Search

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae., Competing Interests: Conflict of interest: F.W.A., P.A., B.J.J.M.B., S.M.D., M.F., M.G., S.V.L., R.M., C.P., M.P., G.G.S., S.S., C.G.-T., T.K.: no conflicts to disclose. G.G.C. is coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischaemia-reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida solutions limited. P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies. C.T. has received speaker fees and/or contributions to congresses from Abbott, Abiomed, Astra Zeneca, Bayer, Böhringer-Ingelheim, Novartis, Pfizer, and Servier; all outside the submitted work., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell 'omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell technology which has demonstrated disease causality for several genetic polymorphisms in long-QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system., Competing Interests: Conflicts of interest: C.G.T. has received funding from Amgen, and personal fees from VivaLyfe, and is listed as an inventor on two heart failure patents., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Several risk factors have been identified to predict worse outcomes in patients affected by SARS-CoV-2 infection. Machine learning algorithms represent a novel approach to identifying a prediction model with a good discriminatory capacity to be easily used in clinical practice. The aim of this study was to obtain a risk score for in-hospital mortality in patients with coronavirus disease infection (COVID-19) based on a limited number of features collected at hospital admission., Methods and Results: We studied an Italian cohort of consecutive adult Caucasian patients with laboratory-confirmed COVID-19 who were hospitalized in 13 cardiology units during Spring 2020. The Lasso procedure was used to select the most relevant covariates. The dataset was randomly divided into a training set containing 80% of the data, used for estimating the model, and a test set with the remaining 20%. A Random Forest modeled in-hospital mortality with the selected set of covariates: its accuracy was measured by means of the ROC curve, obtaining AUC, sensitivity, specificity and related 95% confidence interval (CI). This model was then compared with the one obtained by the Gradient Boosting Machine (GBM) and with logistic regression. Finally, to understand if each model has the same performance in the training and test set, the two AUCs were compared using the DeLong's test. Among 701 patients enrolled (mean age 67.2 ± 13.2 years, 69.5% male individuals), 165 (23.5%) died during a median hospitalization of 15 (IQR, 9-24) days. Variables selected by the Lasso procedure were: age, oxygen saturation, PaO2/FiO2, creatinine clearance and elevated troponin. Compared with those who survived, deceased patients were older, had a lower blood oxygenation, lower creatinine clearance levels and higher prevalence of elevated troponin (all P < 0.001). The best performance out of the samples was provided by Random Forest with an AUC of 0.78 (95% CI: 0.68-0.88) and a sensitivity of 0.88 (95% CI: 0.58-1.00). Moreover, Random Forest was the unique model that provided similar performance in sample and out of sample (DeLong test P = 0.78)., Conclusion: In a large COVID-19 population, we showed that a customizable machine learning-based score derived from clinical variables is feasible and effective for the prediction of in-hospital mortality., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Introduction: The role of sex compared to comorbidities and other prognostic variables in patients with coronavirus disease (COVID-19) is unclear., Methods: This is a retrospective observational study on patients with COVID-19 infection, referred to 13 cardiology units. The primary objective was to assess the difference in risk of death between the sexes. The secondary objective was to explore sex-based heterogeneity in the association between demographic, clinical and laboratory variables, and patients' risk of death., Results: Seven hundred and one patients were included: 214 (30.5%) women and 487 (69.5%) men. During a median follow-up of 15 days, deaths occurred in 39 (18.2%) women and 126 (25.9%) men. In a multivariable Cox regression model, men had a nonsignificantly higher risk of death vs. women (P = 0.07).The risk of death was more than double in men with a low lymphocytes count as compared with men with a high lymphocytes count [overall survival hazard ratio (OS-HR) 2.56, 95% confidence interval (CI) 1.72-3.81]. In contrast, lymphocytes count was not related to death in women (P = 0.03).Platelets count was associated with better outcome in men (OS-HR for increase of 50 × 103 units: 0.88 95% CI 0.78-1.00) but not in women. The strength of association between higher PaO2/FiO2 ratio and lower risk of death was larger in women (OS-HR for increase of 50 mmHg/%: 0.72, 95% CI 0.59-0.89) vs. men (OS-HR: 0.88, 95% CI 0.80-0.98; P = 0.05)., Conclusions: Patients' sex is a relevant variable that should be taken into account when evaluating risk of death from COVID-19. There is a sex-based heterogeneity in the association between