Advertisement

Joint effect of heart failure and coronary artery disease on the risk of death during hospitalization for COVID-19

Published:April 19, 2021DOI:https://doi.org/10.1016/j.ejim.2021.04.007

      Highglights

      • History of heart failure and coronary disease are common comorbidities in patients with COVID-19.
      • Heart failure and coronary disease are associated with a worse prognosis during hospitalization.
      • These two conditions exert a synergistic effect on the risk of in-hospital mortality.
      • This detrimental synergy may be mediated by systemic inflammation and haemodynamic impairment.
      • Further studies are needed to investigate these complex pathophysiologic mechanisms.

      Abstract

      Aims

      heart failure (HF) and coronary artery disease (CAD) are independent predictors of death in patients with COVID-19. The adverse prognostic impact of the combination of HF and CAD in these patients is unclear.

      Methods and results

      we analysed data from 954 consecutive patients hospitalized for SARS-CoV-2 in five Italian Hospitals from February 23 to May 22, 2020. The study was a systematic prospective data collection according to a pre-specified protocol. All-cause mortality during hospitalization was the outcome measure.
      Mean duration of hospitalization was 33 days. Mortality was 11% in the total population and 7.4% in the group without evidence of HF or CAD (reference group). Mortality was 11.6% in the group with CAD and without HF (odds ratio [OR]: 1.6, p = 0.120), 15.5% in the group with HF and without CAD (OR: 2.3, p = 0.032), and 35.6% in the group with CAD and HF (OR: 6.9, p<0.0001).
      The risk of mortality in patients with CAD and HF combined was consistently higher than the sum of risks related to either disorder, resulting in a significant synergistic effect (p<0.0001) of the two conditions. Age-adjusted attributable proportion due to interaction was 64%. Adjusting for the simultaneous effects of age, hypotension, and lymphocyte count did not significantly lower attributable proportion which persisted statistically significant (p = 0.0360).

      Conclusion

      The combination of HF and CAD exerts a marked detrimental impact on the risk of mortality in hospitalized patients with COVID-19, which is independent on other adverse prognostic markers.

      Graphical abstract

      Keywords

      Introduction

      Since the initial coronavirus (SARS-CoV-2) outbreak in the province of Wuhan, China, more than 50 million people have been infected so far, causing unnerving impact on routine patient care and leading to significant excess of morbidity and mortality worldwide [

      Centers for Disease Control and Prevention. People who are at higher risk for severe illness https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html (Accessed on December 01, 2020).

      ].
      Coronavirus-related syndrome (COVID-19) is known to be associated with life-threating interstitial pneumonia, but SARS-CoV-2-related cardiac involvement is now acknowledged to be part of the wide spectrum of COVID-19 [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Madjid M.
      • Safavi-Naeini P.
      • Solomon S.D.
      • Vardeny O.
      Potential effects of coronaviruses on the cardiovascular system: a review.
      ]. Moreover, the prevalence of cardiovascular comorbidities in patients hospitalised for SARS-CoV-2 is not negligible, spanning from 2% to 42% of cases and being associated with a more than two-fold risk of in-hospital death [
      • Inciardi R.M.
      • Adamo M.
      • Lupi L.
      • Cani D.S.
      • Di Pasquale M.
      • Tomasoni D.
      • Italia L.
      • Zaccone G.
      • Tedino C.
      • Fabbricatore D.
      • Curnis A.
      • Faggiano P.
      • Gorga E.
      • Lombardi C.M.
      • Milesi G.
      • Vizzardi E.
      • Volpini M.
      • Nodari S.
      • Specchia C.
      • Maroldi R.
      • Bezzi M.
      • Metra M.
      Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.
      ,
      • Bader F.
      • Manla Y.
      • Atallah B.
      • Starling R.C.
      Heart failure and COVID-19.
      ].
      In this evolving clinical scenario, there is a need of scientific knowledge on prognostic factors for adverse outcome in patients with COVID-19 [
      • Noor F.M.
      • Islam M.M.
      Prevalence and associated risk factors of mortality among COVID-19 patients: a meta-analysis.
      ]. In this context, the United States Centers for Disease Control and Prevention (CDC) has created a list of established and possible risk factors that have been associated with severe disease [

      Centers for Disease Control and Prevention. People who are at higher risk for severe illness https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html (Accessed on December 01, 2020).

      ]. Among established risk factors, history of heart failure (HF) and coronary artery disease (CAD) have been included as heart conditions at increased risk of severe illness and death [

      Centers for Disease Control and Prevention. People who are at higher risk for severe illness https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html (Accessed on December 01, 2020).

      ].
      Although an interaction between these two conditions may be postulated in the general population of HF patients [
      • Silverdal J.
      • Sjoland H.
      • Bollano E.
      • Pivodic A.
      • Dahlstrom U.
      • Fu M.
      Prognostic impact over time of ischaemic heart disease vs. non-ischaemic heart disease in heart failure.
      ], their joint effect on the risk of death among COVID-19 patients remains to be explicitly examined using data collected in a prospective fashion.
      Thus, the main aim of the present study was to investigate the distinct and the potential synergy of HF and CAD on the risk of death in patients hospitalized for COVID-19.

