mortality than COVID-19 itself. Therefore, diagnosis and management are critical for treatment. Specifically, most of the initial treatment options of MIS-C choose intravenous immunoglobulin (IVIG) and steroids as the first-line treatment for patients. Moreover, antagonists of some cytokines are used as potential future therapeutics. Of note, therapeutic plasmapheresis can be used as a treatment for refractory severe MIS-C. We believe that each patient, especially those with comorbid conditions, should have individualized treatment based on both multidisciplinary consensus approach and expert opinion.

Pathophysiological Mechanisms of Cardiac Dysfunction in Transgenic Mice with Viral Myocarditis.

Viral myocarditis is pathologically associated with RNA viruses such as coxsackievirus B3 (CVB3), or more recently, with SARS-CoV-2, but despite intensive research, clinically proven treatment is limited. Here, by use of a transgenic mouse strain (TG) containing a CVB3ΔVP0 genome we unravel virus-mediated cardiac pathophysiological processes in vivo and in vitro. Cardiac function, pathologic ECG alterations, calcium homeostasis, intracellular organization and gene expression were significantly altered in transgenic mice. A marked alteration of mitochondrial structure and gene expression indicates mitochondrial impairment potentially contributing to cardiac contractile dysfunction. An extended picture on viral myocarditis emerges that may help to develop new treatment strategies and to counter cardiac failure.

Serum Vitamin D Levels in Relation to Development of Multisystem Inflammatory Syndrome in Pediatric COVID-19

Objective The aim of the study is to evaluate vitamin D (vit D) levels in children with and without development of multisystem inflammatory syndrome in children (MIS-C) after coronavirus disease 2019 (COVID-19) and also between those with severe and moderate MIS-C. Methods This comprises retrospective data of 68 patients including 34 patients with MIS-C and admitted into the pediatric intensive care unit (MIS-C group) and 34 patients without MIS-C (non-MIS-C group) were analyzed for their presenting characteristics, serum vit D levels, ventilatory needs, and prognostic scores. Results Vit D levels were significantly lower in patients with versus without MIS-C [9 (2-18) vs. 19 (10-43) ng/mL, p <0.001], and also in patients with severe versus moderate MIS-C [7.5 (2-17) vs. 9 (5-18) ng/mL, p = 0.024]. Vit D deficiency (levels <12 ng/mL) was more common in the MIS-C versus non-MIS-C group (79.4 vs. 11.8%, p <0.001) and in severe versus moderate MIS-C (92.9 vs. 70.0%, p <0.001). The severe versus moderate MIS-C was associated with significantly higher levels of procalcitonin [7.6 (0.9-82) vs. 1.7 (0.2-42) ng/mL, p = 0.030] and troponin [211 (4.8-4,545) vs. 14.2 (2.4-3,065) ng/L, p = 0.008] and higher likelihood of reduced ejection fraction (75.0 vs. 15.4%, p = 0.004). Conclusion Our findings indicate the higher prevalence of vit D deficiency in pediatric COVID-19 patients with versus without MIS-C, as well as in those with severe versus moderate MIS-C. Higher troponin and procalcitonin levels and dyspnea at presentation seem also to be risk factors for severe MIS-C, more pronounced cardiac dysfunction, and poorer prognosis.

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin-Angiotensin-Aldosterone System.

This study investigated whether sacubitril/valsartan and ivabradine are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in a rat experimental model of spontaneous hypertension (spontaneously hypertensive rats, SHRs) and whether this potential protection is associated with RAAS alterations. Five groups of three-month-old male Wistar rats and SHRs were treated for six weeks as follows: untreated Wistar controls, Wistar plus sacubitril/valsartan, SHR, SHR plus sacubitril/valsartan, and SHR plus ivabradine. The SHRs developed a systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, and LV systolic and diastolic dysfunction. However, no changes in serum RAAS were observed in SHRs compared with the controls. Elevated SBP in SHRs was decreased by sacubitril/valsartan but not by ivabradine, and only sacubitril/valsartan attenuated LV hypertrophy. Both sacubitril/valsartan and ivabradine reduced LV collagen content and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7, and aldosterone, while ivabradine did not affect the RAAS. We conclude that the SHR is a normal-to-low serum RAAS model of experimental hypertension. While the protection of the hypertensive heart in SHRs by sacubitril/valsartan may be related to an Ang II blockade and the protective Ang 1-7, the benefits of ivabradine were not associated with RAAS modulation.