baseline variables and patients' risk of death., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Data concerning the combined prognostic role of natriuretic peptide (NP) and troponin in patients with COVID-19 are lacking. The aim of the study is to evaluate the combined prognostic value of NPs and troponin in hospitalized COVID-19 patients. From March 1, 2020 to April 9, 2020, consecutive patients with COVID-19 and available data on cardiac biomarkers at admission were recruited. Patients admitted for acute coronary syndrome were excluded. Troponin levels were defined as elevated when greater than the 99 th percentile of normal values. NPs were considered elevated if above the limit for ruling in acute heart failure (HF). A total of 341 patients were included in this study, mean age 68 ± 13 years, 72% were men. During a median follow-up period of 14 days, 81 patients (24%) died. In the Cox regression analysis, patients with elevated both NPs and troponin levels had higher risk of death compared with those with normal levels of both (hazard ratio 2.94; 95% confidence interval 1.31 to 6.64; p = 0.009), and this remained significant after adjustment for age, gender, oxygen saturation, HF history, and chronic kidney disease. Interestingly, NPs provided risk stratification also in patients with normal troponin values (hazard ratio 2.86; 95% confidence interval 1.21 to 6.72; p = 0.016 with high NPs levels). These data show the combined prognostic role of troponin and NPs in COVID-19 patients. NPs value may be helpful in identifying patients with a worse prognosis among those with normal troponin values. Further, NPs' cut-point used for diagnosis of acute HF has a predictive role in patients with COVID-19., Competing Interests: Disclosures Prof Piergiuseppe Agostoni reported nonfinancial support from Menarini, Novartis, and Boehringer; grants from Daiichiò Sankyo and Bayer; and grants and nonfinancial support from Actelion outside the submitted work. Prov Pietro Ameri reported having received speaker and advisor honoraria from Novartis, AstraZeneca, Vifor, Daiichi Sankyo, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, and Merck, Sharp & Dohme and nonfinancial support from Actelion outside the submitted work. Dr Valentina Carubelli received consulting honoraria from CVie Therapeutics Limited, Servier, and Windtree Therapeutics outside the submitted work. Dr. Riccardo Maria Inciardi received speaker and advisor honoraria from Daiichi-Sankyo, Boehringer Ingelheim. Prof Sergio Leonardi reported grants and personal fees from AstraZeneca and personal fees from BMS/Pfizer, Novo Nordisk, and Chiesi outside the submitted work. Prof Carlo Mario Lombardi received speaker and advisor honoraria from Novartis and Astra Zeneca. Dr Andrea Mortara reports personal consulting honoraria from Novartis, Servier, Astra Zeneca for participation to advisory board meetings and receives grants from Novartis and Niccomo for research trials. Prof Massimo Piepoli reported having received research grants and speaking fees from Novartis, Servier, and TRX and nonfinancial support from Vifor outside the submitted work. Prof Michele Senni reported personal fees from Novartis, Abbott, Merck, Bayer, Boehringer, Vifor, and AstraZeneca outside the submitted work. Prof Marco Metra reported personal consulting honoraria from Abbott Vascular, Amgen, Bayer, Edwards Therapeutics, Servier, Vifor Pharma, and Windtree Therapeutics for participation to advisory board meetings and executive committees of clinical trials. All other authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To assess the clinical relevance of a history of atrial fibrillation (AF) in hospitalized patients with coronavirus disease 2019 (COVID-19)., Methods and Results: We enrolled 696 consecutive patients (mean age 67.4 ± 13.2 years, 69.7% males) admitted for COVID-19 in 13 Italian cardiology centres between 1 March and 9 April 2020. One hundred and six patients (15%) had a history of AF and the median hospitalization length was 14 days (interquartile range 9-24). Patients with a history of AF were older and with a higher burden of cardiovascular risk factors. Compared to patients without AF, they showed a higher rate of in-hospital death (38.7% vs. 20.8%; P < 0.001). History of AF was associated with an increased risk of death after adjustment for clinical confounders related to COVID-19 severity and cardiovascular comorbidities, including history of heart failure (HF) and increased plasma troponin [adjusted hazard ratio (HR): 1.73; 95% confidence interval (CI) 1.06-2.84; P = 0.029]. Patients with a history of AF also had more in-hospital clinical events including new-onset AF (36.8% vs. 7.9%; P < 0.001), acute HF (25.3% vs. 6.3%; P < 0.001), and multiorgan failure (13.9% vs. 5.8%; P = 0.010). The association between AF and worse outcome was not modified by previous or concomitant use of anticoagulants or steroid therapy (P for interaction >0.05 for both) and was not related to stroke or bleeding events., Conclusion: Among hospitalized patients with COVID-19, a history of AF contributes to worse clinical course with a higher mortality and in-hospital events including