      Methods

      We analysed data from consecutive patients hospitalized from February 23 to May 22, 2020 in 5 hospitals of the Lombardy region and belonging to the Maugeri Care and Research Institutes Network [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Angeli F.
      • Bachetti T.
      Maugeri Study G: temporal changes in co-morbidities and mortality in patients hospitalized for COVID-19 in Italy.
      ].
      Diagnosis of viral infection was confirmed in all patients by RNA reverse-transcriptase-polimerase-chain-reaction (RT-PCR) assays from nasopharyngeal swab specimens [
      • Li T.
      Diagnosis and clinical management of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection: an operational recommendation of Peking Union Medical College Hospital (V2.0).
      ].
      Notably, our study was not a retrospective collection of clinical notes of patients hospitalized for COVID-19, but rather a pre-designed protocol with subsequent prospective collection of data [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ]. The protocol was approved by the Ethical Committee of our Institution and patients gave their written informed consent to participate [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ].
      Demographic, laboratory, and clinical management data were collected at admission and throughout the entire in-hospital stay. The presence of comorbidities was defined according to documented medical history, as collected by investigators at study site-level, including interrogation of electronic health record data of the Lombardy region.
      All clinical evaluations were performed by attending physicians during the clinical interview and through interrogation of medical records. Comorbidities (including type II diabetes, chronic kidney disease, dyslipidemia, hypertension, CAD, and HF) were defined according to current Guidelines [
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • Bueno H.
      • Cleland J.G.F.
      • Coats A.J.S.
      • Falk V.
      • Gonzalez-Juanatey J.R.
      • Harjola V.P.
      • Jankowska E.A.
      • Jessup M.
      • Linde C.
      • Nihoyannopoulos P.
      • Parissis J.T.
      • Pieske B.
      • Riley J.P.
      • Rosano G.M.C.
      • Ruilope L.M.
      • Ruschitzka F.
      • Rutten F.H.
      • van der Meer P.
      • Group E.S.C.S.D.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Piepoli M.F.
      • Hoes A.W.
      • Agewall S.
      • Albus C.
      • Brotons C.
      • Catapano A.L.
      • Cooney M.T.
      • Corra U.
      • Cosyns B.
      • Deaton C.
      • Graham I.
      • Hall M.S.
      • Hobbs F.D.R.
      • Lochen M.L.
      • Lollgen H.
      • Marques-Vidal P.
      • Perk J.
      • Prescott E.
      • Redon J.
      • Richter D.J.
      • Sattar N.
      • Smulders Y.
      • Tiberi M.
      • van der Worp H.B.
      • van Dis I.
      • Verschuren W.M.M.
      • Binno S.
      • Group E.S.C.S.D.
      2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
      ,
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • Capodanno D.
      • Barbato E.
      • Funck-Brentano C.
      • Prescott E.
      • Storey R.F.
      • Deaton C.
      • Cuisset T.
      • Agewall S.
      • Dickstein K.
      • Edvardsen T.
      • Escaned J.
      • Gersh B.J.
      • Svitil P.
      • Gilard M.
      • Hasdai D.
      • Hatala R.
      • Mahfoud F.
      • Masip J.
      • Muneretto C.
      • Valgimigli M.
      • Achenbach S.
      • Bax J.J.
      • 2019 Group ESCSD:
      ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      ,
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • Federici M.
      • Filippatos G.
      • Grobbee D.E.
      • Hansen T.B.
      • Huikuri H.V.
      • Johansson I.
      • Juni P.
      • Lettino M.
      • Marx N.
      • Mellbin L.G.
      • Ostgren C.J.
      • Rocca B.
      • Roffi M.
      • Sattar N.
      • Seferovic P.M.
      • Sousa-Uva M.
      • Valensi P.
      • Wheeler D.C.
      • Group E.S.C.S.D.
      2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ,
      • Mach F.
      • Baigent C.
      • Catapano A.L.
      • Koskinas K.C.
      • Casula M.
      • Badimon L.
      • Chapman M.J.
      • De Backer G.G.
      • Delgado V.
      • Ference B.A.
      • Graham I.M.
      • Halliday A.
      • Landmesser U.
      • Mihaylova B.
      • Pedersen T.R.
      • Riccardi G.
      • Richter D.J.
      • Sabatine M.S.
      • Taskinen M.R.
      • Tokgozoglu L.
      • Wiklund O.
      • Group E.S.C.S.D.
      2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ,
      • Verdecchia P.
      • Reboldi G.
      • Angeli F.
      The 2020 International Society of Hypertension global hypertension practice guidelines - key messages and clinical considerations.
      ,
      • Felker G.M.
      • Shaw L.K.
      • O'Connor C.M.
      A standardized definition of ischemic cardiomyopathy for use in clinical research.
      ].
      More specifically, HF patients were identified according to history of a symptomatic syndrome, as graded according to the New York Heart Association (NYHA) functional classification, or prior hospitalization for acute heart failure requiring intravenous therapy (diuretics, inotropes or vasodilators) [
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • Bueno H.
      • Cleland J.G.F.
      • Coats A.J.S.
      • Falk V.
      • Gonzalez-Juanatey J.R.
      • Harjola V.P.
      • Jankowska E.A.
      • Jessup M.
      • Linde C.
      • Nihoyannopoulos P.
      • Parissis J.T.
      • Pieske B.
      • Riley J.P.
      • Rosano G.M.C.
      • Ruilope L.M.
      • Ruschitzka F.
      • Rutten F.H.
      • van der Meer P.
      • Group E.S.C.S.D.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ].
      History of CAD was defined by at least one of the following criteria: 1) presence of any epicardial coronary vessels with >75% stenosis tested on coronary angiography; 2) history of acute coronary syndrome; 3) coronary revascularization (either percutaneous transluminal coronary angioplasty or coronary artery bypass grafting) [
      • Felker G.M.
      • Shaw L.K.
      • O'Connor C.M.
      A standardized definition of ischemic cardiomyopathy for use in clinical research.
      ].
      The study outcome was all-cause mortality during hospitalization.
      Statistical analysis. Analyses were performed using Stata, version 16 (StataCorp LP, College Station, TX, USA) and R version 2.9.2 (R Foundation for Statistical Computing, Vienna, Austria). We expressed continuous variables as mean ± standard deviation (SD) and the categorical variables as proportions. We analysed differences in proportions between groups using the χ2 test. Mean values of variables were compared by independent sample t-test.
      We evaluated the effect of prognostic factors on mortality by univariable and multivariable logistic regression analyses. The odds ratios (ORs) from the univariable and multivariable analyses and their corresponding two-sided 95% confidence intervals (CI) were derived from the regression coefficients in the logistic models.
      We tested the prognostic impact of several variables which proved a significant influence on mortality in this setting. They included: age (years) [
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Iaccarino G.
      • Grassi G.
      • Borghi C.
      • Ferri C.
      • Salvetti M.
      • Volpe M.
      • Investigators S.-.R.
      Age and Multimorbidity Predict Death Among COVID-19 Patients: results of the SARS-RAS Study of the Italian Society of Hypertension.
      ]; history of diabetes (yes/no) [
      • Iaccarino G.
      • Grassi G.
      • Borghi C.
      • Ferri C.
      • Salvetti M.
      • Volpe M.
      • Investigators S.-.R.
      Age and Multimorbidity Predict Death Among COVID-19 Patients: results of the SARS-RAS Study of the Italian Society of Hypertension.
      ]; history of hypertension (yes/no) [
      • Izcovich A.
      • Ragusa M.A.
      • Tortosa F.
      • Lavena Marzio M.A.
      • Agnoletti C.
      • Bengolea A.
      • Ceirano A.
      • Espinosa F.
      • Saavedra E.
      • Sanguine V.
      • Tassara A.
      • Cid C.
      • Catalano H.N.
      • Agarwal A.
      • Foroutan F.
      • Rada G.
      Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review.
      ]; history of dyslipidaemia (yes/no) [
      • Izcovich A.
      • Ragusa M.A.
      • Tortosa F.
      • Lavena Marzio M.A.
      • Agnoletti C.
      • Bengolea A.
      • Ceirano A.
      • Espinosa F.
      • Saavedra E.
      • Sanguine V.
      • Tassara A.
      • Cid C.
      • Catalano H.N.
      • Agarwal A.
      • Foroutan F.
      • Rada G.
      Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review.
      ], history of CAD (yes/no) [

      Peng Y., Meng K., He M., Zhu R., Guan H., Ke Z., Leng L., Wang X., Liu B., Hu C., Ji Q., Keerman M., Cheng L., Wu T., Huang K., Zeng Q.: Clinical characteristics and prognosis of 244 cardiovascular patients suffering from coronavirus disease in Wuhan, China. J Am Heart Assoc2020, 9(19):e016796. doi: 10.1161/JAHA.120.016796.

      ], history of HF (yes vs no) [
      • Alvarez-Garcia J.
      • Lee S.
      • Gupta A.
      • Cagliostro M.
      • Joshi A.A.
      • Rivas-Lasarte M.
      • Contreras J.
      • Mitter S.S.
      • LaRocca G.
      • Tlachi P.
      • Brunjes D.
      • Glicksberg B.S.
      • Levin M.A.
      • Nadkarni G.
      • Fayad Z.
      • Fuster V.
      • Mancini D.
      • Lala A.
      Prognostic impact of prior heart failure in patients hospitalized with COVID-19.
      ], history of chronic kidney disease (yes/no) [
      • Iaccarino G.
      • Grassi G.
      • Borghi C.
      • Ferri C.
      • Salvetti M.
      • Volpe M.
      • Investigators S.-.R.
      Age and Multimorbidity Predict Death Among COVID-19 Patients: results of the SARS-RAS Study of the Italian Society of Hypertension.
      ], respiratory failure requiring mechanical ventilation or noninvasive ventilation during hospitalization (yes/no) [
      • Izcovich A.
      • Ragusa M.A.
      • Tortosa F.
      • Lavena Marzio M.A.
      • Agnoletti C.
      • Bengolea A.
      • Ceirano A.
      • Espinosa F.
      • Saavedra E.
      • Sanguine V.
      • Tassara A.
      • Cid C.
      • Catalano H.N.
      • Agarwal A.
      • Foroutan F.
      • Rada G.
      Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review.
      ], hemoglobin levels (1 g/dL) [
      • Taneri P.E.
      • Gomez-Ochoa S.A.
      • Llanaj E.
      • Raguindin P.F.
      • Rojas L.Z.
      • Roa-Diaz Z.M.
      • Salvador D.
      • Groothof D.
      • Minder B.
      • Kopp-Heim D.
      • Hautz W.E.
      • Eisenga M.F.
      • Franco O.H.
      • Glisic M.
      • Muka T.
      Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis.
      ], absolute lymphocyte count (1000/mcl) [
      • Izcovich A.
      • Ragusa M.A.
      • Tortosa F.
      • Lavena Marzio M.A.
      • Agnoletti C.
      • Bengolea A.
      • Ceirano A.
      • Espinosa F.
      • Saavedra E.
      • Sanguine V.
      • Tassara A.
      • Cid C.
      • Catalano H.N.
      • Agarwal A.
      • Foroutan F.
      • Rada G.
      Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review.
      ,

      Peng Y., Meng K., He M., Zhu R., Guan H., Ke Z., Leng L., Wang X., Liu B., Hu C., Ji Q., Keerman M., Cheng L., Wu T., Huang K., Zeng Q.: Clinical characteristics and prognosis of 244 cardiovascular patients suffering from coronavirus disease in Wuhan, China. J Am Heart Assoc2020, 9(19):e016796. doi: 10.1161/JAHA.120.016796.