Time course of lung ultrasound findings in patients with COVID-19 pneumonia and cardiac dysfunction.

BACKGROUND: Lung ultrasound (LUS) is a valuable tool to predict and monitor the COVID-19 pneumonia course. However, the influence of cardiac dysfunction (CD) on LUS findings remains to be studied. Our objective was to determine the effect of CD on LUS in hospitalized patients with COVID-19 pneumonia. MATERIAL AND METHODS: Fifty-one patients with COVID-19 pneumonia participated in the study. Focused echocardiography (FoCUS) was carried out on day 1 to separate patients into two groups depending on whether they had FoCUS signs of CD (CD+ vs CD-). LUS scores, based on the thickness of the pleural line, the B-line characteristics, and the presence or not of consolidations, were obtained three times along the patient's admission (D1, D5, D10) and compared between CD+ and CD- patients. A correlation analysis was carried out between LUS scores and the ratio of the arterial partial pressure of oxygen to the fraction of the inspired oxygen (P/F ratio). RESULTS: Twenty-two patients were CD+ and 29 patients were CD-. Among the CD+ patients, 19 were admitted to the intensive care unit (ICU), seven received invasive mechanical ventilation (IMV), and one did not survive. Among the CD- patients, 11 were admitted to the ICU, one received IMV and seven did not survive. CD+ patients showed a significantly lower P/F ratio than CD- patients. However, LUS scores showed no between-group differences, except for fewer subpleural consolidations in the upper quadrants of CD+ than on CD- patients. CONCLUSION: In patients with COVID-19, CD contributed to a worse clinical course, but it did not induce significant changes in LUS. Our findings suggest that pathophysiological factors other than those reflected by LUS may be responsible for the differences in clinical condition between CD+ and CD- patients.

Heart-targeted amelioration of sepsis-induced myocardial dysfunction by microenvironment responsive nitric oxide nanogenerators in situ.

BACKGROUND: A balanced endogenous level of bioavailable nitric oxide (NO) plays a key role in maintaining cardiovascular homeostasis. The bioactive NO level in the cardiomyocytes was much reduced during sepsis. However, it is clinically challenging for the NO gas therapy due to the lack of spatial and temporal release system with precise control. The purpose of this study is to design a NO-releasing biomaterial with heart-targeted capability responsive to the infectious microenvironment, thus ameliorating lipopolysaccharide (LPS)-induced cardiac dysfunction. RESULTS: The heart-targeted NO delivery and in situ releasing system, PCM-MSN@LA, was synthesized using hollow mesoporous silica nanoparticles (MSN) as the carrier, and L-arginine (LA) as the NO donor. The myocardial delivery was successfully directed to heart by specific peptide (PCM) combined with low-intensity focused ultrasound (LIFU) guidance. The myocardial system synthesized NO from the LA released from PCM-MSN@LA in the presence of increased endogenous nitric oxide synthase (NOS) activity induced by LPS. This targeted NO release in situ achieved extraordinary protective effects against LPS-challenged myocardial injury by reducing the recruitment of inflammatory cells, inhibiting oxidative stress and maintaining the mitochondria integrity. In particular, this protection was not compromised by simultaneous circulation collapse as an adverse event in the context. CONCLUSIONS: PCM-MSN@LA + LIFU exhibited extraordinary cardioprotective effects against severe sepsis in the hearts of LPS-treated animals without the side effect of NO diffusion. This technology has great potential to be served as a novel therapeutic strategy for sepsis-induced myocardial injury.