new-onset AF, acute HF, and multiorgan failure. The mortality risk remains significant after adjustment for variables associated with COVID-19 severity and comorbidities., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: Myocardial injury (MI) in coronavirus disease-19 (COVID-19) is quite prevalent at admission and affects prognosis. Little is known about troponin trajectories and their prognostic role. We aimed to describe the early in-hospital evolution of MI and its prognostic impact., Methods and Results: We performed an analysis from an Italian multicentre study enrolling COVID-19 patients, hospitalized from 1 March to 9 April 2020. MI was defined as increased troponin level. The first troponin was tested within 24 h from admission, the second one between 24 and 48 h. Elevated troponin was defined as values above the 99th percentile of normal values. Patients were divided in four groups: normal, normal then elevated, elevated then normal, and elevated. The outcome was in-hospital death. The study population included 197 patients; 41% had normal troponin at both evaluations, 44% had elevated troponin at both assessments, 8% had normal then elevated troponin, and 7% had elevated then normal troponin. During hospitalization, 49 (25%) patients died. Patients with incident MI, with persistent MI, and with MI only at admission had a higher risk of death compared with those with normal troponin at both evaluations (P < 0.001). At multivariable analysis, patients with normal troponin at admission and MI injury on Day 2 had the highest mortality risk (hazard ratio 3.78, 95% confidence interval 1.10-13.09, P = 0.035)., Conclusions: In patients admitted for COVID-19, re-test MI on Day 2 provides a prognostic value. A non-negligible proportion of patients with incident MI on Day 2 is identified at high risk of death only by the second measurement., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Glucocorticoid therapy has emerged as an effective therapeutic option in hospitalized patients with coronavirus disease 2019 (COVID-19). This study aimed to focus on the impact of relevant clinical and laboratory factors on the protective effect of glucocorticoids on mortality., Methods: A sub-analysis was performed of the multicenter Cardio-COVID-Italy registry, enrolling consecutive patients with COVID-19 admitted to 13 Italian cardiology units between 01 March 2020 and 09 April 2020. The primary endpoint was in-hospital mortality., Results: A total of 706 COVID-19 patients were included (349 treated with glucocorticoids, 357 not treated with glucocorticoids). After adjustment for relevant covariates, use of glucocorticoids was associated with a lower risk of in-hospital mortality (adjusted HR 0.44; 95% CI 0.26-0.72; p = 0.001). A significant interaction was observed between the protective effect of glucocorticoids on mortality and PaO 2 /FiO 2 ratio on admission (p = 0.042), oxygen saturation on admission (p = 0.017), and peak CRP (0.023). Such protective effects of glucocorticoids were mainly observed in patients with lower PaO 2 /FiO 2 ratio (<300), lower oxygen saturation (<90%), and higher CRP (>100 mg/L)., Conclusions: The protective effects of glucocorticoids on mortality in COVID-19 were more evident among patients with worse respiratory parameters and higher systemic inflammation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Pulmonary embolism (PE) has been described in coronavirus disease 2019 (COVID-19) critically ill patients, but the evidence from more heterogeneous cohorts is limited., Methods: Data were retrospectively obtained from consecutive COVID-19 patients admitted to 13 Cardiology Units in Italy, from March 1st to April 9th, 2020, and followed until in-hospital death, discharge, or April 23rd, 2020. The association of baseline variables with computed tomography-confirmed PE was investigated by Cox hazards regression analysis. The relationship between D-dimer levels and PE incidence was evaluated using restricted cubic splines models., Results: The study included 689 patients (67.3 ± 13.2 year-old, 69.4% males), of whom 43.6% were non-invasively ventilated and 15.8% invasively. 52 (7.5%) had PE over 15 (9-24) days of follow-up. Compared with those without PE, these subjects had younger age, higher BMI, less often heart failure and chronic kidney disease, more severe cardio-pulmonary involvement, and higher admission D-dimer [4344 (1099-15,118) vs. 818.5 (417-1460) ng/mL, p < 0.001]. They also received more frequently darunavir/ritonavir, tocilizumab and ventilation support. Furthermore, they faced more bleeding episodes requiring transfusion (15.6% vs. 5.1%, p < 0.001) and non-significantly higher in-hospital mortality (34.6% vs. 22.9%, p = 0.06). In multivariate regression, only D-dimer was associated with PE (HR 1.72, 95% CI 1.13-2.62; p = 0.01). The relation between D-dimer concentrations and PE incidence was linear, without inflection point. Only two subjects had a baseline D-dimer < 500 ng/mL., Conclusions: PE occurs in a sizable proportion of hospitalized COVID-19 patients. The implications of bleeding events and the role of D-dimer in this population need to be clarified.