      ], platelet count (1000/mcL) [
      • Izcovich A.
      • Ragusa M.A.
      • Tortosa F.
      • Lavena Marzio M.A.
      • Agnoletti C.
      • Bengolea A.
      • Ceirano A.
      • Espinosa F.
      • Saavedra E.
      • Sanguine V.
      • Tassara A.
      • Cid C.
      • Catalano H.N.
      • Agarwal A.
      • Foroutan F.
      • Rada G.
      Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review.
      ], and severe hypotension occurred during hospitalization and requiring inotropic support (yes/no) [
      • Izcovich A.
      • Ragusa M.A.
      • Tortosa F.
      • Lavena Marzio M.A.
      • Agnoletti C.
      • Bengolea A.
      • Ceirano A.
      • Espinosa F.
      • Saavedra E.
      • Sanguine V.
      • Tassara A.
      • Cid C.
      • Catalano H.N.
      • Agarwal A.
      • Foroutan F.
      • Rada G.
      Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review.
      ].
      We modeled a multivariable model using the covariates which yielded statistical significance in the univariable analysis. To include predictors in the multivariable model, we used Akaike's information criterion (AIC) and the Bayesian information criterion (BIC) to compare different multivariable models based on their fit to the data. We also calculated the receiver-operating characteristic (ROC) curves for survival models.
      We investigated the interactions between covariates according to established methods [
      • Rothman K.J.
      L. LT, S. G: modern epidemiology.
      ,
      • Andersson T.
      • Alfredsson L.
      • Kallberg H.
      • Zdravkovic S.
      • Ahlbom A.
      Calculating measures of biological interaction.
      ]. In particular, the estimated biologic interaction, defined as the interdependent effect of two or more causes to produce disease, was computed from the proportion of risk in the doubly exposed group resulting from the interaction itself [
      • Andersson T.
      • Alfredsson L.
      • Kallberg H.
      • Zdravkovic S.
      • Ahlbom A.
      Calculating measures of biological interaction.
      ].
      Analyses were performed using a significance level of α=0.05 (2-sided).

      Results

      A total of 954 patients were admitted for COVID-19 during the study period and included in the final analysis. The demographic and clinical features of study population are reported in Table 1. The average length of in-hospital stay was 33 ± 17 days. The prevalence of HF and CAD was 11% and 17%, respectively. When compared with patients without HF, those with a history of HF were older (p<0.0001), and had a higher prevalence of comorbidities including type II diabetes mellitus (p = 0.0030), chronic kidney disease (p<0.0001), CAD (p<0.0001), hypertension (p = 0.0229), and dyslipidaemia (p = 0.0001). Similarly, compared with patients without CAD, those with a history of CAD had a higher prevalence of chronic kidney disease (13% vs 6.0%, p = 0.002), type II diabetes mellitus (36% vs 22%, p<0.0001), hypertension (71% vs 58%, p = 0.001), and dyslipidaemia (52% vs 20%, p<0.0001).
      Table 1Main features of patients included in the analysis.
      VariableOverallHeart Failure
      (N = 954)No (N = 851)Yes (N = 103)p value
      Age, years72 ± 1371 ± 1478 ± 9<0.00001
      Male sex (%)5757530.5553
      Body mass index (Kg/m2)27 ± 626 ± 528 ± 70.0674
      Hypertension (%)6059710.0229
      Dyslipidemia (%)2422400.0001
      Type II DM (%)2523370.0030
      CAD (%)171444<0.0001
      CKD (%)7620<0.0001
      Cancer. (%)1110170.0791
      Noninvasive ventilation (%)2222210.962
      Mechanical Ventilation (%)6720.078
      Severe hypotension (%)76150.0019
      Hemoglobin (g/dl)12 ± 212 ± 211 ± 20.2111
      Lymphocyte count (1,000/μL)1.579 ± 1.171.613 ± 1.221.308 ± 0.720.0005
      Platelet count, x 103 (μL)265 ± 106270 ± 105225 ± 990.0001
      Platelet count <150,000/μL, (%)1110230.0001
      Length of in-hospital stay (days)33 ± 1734 ± 1729 ± 200.0004
      Patients with history of HF had lower lymphocyte (p = 0.0052) and platelet count (p<0.0001).
      During hospitalization, severe hypotension (p = 0.019) occurred more frequently among patients with HF (Table 1). Overall, incidence of death was 11%.
      Age, hypertension, severe hypotension, lymphocytopenia, and low platelet count recorded during in-hospital stay, pre-existing HF and known history of CAD were associated with an increased risk of death (all p<0.05, Table 2).
      Table 2Results of univariable analyses exploring predictors of in-hospital death.
      VariableComparisonOdds ratio (95% CI)p value
      Age5 years1.59 (1.40–1.81)<0.0001
      Female sexYes vs. No0.73 (0.47–1.12)0.145
      DyslipidemiaYes vs. No1.08 (0.67–1.76)0.743
      DiabetesYes vs. No1.37 (0.86–2.19)0.189
      HypertensionYes vs. No1.68 (1.05–2.69)0.030
      Coronary Artery DiseaseYes vs. No2.54 (1.58–4.07)<0.0001
      Heart FailureYes vs. No3.69 (2.21–6.17)<0.0001
      Chronic Kidney DiseaseYes vs. No1.51 (0.72–3.16)0.272
      CancerYes vs. No1.09 (0.56–2.12)0.796
      Noninvasive ventilationYes vs. No0.99 (0.59–1.66)0.962
      Mechanical VentilationYes vs. No0.30 (0.10–1.24)0.097
      Severe hypotensionyes vs. no2.49 (1.33–4.67)0.004
      Hemoglobin1 g/dl0.92 (0.81–1.03)0.150
      Lymphocyte count1,000/μL0.37 (0.24–0.57)<0.0001
      Platelet count10,000/μL0.73 (0.58–0.93)0.011
      Nonetheless, adjustment for age had a stronger effect on the risk of adverse outcome ameliorating the prognostic impact of some covariates. Indeed, only history of HF (p<0.0001), CAD (p = 0.003, Fig. 1), lymphocyte count (p = 0.001), and severe hypotension (p<0.0001) remained statistically significant when controlled for age. When forcing all these covariates in the same multivariable model (AIC=456, BIC=484, and ROC area=0.82 [95% CI: 0.77–0.86]), both HF (OR=1.9 [95% CI: 1.0–3.5], p = 0.039) and CAD (OR=1.9 [95% CI: 1.1–3.3], p = 0.024) were associated with an increased risk of death (Table 3).
      Fig. 1
      Fig. 1Probability (%) of in-hospital death according to age in patients with and without coronary artery disease and heart failure (all p<0.05).
      Table 3Multivariable model exploring factors associated with all-cause mortality.
      VariableComparisonOdds ratioStandard errorzP>|z|95% Confidence interval
      Age5 years1.570.1205.890.0001.35 to 1.82
      Severe hypotensionYes vs No3.201.2203.060.0021.52 to 6.76
      Lymphocyte count1000/μL0.530.115−2.930.0030.35 to 0.81
      Heart FailureYes vs No1.900.5942.060.0391.03 to 3.51
      Coronary Artery DiseaseYes vs No1.880.5282.260.0241.09 to 3.26
      To explore interactions between covariates, we stratified the total population into four mutually exclusive groups according to the presence or absence of HF or CAD. Crude rate of in-hospital mortality was 7.4% in the group of patients without HF or CAD (Fig. 2). Mortality was 11.6% in the group with evidence of CAD but no evidence of HF, 15.5% in the group with HF but no evidence of CAD and it raised to 35.6% in the group with coexistence of CAD and HF (OR=6.9 [95% CI: 3.5–13.5], p<0.0001, Fig. 2). Of note, risk for in-hospital death in those who were affected by both disorders was much higher than the sum of risks related to either disorder (HF or CAD), excluding an additive interaction between HF and CAD (p = 0.291). Conversely, this resulted in a significant synergistic effect (p<0.0001) of the two conditions and in a significant age-adjusted attributable proportions due to interaction (64%, 95% CI: 28%−98%, p = 0.0005 – Fig. 3, left panel). Adjusting for the simultaneous effects of age, hypotension, and lymphocyte count (Fig. 3, right panel) did not significantly lower attributable proportion which persisted statistically significant (p = 0.0360).
      Fig. 2
      Fig. 2Crude rates of in-hospital mortality in the four mutually exclusive groups defined by the presence or absence of heart failure and coronary artery disease. Absence of the two conditions was set as reference for the computation of the risk of death.
      Legend: CI=confidence interval; OR=odds ratio.
      Fig. 3
      Fig. 3Prognostic models exploring the joint effect of heart failure and coronary artery disease. The proportion of the risk in the doubly exposed group that is due to the interaction itself (attributable proportion) is also reported. The full model was adjusted by age, occurrence of severe hypotension during hospitalization, and lymphocyte count.
      Legend: AP=attributable proportion; CI=confidence interval; OR=odds ratio.
      No other significant interactions between covariates were documented.