Distinctive Phenotype of Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 According to Patients' Age: A Monocentric Experience.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a disease temporally related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it is characterized by fever, conjunctival injections, rash, gastrointestinal symptoms, and cardiovascular complications. We evaluated the clinical presentation, laboratory findings, imaging features, therapeutic interventions, and hospital course of a monocentric cohort, and we analyzed these findings according to two age groups. METHODS: Patients with MIS-C admitted to a Tertiary Care Pediatric Hospital from November 2020 to November 2021 were considered for the enrollment. RESULTS: Overall, 35 consecutive patients were included. Most of the children did not require intensive care unit at the admission. The clinical presentation of MIS-C slightly differs according to age groups. Mucocutaneus involvement was more frequent in younger patients, while abdominal symptoms were present in 54% of patients aged less than 5 years and in 95% of patients aged more than 5 years (p < 0.05). In addition, the number of cases with troponin above the normal reference value was significantly higher in older patients (77%) compared to younger cases (15%) (p < 0.01). CONCLUSIONS: MIS-C is a new emerging condition and represents a challenge to pediatricians due to the severity of presentation. Further studies to better characterize the long-term outcome of MIS-C patients are mandatory.

Distinguishing immune activation and inflammatory signatures of multisystem inflammatory syndrome in children (MIS-C) versus hemophagocytic lymphohistiocytosis (HLH).

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening sequela of severe acute respiratory syndrome coronavirus 2 infection characterized by hyperinflammation and multiorgan dysfunction. Although hyperinflammation is a prominent manifestation of MIS-C, there is limited understanding of how the inflammatory state of MIS-C differs from that of well-characterized hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH). OBJECTIVES: We sought to compare the qualitative and quantitative inflammatory profile differences between patients with MIS-C, coronavirus disease 2019, and HLH. METHODS: Clinical data abstraction from patient charts, T-cell immunophenotyping, and multiplex cytokine and chemokine profiling were performed for patients with MIS-C, patients with coronavirus disease 2019, and patients with HLH. RESULTS: We found that both patients with MIS-C and patients with HLH showed robust T-cell activation, markers of senescence, and exhaustion along with elevated TH1 and proinflammatory cytokines such as IFN-γ, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10. In comparison, the amplitude of T-cell activation and the levels of cytokines/chemokines were higher in patients with HLH when compared with patients with MIS-C. Distinguishing inflammatory features of MIS-C included elevation in TH2 inflammatory cytokines such as IL-4 and IL-13 and cytokine mediators of angiogenesis, vascular injury, and tissue repair such as vascular endothelial growth factor A and platelet-derived growth factor. Immune activation and hypercytokinemia in MIS-C resolved at follow-up. In addition, when these immune parameters were correlated with clinical parameters, CD8+ T-cell activation correlated with cardiac dysfunction parameters such as B-type natriuretic peptide and troponin and inversely correlated with platelet count. CONCLUSIONS: Overall, this study characterizes unique and overlapping immunologic features that help to define the hyperinflammation associated with MIS-C versus HLH.

Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes.

Patients with coronavirus disease 2019 (COVID-19) commonly have manifestations of heart disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 27 proteins. Currently, SARS-CoV-2 gene-induced abnormalities of human heart muscle cells remain elusive. Here, we comprehensively characterized the detrimental effects of a SARS-CoV-2 gene, Orf9c, on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) by preforming multi-omic analyses. Transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with Orf9c overexpression (Orf9cOE) identified concordantly up-regulated genes enriched into stress-related apoptosis and inflammation signaling pathways, and down-regulated CM functional genes. Proteomic analysis revealed enhanced expressions of apoptotic factors, whereas reduced protein factors for ATP synthesis by Orf9cOE. Orf9cOE significantly reduced cellular ATP level, induced apoptosis, and caused electrical dysfunctions of hPSC-CMs. Finally, drugs approved by the U.S. Food and Drug Administration, namely, ivermectin and meclizine, restored ATP levels and ameliorated CM death and functional abnormalities of Orf9cOE hPSC-CMs. Overall, we defined the molecular mechanisms underlying the detrimental impacts of Orf9c on hPSC-CMs and explored potentially therapeutic approaches to ameliorate Orf9c-induced cardiac injury and abnormalities.