The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-β, IL8 and IL1β). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pandolfi, Bozzini, Frangipane, Percivalle, De Luigi, Violatto, Lopez, Gabanti, Carsana, D’Amato, Morosini, De Amici, Nebuloni, Fossali, Colombo, Saracino, Codullo, Gnecchi, Bigini, Baldanti, Lilleri and Meloni.)

Anti-inflammatory and immune-modulatory therapies have been proposed for the treatment of COVID-19 and its most serious complications. Among others, the use of mesenchymal stromal cells (MSCs) is under investigation given their well-documented anti-inflammatory and immunomodulatory properties. However, some critical issues regarding the possibility that MSCs could be infected by the virus have been raised. Angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2) are the main host cell factors for the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), entry, but so far it is unclear if human MSCs do or do not express these two proteins. To elucidate these important aspects, we evaluated if human MSCs from both fetal and adult tissues constitutively express ACE2 and TMPRSS2 and, most importantly, if they can be infected by SARS-CoV-2. We evaluated human MSCs derived from amnios, cord blood, cord tissue, adipose tissue, and bone marrow. ACE2 and TMPRSS2 were expressed by the SARS-CoV-2-permissive human pulmonary Calu-3 cell line but not by all the MSCs tested. MSCs were then exposed to SARS-CoV-2 wild strain without evidence of cytopathic effect. Moreover, we also excluded that the MSCs could be infected without showing lytic effects since their conditioned medium after SARS-CoV-2 exposure did not contain viral particles. Our data, demonstrating that MSCs derived from different human tissues are not permissive to SARS-CoV-2 infection, support the safety of MSCs as potential therapy for COVID-19., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Aims: To assess the prognostic value of a history of heart failure (HF) in patients with coronavirus disease 2019 (COVID-19)., Methods and Results: We enrolled 692 consecutive patients admitted for COVID-19 in 13 Italian cardiology centres between 1 March and 9 April 2020. Mean age was 67.4 ± 13.2 years, 69.5% of patients were males, 90 (13.0%) had a history of HF, median hospitalization length was 14 days (interquartile range 9-24). In-hospital death occurred in 37 of 90 patients (41.1%) with HF history vs. 126 of those with no HF history (20.9%). The increased risk of death associated with HF history remained significant after adjustment for clinical variables related to COVID-19 and HF severity, including comorbidities, oxygen saturation, lymphocyte count and plasma troponin [adjusted hazard ratio (HR) for death: 2.25; 95% confidence interval (CI) 1.26-4.02; P = 0.006 at multivariable Cox regression model including 404 patients]. Patients with a history of HF also had more in-hospital complications including acute HF (33.3% vs. 5.1%, P < 0.001), acute renal failure (28.1% vs. 12.9%, P < 0.001), multiorgan failure (15.9% vs. 5.8%, P = 0.004) and sepsis (18.4% vs. 8.9%, P = 0.006). Other independent predictors of outcome were age, sex, oxygen saturation and oxygen partial pressure at arterial gas analysis/fraction of inspired oxygen ratio (PaO 2 /FiO 2 ). In-hospital treatment with corticosteroids and heparin had beneficial effects (adjusted HR for death: 0.46; 95% CI 0.29-0.74; P = 0.001; n = 404 for corticosteroids, and adjusted HR 0.41; 95% CI 0.25-0.67; P < 0.001; n = 364 for heparin)., Conclusions: Hospitalized patients with COVID-19 and a history of HF have an extremely poor outcome with higher mortality and in-hospital complications. HF history is an independent predictor of increased in-hospital mortality., (© 2020 European Society of Cardiology.)