      Discussion

      The present study provides novel data supporting the detrimental impact of the coexistence of HF and CAD on short-term mortality in patients with COVID-19.
      Some reports have recently evaluated the detrimental prognostic effect of CAD or HF in patients with COVID-19 [
      • Inciardi R.M.
      • Adamo M.
      • Lupi L.
      • Cani D.S.
      • Di Pasquale M.
      • Tomasoni D.
      • Italia L.
      • Zaccone G.
      • Tedino C.
      • Fabbricatore D.
      • Curnis A.
      • Faggiano P.
      • Gorga E.
      • Lombardi C.M.
      • Milesi G.
      • Vizzardi E.
      • Volpini M.
      • Nodari S.
      • Specchia C.
      • Maroldi R.
      • Bezzi M.
      • Metra M.
      Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Iaccarino G.
      • Grassi G.
      • Borghi C.
      • Ferri C.
      • Salvetti M.
      • Volpe M.
      • Investigators S.-.R.
      Age and Multimorbidity Predict Death Among COVID-19 Patients: results of the SARS-RAS Study of the Italian Society of Hypertension.
      ,

      Peng Y., Meng K., He M., Zhu R., Guan H., Ke Z., Leng L., Wang X., Liu B., Hu C., Ji Q., Keerman M., Cheng L., Wu T., Huang K., Zeng Q.: Clinical characteristics and prognosis of 244 cardiovascular patients suffering from coronavirus disease in Wuhan, China. J Am Heart Assoc2020, 9(19):e016796. doi: 10.1161/JAHA.120.016796.

      ,
      • van Gerwen M.
      • Alsen M.
      • Little C.
      • Barlow J.
      • Genden E.
      • Naymagon L.
      • Tremblay D.
      Risk factors and outcomes of COVID-19 in New York City; a retrospective cohort study.
      ,
      • Loffi M.
      • Piccolo R.
      • Regazzoni V.
      • Di Tano G.
      • Moschini L.
      • Robba D.
      • Quinzani F.
      • Esposito G.
      • Franzone A.
      • Danzi G.B.
      Coronary artery disease in patients hospitalised with Coronavirus disease 2019 (COVID-19) infection.
      ,
      • Tomasoni D.
      • Inciardi R.M.
      • Lombardi C.M.
      • Tedino C.
      • Agostoni P.
      • Ameri P.
      • Barbieri L.
      • Bellasi A.
      • Camporotondo R.
      • Canale C.
      • Carubelli V.
      • Carugo S.
      • Catagnano F.
      • Dalla Vecchia L.A.
      • Danzi G.B.
      • Di Pasquale M.
      • Gaudenzi M.
      • Giovinazzo S.
      • Gnecchi M.
      • Iorio A.
      • La Rovere M.T.
      • Leonardi S.
      • Maccagni G.
      • Mapelli M.
      • Margonato D.
      • Merlo M.
      • Monzo L.
      • Mortara A.
      • Nuzzi V.
      • Piepoli M.
      • Porto I.
      • Pozzi A.
      • Sarullo F.
      • Sinagra G.
      • Volterrani M.
      • Zaccone G.
      • Guazzi M.
      • Senni M.
      • Metra M.
      Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study.
      ], including monocentre [
      • Loffi M.
      • Piccolo R.
      • Regazzoni V.
      • Di Tano G.
      • Moschini L.
      • Robba D.
      • Quinzani F.
      • Esposito G.
      • Franzone A.
      • Danzi G.B.
      Coronary artery disease in patients hospitalised with Coronavirus disease 2019 (COVID-19) infection.
      ] and multicentre [
      • Tomasoni D.
      • Inciardi R.M.
      • Lombardi C.M.
      • Tedino C.
      • Agostoni P.
      • Ameri P.
      • Barbieri L.
      • Bellasi A.
      • Camporotondo R.
      • Canale C.
      • Carubelli V.
      • Carugo S.
      • Catagnano F.
      • Dalla Vecchia L.A.
      • Danzi G.B.
      • Di Pasquale M.
      • Gaudenzi M.
      • Giovinazzo S.
      • Gnecchi M.
      • Iorio A.
      • La Rovere M.T.
      • Leonardi S.
      • Maccagni G.
      • Mapelli M.
      • Margonato D.
      • Merlo M.
      • Monzo L.
      • Mortara A.
      • Nuzzi V.
      • Piepoli M.
      • Porto I.
      • Pozzi A.
      • Sarullo F.
      • Sinagra G.
      • Volterrani M.
      • Zaccone G.
      • Guazzi M.
      • Senni M.
      • Metra M.
      Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study.
      ] studies from Italy. However, never before the joint effect of these 2 conditions has been assessed in a prospective fashion. More specifically, our study is the first one investigating the potential synergism between HF and CAD on short-term risk of mortality among COVID-19 patients and extending previous data from general population studies of patients with HF [
      • Frazier C.G.
      • Alexander K.P.
      • Newby L.K.
      • Anderson S.
      • Iverson E.
      • Packer M.
      • Cohn J.
      • Goldstein S.
      • Douglas P.S.
      Associations of gender and etiology with outcomes in heart failure with systolic dysfunction: a pooled analysis of 5 randomized control trials.
      ,
      • Lee D.S.
      • Gona P.
      • Vasan R.S.
      • Larson M.G.
      • Benjamin E.J.
      • Wang T.J.
      • Tu J.V.
      • Levy D.
      Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the framingham heart study of the national heart, lung, and blood institute.
      ]. A recent analysis of a Registry from Sweden showed that CAD is a powerful and independent predictor of death in patients with non-valvular HF [
      • Silverdal J.
      • Sjoland H.
      • Bollano E.
      • Pivodic A.
      • Dahlstrom U.
      • Fu M.
      Prognostic impact over time of ischaemic heart disease vs. non-ischaemic heart disease in heart failure.
      ]. Since patients were followed for a median of 2.4 years, [
      • Silverdal J.
      • Sjoland H.
      • Bollano E.
      • Pivodic A.
      • Dahlstrom U.
      • Fu M.
      Prognostic impact over time of ischaemic heart disease vs. non-ischaemic heart disease in heart failure.
      ] the impact of the combination between HF and CAD in the short-term remained unclear.
      Results of our analysis suggest that COVID-19 might act as a destabilizing factor accelerating the adverse impact of the coexistence of HF and CAD.
      HF and CAD both portended a significant impact on adverse outcome and exerted a synergistic effect with regard to the risk of death. Specifically, the proportion of the risk in the doubly exposed group that is due to the interaction itself was 64% (Fig. 3). Notably, when additionally adjusting for other prognostic factors (age [
      • Loffi M.
      • Piccolo R.
      • Regazzoni V.
      • Di Tano G.
      • Moschini L.
      • Robba D.
      • Quinzani F.
      • Esposito G.
      • Franzone A.
      • Danzi G.B.
      Coronary artery disease in patients hospitalised with Coronavirus disease 2019 (COVID-19) infection.
      ,
      • Rey J.R.
      • Caro-Codon J.
      • Rosillo S.O.
      • Iniesta A.M.
      • Castrejon-Castrejon S.
      • Marco-Clement I.
      • Martin-Polo L.
      • Merino-Argos C.
      • Rodriguez-Sotelo L.
      • Garcia-Veas J.M.
      • Martinez-Marin L.A.
      • Martinez-Cossiani M.
      • Buno A.
      • Gonzalez-Valle L.
      • Herrero A.
      • Lopez-Sendon J.L.
      • Merino J.L.
      Investigators C-C: heart failure in COVID-19 patients: prevalence, incidence and prognostic implications.
      ], hypotension occurring during hospitalization [