Cardiac dysfunction and mortality in critically ill patients with COVID-19: A Swedish multicentre observational study.

BACKGROUND: The prevalence and importance of cardiac dysfunction in critically ill patients with COVID-19 in Sweden is not yet established. The aim of the study was to assess the prevalence of cardiac dysfunction and elevated pulmonary artery pressure (PAP), and its influence on mortality in patients with COVID-19 in intensive care in Sweden. METHODS: This was a multicentre observational study performed in five intensive care units (ICUs) in Sweden. Patients admitted to participating ICU with COVID-19 were examined with echocardiography within 72 h from admission and again after 4 to 7 days. Cardiac dysfunction was defined as left ventricular (LV) dysfunction (ejection fraction <50% and/or regional hypokinesia) or right ventricular (RV) dysfunction (defined as TAPSE <17 mm or visually assessed moderate/severe RV dysfunction). RESULTS: We included 132 patients, of whom 127 (96%) were intubated. Cardiac dysfunction was found in 42 (32%) patients. Most patients had cardiac dysfunction at the first assessment (n = 35) while a few developed cardiac dysfunction later (n = 7) and some changed type of dysfunction (n = 3). LV dysfunction was found in 21 and RV dysfunction in 19 patients, while 5 patients had combined dysfunction. Elevated PAP was found in 34 patients (26%) and was more common in patients with RV dysfunction. RV dysfunction and elevated PAP were independently associated with an increased risk of death (OR 3.98, p = .013 and OR 3.88, p = .007, respectively). CONCLUSIONS: Cardiac dysfunction occurs commonly in critically ill patients with COVID-19 in Sweden. RV dysfunction and elevated PAP are associated with an increased risk of death.

Prevalence of Cardiac Dysfunction in MIS-C in Children (MIS-C) related to COVID-19

Background: COVID-19 in children normally causes mild infectious illness, but serious repercussions can occur in combination with both acute infection and related phenomena in children, like the Multisystem Inflammatory Syndrome (MIS-C). In rural hospitals, there is less information available on Cardiac abnormality in MIS-C. Objectives: To know the prevalence of cardiac dysfunction of MIS-C children having COVID-19. Methodology: The MIS-C patients in this prospective research will be diagnosed using WHO criteria. On admission, MIS-C patients with cardiac marker positive will have an anomaly in one or more of the following: Electrocardiography, Brain Natriuretic Peptide (BNP), serum troponin, and/or echocardiogram. Results: We will determine the prevalence of cardiac dysfunction in MIS-C when the study is completed. We will compare outcome factors such as hospital stay days, ICU admission, and death based on the therapy received. We all also study the correlation between the inflammatory marker and LV dysfunction. Conclusion: The study will most likely provide information on the prevalence of heart abnormality in MIS-C children. Also, the outcome of the MIS-C with cardiac dysfunction will be revealed.

Novel effects of acute COVID-19 on cardiac mechanical function: Two case studies.

The spread of the novel coronavirus 2019 (COVID-19) has caused a global pandemic. The disease has spread rapidly, and research shows that COVID-19 can induce long-lasting cardiac damage. COVID-19 can result in elevated cardiac biomarkers indicative of acute cardiac injury, and research utilizing echocardiography has shown that there is mechanical dysfunction in these patients as well, especially when observing the isovolumic, systolic, and diastolic portions of the cardiac cycle. The purpose of this study was to present two case studies on COVID-19 positive patients who had their cardiac mechanical function assessed every day during the acute period to show that cardiac function in these patients was altered, and the damage occurring can change from day-to-day. Participant 1 showed compromised cardiac function in the systolic time, diastolic time, isovolumic time, and the calculated heart performance index (HPI), and these impairments were sustained even 23 days post-symptom onset. Furthermore, Participant 1 showed prolonged systolic periods that lasted longer than the diastolic periods, indicative of elevated pulmonary artery pressure. Participant 2 showed decreases in systole and consequently, increases in HPI during the 3 days post-symptom onset, and these changes returned to normal after day 4. These results showed that daily observation of cardiac function can provide detailed information about the overall mechanism by which cardiac dysfunction is occurring and that COVID-19 can induce cardiac damage in unique patterns and thus can be studied on a case-by-case basis, day-to-day during infection. This could allow us to move toward more personalized cardiovascular medical treatment.