Importance: Myocardial injury, detected by elevated plasma troponin levels, has been associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19). However, the initial data were reported from single-center or 2-center studies in Chinese populations. Compared with these patients, European and US patients are older, with more comorbidities and higher mortality rates., Objective: To evaluate the prevalence and prognostic value of myocardial injury, detected by elevated plasma troponin levels, in a large population of White Italian patients with COVID-19., Design, Setting, and Participants: This is a multicenter, cross-sectional study enrolling consecutive patients with laboratory-confirmed COVID-19 who were hospitalized in 13 Italian cardiology units from March 1 to April 9, 2020. Patients admitted for acute coronary syndrome were excluded. Elevated troponin levels were defined as values greater than the 99th percentile of normal values., Main Outcomes and Measures: Clinical characteristics and outcomes stratified as elevated or normal cardiac troponin levels at admission, defined as troponin T or troponin I at a level greater than the 99th percentile of normal values., Results: A total of 614 patients with COVID-19 were included in this study (mean age [SD], 67 [13] years; 70.8% male), of whom 148 patients (24.1%) died during the hospitalization. Elevated troponin levels were found in 278 patients (45.3%). These patients were older (mean [SD] age, 64.0 [13.6] years vs 71.3 [12.0] years; P < .001) and had higher prevalence of hypertension (168 patients [50.5%] vs 182 patients [65.9%]; P < .001), heart failure (24 [7.2%]; 63 [22.8%]; P < .001), coronary artery disease (50 [15.0%] vs 87 [31.5%]; P < .001), and atrial fibrillation (33 [9.9%] vs 67 [24.3%]; P < .001). Elevated troponin levels were associated with an increased in-hospital mortality (37% vs 13%; HR, 1.71 [95% CI, 1.13-2.59]; P = .01 via multivariable Cox regression analysis), and this was independent from concomitant cardiac disease. Elevated troponin levels were also associated with a higher risk of in-hospital complications: heart failure (44 patients [19.2%] vs 7 patients [2.9%]; P < .001), sepsis (31 [11.7%] vs 21 [6.4%]; P = .03), acute kidney failure (41 [20.8%] vs 13 [6.2%]; P < .001), multiorgan failure (21 [10.9%] vs 6 [2.9%]; P = .003), pulmonary embolism (27 [9.9%] vs 17 [5.2%]; P = .04), delirium (13 [6.8%] vs 3 [1.5%]; P = .02), and major bleeding (16 [7.0%] vs 4 [1.6%]; P = .008)., Conclusions and Relevance: In this multicenter, cross-sectional study of Italian patients with COVID-19, elevated troponin was an independent variable associated with in-hospital mortality and a greater risk of cardiovascular and noncardiovascular complications during a hospitalization for COVID-19.

In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro. While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring is challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrated that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation and halted the beating at high concentration due to the combined effect of HCQ on multiple ion currents. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs. asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine. [ABSTRACT FROM AUTHOR]

The correlation between myocardial injury and clinical outcome in COVID-19 patients is gaining attention in the literature. The aim of the present study was to evaluate the role of cardiac involvement and of respiratory failure in a cohort of COVID-19 patients hospitalized in an academic hospital in Lombardy, one of the most affected Italian (and worldwide) regions by the epidemic. The study included 405 consecutive patients with confirmed COVID-19 admitted to a medical ward from February 25th to March 31st, 2020. Follow-up of surviving patients ended either at hospital discharge or by July 30th, 2020. Myocardial injury was defined on the basis of the presence of blood levels of hs-TnI above the 99th percentile upper reference limit. Respiratory function was assessed as PaO2/FiO2 (P/F) ratio. The primary end-point was death for any cause. During hospitalization, 124 patients died. Death rate increased from 7.9% in patients with normal hs-TnI plasma levels and no cardiac comorbidity to 61.5% in patients with elevated hs-TnI and cardiac involvement (p < 0.001). At multivariable analysis, older age, P/F ratio < 200 (both p < 0.001) and hs-TnI plasma levels were independent predictors of death. However, it must be emphasized that the median values of hs-TnI were within normal range in non-survivors. Cardiac involvement at presentation was associated with poor prognosis in COVID-19 patients, but, even in a population of COVID-19 patients who did not require invasive ventilation at hospital admission, mortality was mainly driven by older age and respiratory failure. [ABSTRACT FROM AUTHOR]