      Peng Y., Meng K., He M., Zhu R., Guan H., Ke Z., Leng L., Wang X., Liu B., Hu C., Ji Q., Keerman M., Cheng L., Wu T., Huang K., Zeng Q.: Clinical characteristics and prognosis of 244 cardiovascular patients suffering from coronavirus disease in Wuhan, China. J Am Heart Assoc2020, 9(19):e016796. doi: 10.1161/JAHA.120.016796.

      ,
      • Alvarez-Garcia J.
      • Lee S.
      • Gupta A.
      • Cagliostro M.
      • Joshi A.A.
      • Rivas-Lasarte M.
      • Contreras J.
      • Mitter S.S.
      • LaRocca G.
      • Tlachi P.
      • Brunjes D.
      • Glicksberg B.S.
      • Levin M.A.
      • Nadkarni G.
      • Fayad Z.
      • Fuster V.
      • Mancini D.
      • Lala A.
      Prognostic impact of prior heart failure in patients hospitalized with COVID-19.
      ], and lymphocyte count [

      Peng Y., Meng K., He M., Zhu R., Guan H., Ke Z., Leng L., Wang X., Liu B., Hu C., Ji Q., Keerman M., Cheng L., Wu T., Huang K., Zeng Q.: Clinical characteristics and prognosis of 244 cardiovascular patients suffering from coronavirus disease in Wuhan, China. J Am Heart Assoc2020, 9(19):e016796. doi: 10.1161/JAHA.120.016796.

      ]), this synergistic effect retained its statistical significance. Of note, age had a stronger effect on the risk of adverse outcome ameliorating the prognostic impact of some covariates. Conversely, sex did not refine risk stratification in our study population (p = 0.145), showing a similar distribution between groups identified by the presence or absence of HF or CAD (p = 0.090).
      In this context, a bi-faced mechanism for the occurrence of acute coronary events in an acute systemic viral infection has been hypothesized [
      • Sheth A.R.
      • Grewal U.S.
      • Patel H.P.
      • Thakkar S.
      • Garikipati S.
      • Gaddam J.
      • Bawa D.
      Possible mechanisms responsible for acute coronary events in COVID-19.
      ]. It includes both the rapid formation of new coronary plaques, along with acute plaque change in pre-existing plaques, and direct myocardial injury secondary to acute systemic viral infection [
      • Sheth A.R.
      • Grewal U.S.
      • Patel H.P.
      • Thakkar S.
      • Garikipati S.
      • Gaddam J.
      • Bawa D.
      Possible mechanisms responsible for acute coronary events in COVID-19.
      ].
      Although acute respiratory distress syndrome and septic shock have been described as major in-hospital death causes in these patients [
      • Inciardi R.M.
      • Adamo M.
      • Lupi L.
      • Cani D.S.
      • Di Pasquale M.
      • Tomasoni D.
      • Italia L.
      • Zaccone G.
      • Tedino C.
      • Fabbricatore D.
      • Curnis A.
      • Faggiano P.
      • Gorga E.
      • Lombardi C.M.
      • Milesi G.
      • Vizzardi E.
      • Volpini M.
      • Nodari S.
      • Specchia C.
      • Maroldi R.
      • Bezzi M.
      • Metra M.
      Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.
      ,
      • Tomasoni D.
      • Inciardi R.M.
      • Lombardi C.M.
      • Tedino C.
      • Agostoni P.
      • Ameri P.
      • Barbieri L.
      • Bellasi A.
      • Camporotondo R.
      • Canale C.
      • Carubelli V.
      • Carugo S.
      • Catagnano F.
      • Dalla Vecchia L.A.
      • Danzi G.B.
      • Di Pasquale M.
      • Gaudenzi M.
      • Giovinazzo S.
      • Gnecchi M.
      • Iorio A.
      • La Rovere M.T.
      • Leonardi S.
      • Maccagni G.
      • Mapelli M.
      • Margonato D.
      • Merlo M.
      • Monzo L.
      • Mortara A.
      • Nuzzi V.
      • Piepoli M.
      • Porto I.
      • Pozzi A.
      • Sarullo F.
      • Sinagra G.
      • Volterrani M.
      • Zaccone G.
      • Guazzi M.
      • Senni M.
      • Metra M.
      Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study.
      ], COVID-19 is also associated with a wide spectrum of clinical manifestations, including cardiac involvement [
      • Tomasoni D.
      • Inciardi R.M.
      • Lombardi C.M.
      • Tedino C.
      • Agostoni P.
      • Ameri P.
      • Barbieri L.
      • Bellasi A.
      • Camporotondo R.
      • Canale C.
      • Carubelli V.
      • Carugo S.
      • Catagnano F.
      • Dalla Vecchia L.A.
      • Danzi G.B.
      • Di Pasquale M.
      • Gaudenzi M.
      • Giovinazzo S.
      • Gnecchi M.
      • Iorio A.
      • La Rovere M.T.
      • Leonardi S.
      • Maccagni G.
      • Mapelli M.
      • Margonato D.
      • Merlo M.
      • Monzo L.
      • Mortara A.
      • Nuzzi V.
      • Piepoli M.
      • Porto I.
      • Pozzi A.
      • Sarullo F.
      • Sinagra G.
      • Volterrani M.
      • Zaccone G.
      • Guazzi M.
      • Senni M.
      • Metra M.
      Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study.
      ,
      • Rey J.R.
      • Caro-Codon J.
      • Rosillo S.O.
      • Iniesta A.M.
      • Castrejon-Castrejon S.
      • Marco-Clement I.
      • Martin-Polo L.
      • Merino-Argos C.
      • Rodriguez-Sotelo L.
      • Garcia-Veas J.M.
      • Martinez-Marin L.A.
      • Martinez-Cossiani M.
      • Buno A.
      • Gonzalez-Valle L.
      • Herrero A.
      • Lopez-Sendon J.L.
      • Merino J.L.
      Investigators C-C: heart failure in COVID-19 patients: prevalence, incidence and prognostic implications.
      ,
      • Bangalore S.
      • Sharma A.
      • Slotwiner A.
      • Yatskar L.
      • Harari R.
      • Shah B.
      • Ibrahim H.
      • Friedman G.H.
      • Thompson C.
      • Alviar C.L.
      • Chadow H.L.
      • Fishman G.I.
      • Reynolds H.R.
      • Keller N.
      • Hochman J.S.
      ST-segment elevation in patients with Covid-19 - a case series.
      ] due to the enhanced systemic inflammation (cytokine storm) [
      • Madjid M.
      • Safavi-Naeini P.
      • Solomon S.D.
      • Vardeny O.
      Potential effects of coronaviruses on the cardiovascular system: a review.
      ], thromboembolic complications [
      • Helms J.
      • Tacquard C.
      • Severac F.
      • Leonard-Lorant I.
      • Ohana M.
      • Delabranche X.
      • Merdji H.
      • Clere-Jehl R.
      • Schenck M.
      • Fagot Gandet F.
      • Fafi-Kremer S.
      • Castelain V.
      • Schneider F.
      • Grunebaum L.
      • Angles-Cano E.
      • Sattler L.
      • Mertes P.M.
      • Meziani F.
      • Group C.T.
      High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      ], and direct myocardial cytopathic effect [
      • Lindner D.
      • Fitzek A.
      • Brauninger H.
      • Aleshcheva G.
      • Edler C.
      • Meissner K.
      • Scherschel K.
      • Kirchhof P.
      • Escher F.
      • Schultheiss H.P.
      • Blankenberg S.
      • Puschel K.
      • Westermann D.
      Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases.
      ] during viral infection.
      Furthermore, the expression of SARS-CoV-2 receptors on pericytes and cardiomyocytes in failing human hearts may potentially explain microvascular dysfunction and worsening HF in patients with known coronary and structural heart disease [
      • Chen L.
      • Li X.
      • Chen M.
      • Feng Y.
      • Xiong C.
      The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: aCE2centric Infective Disease?.
      ].
      Taken together, these observations suggest that the powerful systemic inflammation occurring during SARS-CoV-2 infection, the myocardial involvement, and the ensuing haemodynamic impairment might act in synergy with pre-existent coronary disease and play a pivotal role as the leading cause of death in patients with HF.
      Although the lungs are believed to be the site at which SARS-CoV-2 replicates, infected patients show the involvement of several organs, including heart and vessels. In other words, the clinical spectrum of COVID-19 is not limited to local pneumonia, but rather represents a multisystem illness with involvement of different organs and potential for systemic complications [
      • Robba C.
      • Battaglini D.
      • Pelosi P.
      • Rocco P.R.M.
      Multiple organ dysfunction in SARS-CoV-2: mODS-CoV-2.
      ,
      • Berlin D.A.
      • Gulick R.M.
      • Martinez F.J.
      Severe Covid-19.
      ,
      • Gandhi R.T.
      • Lynch J.B.
      • Del Rio C.
      Mild or Moderate Covid-19.
      ].
      From a practical point of view, the presence of multimorbidity identifies patients at risk for severe COVID-19 [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: aCE2centric Infective Disease?.
      ,
      • Robba C.
      • Battaglini D.
      • Pelosi P.
      • Rocco P.R.M.
      Multiple organ dysfunction in SARS-CoV-2: mODS-CoV-2.
      ,
      • Berlin D.A.
      • Gulick R.M.
      • Martinez F.J.
      Severe Covid-19.
      ,
      • Gandhi R.T.
      • Lynch J.B.
      • Del Rio C.
      Mild or Moderate Covid-19.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Verdecchia P.
      • Reboldi G.
      • Cavallini C.
      • Mazzotta G.
      • Angeli F.
      [ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus].
      ]. In this context, our results suggest that prompt recognition at admission of HF and CAD as comorbidities might be helpful to identify patients at increased risk of death, therefore warranting a more intensive clinical monitoring management.
      Nonetheless, the impact of the coexistence of HF and CAD on short-term mortality, a finding of considerable clinical interest, remains to be fully elucidated. Further studies are needed to investigate the pathophysiological role of SARS-CoV-2 in these high-risk patients.