Suppression of Inflammatory Cardiac Cytokine Network in Rats with Untreated Obesity and Pre-Diabetes by AT2 Receptor Agonist NP-6A4.

Obesity affects over 42% of the United States population and exacerbates heart disease, the leading cause of death in men and women. Obesity also increases pro-inflammatory cytokines that cause chronic tissue damage to vital organs. The standard-of-care does not sufficiently attenuate these inflammatory sequelae. Angiotensin II receptor AT2R is an anti-inflammatory and cardiovascular protective molecule; however, AT2R agonists are not used in the clinic to treat heart disease. NP-6A4 is a new AT2R peptide agonist with an FDA orphan drug designation for pediatric cardiomyopathy. NP-6A4 increases AT2R expression (mRNA and protein) and nitric oxide generation in human cardiovascular cells. AT2R-antagonist PD123319 and AT2RSiRNA suppress NP-6A4-effects indicating that NP-6A4 acts through AT2R. To determine whether NP-6A4 would mitigate cardiac damage from chronic inflammation induced by untreated obesity, we investigated the effects of 2-weeks NP-6A4 treatment (1.8 mg/kg delivered subcutaneously) on cardiac pathology of male Zucker obese (ZO) rats that display obesity, pre-diabetes and cardiac dysfunction. NP-6A4 attenuated cardiac diastolic and systolic dysfunction, cardiac fibrosis and cardiomyocyte hypertrophy, but increased myocardial capillary density. NP-6A4 treatment suppressed tubulointerstitial injury marker urinary ß-NAG, and liver injury marker alkaline phosphatase in serum. These protective effects of NP-6A4 occurred in the presence of obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and without modulating blood pressure. NP-6A4 increased expression of AT2R (consistent with human cells) and cardioprotective erythropoietin (EPO) and Notch1 in ZO rat heart, but suppressed nineteen inflammatory cytokines. Cardiac miRNA profiling and in silico analysis showed that NP-6A4 activated a unique miRNA network that may regulate expression of AT2R, EPO, Notch1 and inflammatory cytokines, and mitigate cardiac pathology. Seventeen pro-inflammatory and pro-fibrotic cytokines that increase during lethal cytokine storms caused by infections such as COVID-19 were among the cytokines suppressed by NP-6A4 treatment in ZO rat heart. Thus, NP-6A4 activates a novel anti-inflammatory network comprised of 21 proteins in the heart that was not reported previously. Since NP-6A4's unique mode of action suppresses pro-inflammatory cytokine network and attenuates myocardial damage, it can be an ideal adjuvant drug with other anti-glycemic, anti-hypertensive, standard-of-care drugs to protect the heart tissues from pro-inflammatory and pro-fibrotic cytokine attack induced by obesity.

Early echocardiographic findings in patients hospitalized for COVID-19 pneumonia: a prospective, single center study.

BACKGROUND: Cardiac dysfunction, mainly assessed by biomarker alterations, has been described in COVID-19 infection. However, there are still areas of uncertainty regarding its effective role in disease evolution. Aim of this study was to evaluate early echocardiographic parameters in COVID pneumonia and their association with severity disease and prognosis. METHODS: An echocardiographic examination was performed within 72 h from admission in 64 consecutive patients hospitalized for COVID-19 pneumonia in our medium-intensity care unit, from March 30th to May 15th 2020. Six patients were excluded for inadequate acoustic window. RESULTS: Fifty-eight consecutive patients were finally enrolled, with a median age of 58 years. Twenty-two (38%) were classifiable as severe COVID-19 disease. Eight out of 58 patients experienced adverse evolution (six died, two were admitted to ICU and received mechanical ventilation), all of them in the severe pneumonia group. Severe pneumonia patients showed higher troponin, IL-6 and D-Dimer values. No significant new onset alterations of left and right ventricular systolic function parameters were observed. Patients with severe pneumonia showed higher mean estimated systolic pulmonary artery pressure (sPAP) (30.7 ± 5.2 mmHg vs 26.2 ± 4.3 mmHg, p = 0.006), even if in the normality range values. No differences in echocardiographic parameters were retrieved in patients with adverse events with respect to those with favorable clinical course. CONCLUSION: A mild sPAP increase in severe pneumonia patients with respect to those with milder disease was the only significant finding at early echocardiographic examination, without other signs of new onset major cardiac dysfunction. Future studies are needed to deepen the knowledge regarding minor cardiac functional perturbation in the evolution of a complex systemic disorder, in which the respiratory involvement appears as the main character, at least in non-ICU patients.