      Limitations

      The present analysis investigated the prognostic role of HF and its complex interplay with CAD in a large prospective cohort of patients hospitalised for COVID-19.
      We analysed data from consecutive patients hospitalized in 5 hospitals of the Lombardy region. Thus, our study population should not be considered as representative of all the regional COVID-19 patients [
      • Alicandro G.
      • Remuzzi G.
      • La Vecchia C.
      COVID-19 pandemic and total mortality in the first six months of 2020 in Italy.
      ].
      Although Garcia et al. [
      • Alvarez-Garcia J.
      • Lee S.
      • Gupta A.
      • Cagliostro M.
      • Joshi A.A.
      • Rivas-Lasarte M.
      • Contreras J.
      • Mitter S.S.
      • LaRocca G.
      • Tlachi P.
      • Brunjes D.
      • Glicksberg B.S.
      • Levin M.A.
      • Nadkarni G.
      • Fayad Z.
      • Fuster V.
      • Mancini D.
      • Lala A.
      Prognostic impact of prior heart failure in patients hospitalized with COVID-19.
      ] recently reported no prognostic differences in terms of in-hospital mortality according to left ventricular ejection fraction, in our study no echocardiographic parameters of systolic function were available.
      Furthermore, underlying causes of HF, pre-clinical CAD, anatomic coronary complexity, prior incomplete coronary revascularization, and levels of cardiac biomarkers (including troponin and natriuretic peptides) during hospitalization were not routinely collected.

      Author-Disclosure-Form

      All authors:
      Fabio Angeli
      Jacopo Marazzato
      Paolo Verdecchia
      Antonella Balestrino
      Claudio Bruschi
      Piero Ceriana
      Luca Chiovato
      Laura Adelaide Dalla Vecchia
      Roberto De Ponti
      Francesco Fanfulla
      Maria Teresa La Rovere
      Francesca Perego
      Simonetta Scalvini
      Antonio Spanevello
      Egidio Traversi
      Dina Visca
      Michele Vitacca
      Tiziana Bachetti
      We confirm that:
      • 1
        The manuscript submitted represents original work and has not been previously published or simultaneously submitted elsewhere for publication.
      • 2
        The manuscript has been read and approved by all authors.
      • 3
        None of the authors of this study has financial or other reasons that could lead to a conflict of interest.

      Declaration of Competing Interest

      none declared.

      Funding

      this work was supported by the “Ricerca Corrente” Funding scheme of the Ministry of Health, Italy.

      Acknowledgments

      we thank Adriana Olivares, Marta Lovagnini, and Riccardo Sideri for their work as data manager

      References

      1. Centers for Disease Control and Prevention. People who are at higher risk for severe illness https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html (Accessed on December 01, 2020).