Right Ventricular Strain Is Common in Intubated COVID-19 Patients and Does Not Reflect Severity of Respiratory Illness.

BACKGROUND: Right ventricular (RV) dysfunction is common and associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19). In non-COVID-19 acute respiratory distress syndrome, RV dysfunction develops due to pulmonary hypoxic vasoconstriction, inflammation, and alveolar overdistension or atelectasis. Although similar pathogenic mechanisms may induce RV dysfunction in COVID-19, other COVID-19-specific pathology, such as pulmonary endothelialitis, thrombosis, or myocarditis, may also affect RV function. We quantified RV dysfunction by echocardiographic strain analysis and investigated its correlation with disease severity, ventilatory parameters, biomarkers, and imaging findings in critically ill COVID-19 patients. METHODS: We determined RV free wall longitudinal strain (FWLS) in 32 patients receiving mechanical ventilation for COVID-19-associated respiratory failure. Demographics, comorbid conditions, ventilatory parameters, medications, and laboratory findings were extracted from the medical record. Chest imaging was assessed to determine the severity of lung disease and the presence of pulmonary embolism. RESULTS: Abnormal FWLS was present in 66% of mechanically ventilated COVID-19 patients and was associated with higher lung compliance (39.6 vs 29.4 mL/cmH2O, P = 0.016), lower airway plateau pressures (21 vs 24 cmH2O, P = 0.043), lower tidal volume ventilation (5.74 vs 6.17 cc/kg, P = 0.031), and reduced left ventricular function. FWLS correlated negatively with age (r = -0.414, P = 0.018) and with serum troponin (r = 0.402, P = 0.034). Patients with abnormal RV strain did not exhibit decreased oxygenation or increased disease severity based on inflammatory markers, vasopressor requirements, or chest imaging findings. CONCLUSIONS: RV dysfunction is common among critically ill COVID-19 patients and is not related to abnormal lung mechanics or ventilatory pressures. Instead, patients with abnormal FWLS had more favorable lung compliance. RV dysfunction may be secondary to diffuse intravascular micro- and macro-thrombosis or direct myocardial damage. TRIAL REGISTRATION: National Institutes of Health #NCT04306393. Registered 10 March 2020, https://clinicaltrials.gov/ct2/show/NCT04306393.

Cardiac involvement in COVID-19 patients: mid-term follow up by cardiovascular magnetic resonance.

BACKGROUND: Coronavirus disease 2019 (COVID-19) induces myocardial injury, either direct myocarditis or indirect injury due to systemic inflammatory response. Myocardial involvement has been proved to be one of the primary manifestations of COVID-19 infection, according to laboratory test, autopsy, and cardiovascular magnetic resonance (CMR). However, the middle-term outcome of cardiac involvement after the patients were discharged from the hospital is yet unknown. The present study aimed to evaluate mid-term cardiac sequelae in recovered COVID-19 patients by CMR METHODS: A total of 47 recovered COVID-19 patients were prospectively recruited and underwent CMR examination. The CMR protocol consisted of black blood fat-suppressed T2 weighted imaging, T2 star mapping, left ventricle (LV) cine imaging, pre- and post-contrast T1 mapping, and late gadolinium enhancement (LGE). LGE were assessed in mixed both recovered COVID-19 patients and healthy controls. The LV and right ventricle (RV) function and LV mass were assessed and compared with healthy controls. RESULTS: A total of 44 recovered COVID-19 patients and 31 healthy controls were studied. LGE was found in 13 (30%) of COVID-19 patients. All LGE lesions were located in the mid myocardium and/or sub-epicardium with a scattered distribution. Further analysis showed that LGE-positive patients had significantly decreased LV peak global circumferential strain (GCS), RV peak GCS, RV peak global longitudinal strain (GLS) as compared to non-LGE patients (p < 0.05), while no difference was found between the non-LGE patients and healthy controls. CONCLUSION: Myocardium injury existed in 30% of COVID-19 patients. These patients have depressed LV GCS and peak RV strains at the 3-month follow-up. CMR can monitor the COVID-19-induced myocarditis progression, and CMR strain analysis is a sensitive tool to evaluate the recovery of LV and RV dysfunction.