        • Angeli F.
        • Spanevello A.
        • De Ponti R.
        • Visca D.
        • Marazzato J.
        • Palmiotto G.
        • Feci D.
        • Reboldi G.
        • Fabbri L.M.
        • Verdecchia P.
        Electrocardiographic features of patients with COVID-19 pneumonia.
        Eur J Intern Med. 2020; 78: 101-106https://doi.org/10.1016/j.ejim.2020.06.015
        • Madjid M.
        • Safavi-Naeini P.
        • Solomon S.D.
        • Vardeny O.
        Potential effects of coronaviruses on the cardiovascular system: a review.
        JAMA Cardiol. 2020; 5: 831-840https://doi.org/10.1001/jamacardio.2020.1286
        • Inciardi R.M.
        • Adamo M.
        • Lupi L.
        • Cani D.S.
        • Di Pasquale M.
        • Tomasoni D.
        • Italia L.
        • Zaccone G.
        • Tedino C.
        • Fabbricatore D.
        • Curnis A.
        • Faggiano P.
        • Gorga E.
        • Lombardi C.M.
        • Milesi G.
        • Vizzardi E.
        • Volpini M.
        • Nodari S.
        • Specchia C.
        • Maroldi R.
        • Bezzi M.
        • Metra M.
        Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.
        Eur Heart J. 2020; 41: 1821-1829https://doi.org/10.1093/eurheartj/ehaa388
        • Bader F.
        • Manla Y.
        • Atallah B.
        • Starling R.C.
        Heart failure and COVID-19.
        Heart Fail Rev. 2020; https://doi.org/10.1007/s10741-020-10008-2
        • Noor F.M.
        • Islam M.M.
        Prevalence and associated risk factors of mortality among COVID-19 patients: a meta-analysis.
        J Community Health. 2020; 45: 1270-1282https://doi.org/10.1007/s10900-020-00920-x
        • Silverdal J.
        • Sjoland H.
        • Bollano E.
        • Pivodic A.
        • Dahlstrom U.
        • Fu M.
        Prognostic impact over time of ischaemic heart disease vs. non-ischaemic heart disease in heart failure.
        ESC Heart Fail. 2020; 7: 264-273https://doi.org/10.1002/ehf2.12568
        • Angeli F.
        • Bachetti T.
        Maugeri Study G: temporal changes in co-morbidities and mortality in patients hospitalized for COVID-19 in Italy.
        Eur J Intern Med. 2020; https://doi.org/10.1016/j.ejim.2020.10.019
        • Li T.
        Diagnosis and clinical management of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection: an operational recommendation of Peking Union Medical College Hospital (V2.0).
        Emerg Microbes Infect. 2020; 9: 582-585https://doi.org/10.1080/22221751.2020.1735265
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • Bueno H.
        • Cleland J.G.F.
        • Coats A.J.S.
        • Falk V.
        • Gonzalez-Juanatey J.R.
        • Harjola V.P.
        • Jankowska E.A.
        • Jessup M.
        • Linde C.
        • Nihoyannopoulos P.
        • Parissis J.T.
        • Pieske B.
        • Riley J.P.
        • Rosano G.M.C.
        • Ruilope L.M.
        • Ruschitzka F.
        • Rutten F.H.
        • van der Meer P.
        • Group E.S.C.S.D.
        2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
        Eur Heart J. 2016; 37: 2129-2200https://doi.org/10.1093/eurheartj/ehw128
        • Piepoli M.F.
        • Hoes A.W.
        • Agewall S.
        • Albus C.
        • Brotons C.
        • Catapano A.L.
        • Cooney M.T.
        • Corra U.
        • Cosyns B.
        • Deaton C.
        • Graham I.
        • Hall M.S.
        • Hobbs F.D.R.
        • Lochen M.L.
        • Lollgen H.
        • Marques-Vidal P.
        • Perk J.
        • Prescott E.
        • Redon J.
        • Richter D.J.
        • Sattar N.
        • Smulders Y.
        • Tiberi M.
        • van der Worp H.B.
        • van Dis I.
        • Verschuren W.M.M.
        • Binno S.
        • Group E.S.C.S.D.
        2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
        Eur Heart J. 2016; 37: 2315-2381https://doi.org/10.1093/eurheartj/ehw106
        • Knuuti J.
        • Wijns W.
        • Saraste A.
        • Capodanno D.
        • Barbato E.
        • Funck-Brentano C.
        • Prescott E.
        • Storey R.F.
        • Deaton C.
        • Cuisset T.
        • Agewall S.
        • Dickstein K.
        • Edvardsen T.
        • Escaned J.
        • Gersh B.J.
        • Svitil P.
        • Gilard M.
        • Hasdai D.
        • Hatala R.
        • Mahfoud F.
        • Masip J.
        • Muneretto C.
        • Valgimigli M.
        • Achenbach S.
        • Bax J.J.
        • 2019 Group ESCSD:
        ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
        Eur Heart J. 2020; 41: 407-477https://doi.org/10.1093/eurheartj/ehz425
        • Cosentino F.
        • Grant P.J.
        • Aboyans V.
        • Bailey C.J.
        • Ceriello A.
        • Delgado V.
        • Federici M.
        • Filippatos G.
        • Grobbee D.E.
        • Hansen T.B.
        • Huikuri H.V.
        • Johansson I.
        • Juni P.
        • Lettino M.
        • Marx N.
        • Mellbin L.G.
        • Ostgren C.J.
        • Rocca B.
        • Roffi M.
        • Sattar N.
        • Seferovic P.M.
        • Sousa-Uva M.
        • Valensi P.
        • Wheeler D.C.
        • Group E.S.C.S.D.
        2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
        Eur Heart J. 2020; 41: 255-323https://doi.org/10.1093/eurheartj/ehz486
        • Mach F.
        • Baigent C.
        • Catapano A.L.
        • Koskinas K.C.
        • Casula M.
        • Badimon L.
        • Chapman M.J.
        • De Backer G.G.
        • Delgado V.
        • Ference B.A.
        • Graham I.M.
        • Halliday A.
        • Landmesser U.
        • Mihaylova B.
        • Pedersen T.R.
        • Riccardi G.
        • Richter D.J.
        • Sabatine M.S.
        • Taskinen M.R.
        • Tokgozoglu L.
        • Wiklund O.
        • Group E.S.C.S.D.
        2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
        Eur Heart J. 2020; 41: 111-188https://doi.org/10.1093/eurheartj/ehz455
        • Verdecchia P.
        • Reboldi G.
        • Angeli F.
        The 2020 International Society of Hypertension global hypertension practice guidelines - key messages and clinical considerations.
        Eur J Intern Med. 2020; 82: 1-6https://doi.org/10.1016/j.ejim.2020.09.001
        • Felker G.M.
        • Shaw L.K.
        • O'Connor C.M.
        A standardized definition of ischemic cardiomyopathy for use in clinical research.
        J Am Coll Cardiol. 2002; 39: 210-218https://doi.org/10.1016/s0735-1097(01)01738-7
        • Zhou F.
        • Yu T.
        • Du R.
        • Fan G.
        • Liu Y.
        • Liu Z.
        • Xiang J.
        • Wang Y.
        • Song B.
        • Gu X.
        • Guan L.
        • Wei Y.
        • Li H.
        • Wu X.
        • Xu J.
        • Tu S.
        • Zhang Y.
        • Chen H.
        • Cao B.
        Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
        Lancet. 2020; 395: 1054-1062https://doi.org/10.1016/S0140-6736(20)30566-3
        • Iaccarino G.
        • Grassi G.
        • Borghi C.
        • Ferri C.
        • Salvetti M.
        • Volpe M.
        • Investigators S.-.R.
        Age and Multimorbidity Predict Death Among COVID-19 Patients: results of the SARS-RAS Study of the Italian Society of Hypertension.
        Hypertension. 2020; 76: 366-372https://doi.org/10.1161/HYPERTENSIONAHA.120.15324
        • Izcovich A.
        • Ragusa M.A.
        • Tortosa F.
        • Lavena Marzio M.A.
        • Agnoletti C.
        • Bengolea A.
        • Ceirano A.
        • Espinosa F.
        • Saavedra E.
        • Sanguine V.
        • Tassara A.
        • Cid C.
        • Catalano H.N.
        • Agarwal A.
        • Foroutan F.
        • Rada G.
        Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review.
        PLoS ONE. 2020; 15 (e0241955)https://doi.org/10.1371/journal.pone.0241955
      2. Peng Y., Meng K., He M., Zhu R., Guan H., Ke Z., Leng L., Wang X., Liu B., Hu C., Ji Q., Keerman M., Cheng L., Wu T., Huang K., Zeng Q.: Clinical characteristics and prognosis of 244 cardiovascular patients suffering from coronavirus disease in Wuhan, China. J Am Heart Assoc2020, 9(19):e016796. doi: 10.1161/JAHA.120.016796.

        • Alvarez-Garcia J.
        • Lee S.
        • Gupta A.
        • Cagliostro M.
        • Joshi A.A.
        • Rivas-Lasarte M.
        • Contreras J.
        • Mitter S.S.
        • LaRocca G.
        • Tlachi P.
        • Brunjes D.
        • Glicksberg B.S.
        • Levin M.A.
        • Nadkarni G.
        • Fayad Z.
        • Fuster V.
        • Mancini D.
        • Lala A.
        Prognostic impact of prior heart failure in patients hospitalized with COVID-19.
        J Am Coll Cardiol. 2020; 76: 2334-2348https://doi.org/10.1016/j.jacc.2020.09.549
        • Taneri P.E.
        • Gomez-Ochoa S.A.
        • Llanaj E.
        • Raguindin P.F.
        • Rojas L.Z.
        • Roa-Diaz Z.M.
        • Salvador D.
        • Groothof D.
        • Minder B.
        • Kopp-Heim D.
        • Hautz W.E.
        • Eisenga M.F.
        • Franco O.H.
        • Glisic M.
        • Muka T.
        Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis.
        Eur J Epidemiol. 2020; 35 (Jr.): 763-773https://doi.org/10.1007/s10654-020-00678-5
        • Rothman K.J.
        L. LT, S. G: modern epidemiology.
        3rd ed. 2008 Lippincott Williams & Wilkins, 2008
        • Andersson T.
        • Alfredsson L.
        • Kallberg H.
        • Zdravkovic S.
        • Ahlbom A.
        Calculating measures of biological interaction.
        Eur J Epidemiol. 2005; 20: 575-579https://doi.org/10.1007/s10654-005-7835-x
        • van Gerwen M.
        • Alsen M.
        • Little C.
        • Barlow J.
        • Genden E.
        • Naymagon L.
        • Tremblay D.
        Risk factors and outcomes of COVID-19 in New York City; a retrospective cohort study.
        J Med Virol. 2020; https://doi.org/10.1002/jmv.26337
        • Loffi M.
        • Piccolo R.
        • Regazzoni V.
        • Di Tano G.
        • Moschini L.
        • Robba D.
        • Quinzani F.
        • Esposito G.
        • Franzone A.
        • Danzi G.B.
        Coronary artery disease in patients hospitalised with Coronavirus disease 2019 (COVID-19) infection.
        Open Heart. 2020; 7https://doi.org/10.1136/openhrt-2020-001428
        • Tomasoni D.
        • Inciardi R.M.
        • Lombardi C.M.
        • Tedino C.
        • Agostoni P.
        • Ameri P.
        • Barbieri L.
        • Bellasi A.
        • Camporotondo R.
        • Canale C.
        • Carubelli V.
        • Carugo S.
        • Catagnano F.
        • Dalla Vecchia L.A.
        • Danzi G.B.
        • Di Pasquale M.
        • Gaudenzi M.
        • Giovinazzo S.
        • Gnecchi M.
        • Iorio A.
        • La Rovere M.T.
        • Leonardi S.
        • Maccagni G.
        • Mapelli M.
        • Margonato D.
        • Merlo M.
        • Monzo L.
        • Mortara A.
        • Nuzzi V.
        • Piepoli M.
        • Porto I.
        • Pozzi A.
        • Sarullo F.
        • Sinagra G.
        • Volterrani M.
        • Zaccone G.
        • Guazzi M.
        • Senni M.
        • Metra M.
        Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study.
        Eur J Heart Fail. 2020; https://doi.org/10.1002/ejhf.2052
        • Frazier C.G.
        • Alexander K.P.
        • Newby L.K.
        • Anderson S.
        • Iverson E.
        • Packer M.
        • Cohn J.
        • Goldstein S.
        • Douglas P.S.
        Associations of gender and etiology with outcomes in heart failure with systolic dysfunction: a pooled analysis of 5 randomized control trials.
        J Am Coll Cardiol. 2007; 49: 1450-1458https://doi.org/10.1016/j.jacc.2006.11.041
        • Lee D.S.
        • Gona P.
        • Vasan R.S.
        • Larson M.G.
        • Benjamin E.J.
        • Wang T.J.
        • Tu J.V.
        • Levy D.
        Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the framingham heart study of the national heart, lung, and blood institute.
        Circulation. 2009; 119: 3070-3077https://doi.org/10.1161/CIRCULATIONAHA.108.815944
        • Rey J.R.
        • Caro-Codon J.
        • Rosillo S.O.
        • Iniesta A.M.
        • Castrejon-Castrejon S.
        • Marco-Clement I.
        • Martin-Polo L.
        • Merino-Argos C.
        • Rodriguez-Sotelo L.
        • Garcia-Veas J.M.
        • Martinez-Marin L.A.
        • Martinez-Cossiani M.
        • Buno A.
        • Gonzalez-Valle L.
        • Herrero A.
        • Lopez-Sendon J.L.
        • Merino J.L.
        Investigators C-C: heart failure in COVID-19 patients: prevalence, incidence and prognostic implications.
        Eur J Heart Fail. 2020; https://doi.org/10.1002/ejhf.1990
        • Sheth A.R.
        • Grewal U.S.
        • Patel H.P.
        • Thakkar S.
        • Garikipati S.
        • Gaddam J.
        • Bawa D.
        Possible mechanisms responsible for acute coronary events in COVID-19.
        Med Hypotheses. 2020; 143110125https://doi.org/10.1016/j.mehy.2020.110125
        • Bangalore S.
        • Sharma A.
        • Slotwiner A.
        • Yatskar L.
        • Harari R.
        • Shah B.
        • Ibrahim H.
        • Friedman G.H.
        • Thompson C.
        • Alviar C.L.
        • Chadow H.L.
        • Fishman G.I.
        • Reynolds H.R.
        • Keller N.
        • Hochman J.S.
        ST-segment elevation in patients with Covid-19 - a case series.
        N Engl J Med. 2020; 382: 2478-2480https://doi.org/10.1056/NEJMc2009020
        • Helms J.
        • Tacquard C.
        • Severac F.
        • Leonard-Lorant I.
        • Ohana M.
        • Delabranche X.
        • Merdji H.
        • Clere-Jehl R.
        • Schenck M.
        • Fagot Gandet F.
        • Fafi-Kremer S.
        • Castelain V.
        • Schneider F.
        • Grunebaum L.
        • Angles-Cano E.
        • Sattler L.
        • Mertes P.M.
        • Meziani F.
        • Group C.T.
        High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
        Intensive Care Med. 2020; 46: 1089-1098https://doi.org/10.1007/s00134-020-06062-x
        • Lindner D.
        • Fitzek A.
        • Brauninger H.
        • Aleshcheva G.
        • Edler C.
        • Meissner K.
        • Scherschel K.
        • Kirchhof P.
        • Escher F.
        • Schultheiss H.P.
        • Blankenberg S.
        • Puschel K.
        • Westermann D.
        Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases.
        JAMA Cardiol. 2020; 5: 1281-1285https://doi.org/10.1001/jamacardio.2020.3551
        • Chen L.
        • Li X.
        • Chen M.
        • Feng Y.
        • Xiong C.
        The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2.
        Cardiovasc Res. 2020; 116: 1097-1100https://doi.org/10.1093/cvr/cvaa078
        • Verdecchia P.
        • Cavallini C.
        • Spanevello A.
        • Angeli F.
        COVID-19: aCE2centric Infective Disease?.
        Hypertension. 2020; 76: 294-299https://doi.org/10.1161/HYPERTENSIONAHA.120.15353
        • Robba C.
        • Battaglini D.
        • Pelosi P.
        • Rocco P.R.M.
        Multiple organ dysfunction in SARS-CoV-2: mODS-CoV-2.
        Expert Rev Respir Med. 2020; 14: 865-868https://doi.org/10.1080/17476348.2020.1778470
        • Berlin D.A.
        • Gulick R.M.
        • Martinez F.J.
        Severe Covid-19.
        N Engl J Med. 2020; 383: 2451-2460https://doi.org/10.1056/NEJMcp2009575
        • Gandhi R.T.
        • Lynch J.B.
        • Del Rio C.
        Mild or Moderate Covid-19.
        N Engl J Med. 2020; 383: 1757-1766https://doi.org/10.1056/NEJMcp2009249
        • Verdecchia P.
        • Cavallini C.
        • Spanevello A.
        • Angeli F.
        The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
        Eur J Intern Med. 2020; 76: 14-20https://doi.org/10.1016/j.ejim.2020.04.037
        • Verdecchia P.
        • Reboldi G.
        • Cavallini C.
        • Mazzotta G.
        • Angeli F.
        [ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus].
        G Ital Cardiol (Rome). 2020; 21: 321-327https://doi.org/10.1714/3343.33127
        • Alicandro G.
        • Remuzzi G.
        • La Vecchia C.
        COVID-19 pandemic and total mortality in the first six months of 2020 in Italy.
        Med Lav. 2020; 111: 351-353https://doi.org/10.23749/mdl.v111i5.10786