Network pharmacology and RNA-sequencing reveal the molecular mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up to 20%-30% of patients hospitalized with COVID-19 have evidence of cardiac dysfunction. Xuebijing injection is a compound injection containing five traditional Chinese medicine ingredients, which can protect cells from SARS-CoV-2-induced cell death and improve cardiac function. However, the specific protective mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction remains unclear. METHODS: The therapeutic effect of Xuebijing injection on COVID-19 was validated by the TCM Anti COVID-19 (TCMATCOV) platform. RNA-sequencing (RNA-seq) data from GSE150392 was used to find differentially expressed genes (DEGs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. Data from GSE151879 was used to verify the expression of Angiotensin I Converting Enzyme 2 (ACE2) and central hub genes in both human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) and adult human CMs with SARS-CoV-2 infection. RESULTS: A total of 97 proteins were identified as the therapeutic targets of Xuebijing injection for COVID-19. There were 22 DEGs in SARS-CoV-2 infected hiPSC-CMs overlapped with the 97 therapeutic targets, which might be the therapeutic targets of Xuebijing injection on COVID-19-induced cardiac dysfunction. Based on the bioinformatics analysis, 7 genes (CCL2, CXCL8, FOS, IFNB1, IL-1A, IL-1B, SERPINE1) were identified as central hub genes and enriched in pathways including cytokines, inflammation, cell senescence and oxidative stress. ACE2, the receptor of SARS-CoV-2, and the 7 central hub genes were differentially expressed in at least two kinds of SARS-CoV-2 infected CMs. Besides, FOS and quercetin exhibited the tightest binding by molecular docking analysis. CONCLUSION: Our study indicated the underlying protective effect of Xuebijing injection on COVID-19, especially on COVID19-induced cardiac dysfunction, which provided the theoretical basis for exploring the potential protective mechanism of Xuebijing injection on COVID19-induced cardiac dysfunction.

Microvascular Angiopathic Consequences of COVID-19.

The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first appeared in Wuhan, China in December, 2019. Ever increasing data is continuing to emerge about the impact of COVID-19 on cardiovascular tissue and other organ system. Clinical features associated with COVID-19 suggest that endothelial cell dysfunction and microvascular thrombosis are to a large extent contributing to resultant multi-organ complications. This review is aimed at highlighting the critical aspects associated with COVID-19 and its presumed microvascular angiopathic consequences on the cardiovascular system leading to multi-organ dysfunction.

Cardiac Abnormalities Seen in Pediatric Patients During the SARS-CoV2 Pandemic: An International Experience.

Background During the SARS-CoV2 pandemic, there has been increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi-system inflammatory syndrome (MIS-C) during the SARS-CoV2 pandemic. Methods and Results We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain and Pakistan with MIS-C and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings and initial therapies. A total of 55 patients presented with MIS-C. Thirty-five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion and 11 (20%) with coronary abnormalities. Twenty-seven (49%) required ICU admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT pro-BNP, D-dimer and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular (AV) block, transient AV block and ventricular tachycardia. Conclusions We describe the first international cohort of pediatric patients with MIS-C during the SARS-CoV2 pandemic with a range of cardiac manifestations. This paper brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow-up.