key: cord-0871236-41qgsoyh authors: Sinclair, Jane E.; Zhu, Yanshan; Xu, Gang; Ma, Wei; Shi, Haiyan; Ma, Kun-Long; Cao, Chun-Feng; Kong, Ling-Xi; Wan, Ke-Qiang; Liao, Juan; Wang, Hai-Qiang; Arentz, Matt; Redd, Meredith A.; Gallo, Linda A.; Short, Kirsty R. title: A meta-analysis on the role of pre-existing chronic disease in the cardiac complications of SARS-CoV-2 infection date: 2021-03-05 journal: iScience DOI: 10.1016/j.isci.2021.102264 sha: f3fb00ad88987c4926fb1bd5cc30ab37a979695a doc_id: 871236 cord_uid: 41qgsoyh Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with multiple direct and indirect cardiovascular complications. We sought to analyse the association of host co-morbidities (chronic respiratory illnesses, cardiovascular disease (CVD), hypertension or diabetes mellitus (DM)) with the acute cardiovascular complications associated with SARS-CoV-2 infection. Individual analyses of the majority of studies found median age was higher by ∼10 years in patients with cardiovascular complications. Pooled analyses showed development of SARS-CoV-2 cardiovascular complications was significantly increased in patients with chronic respiratory illness (odds ratio (OR) 1.67[1.48,1.88]), CVD (OR 3.37[2.57,4.43]), hypertension (OR 2.68[2.11,3.41]), DM (OR 1.60[1.31,1.95]) and male sex (OR 1.31[1.21,1.42]), findings that were mostly conserved during sub-analysis of studies stratified into global geographic regions. Age, chronic respiratory illness, CVD, hypertension, DM and male sex may represent prognostic factors for the development of cardiovascular complications in COVID-19 disease, highlighting the need for a multidisciplinary approach to chronic disease patient management. populations as well as other relevant data are listed in Table 2 . The definition of cardiac complications varied 109 between studies, ranging from acute cardiac injury to fulminant myocarditis. 20 studies measured cardiac 110 outcomes on the day of admission Barman et al., 2020; Bertini et al., 2020; Duerr et al., 111 2020; Ferrante et al., 2020; Ghio et al., 2020; Guo et al., 2020; Lairez et al., 2020; Lala et al., 2020; Liu et al., 112 2020; Lombardi et al., 2020; Lorente-Ros et al., 2020; Ma et al., 2020; Pagnesi et al., 2020; Raad et al., 2020; 113 Shahrokh et al., 2020; Shi et al., 2020; Song et al., 2020; Szekely et al., 2020; Xu H., et al., 2020) , and one at the 114 time of patient death , with the remaining eight studies not specifying the time of 115 assessment Linschoten and Asselbergs, 2020; Sala et al., 2020; Shah et al., 2020; Toraih et 116 al., 2020; Wei et al., 2020; Xie et al., 2020) . The studies were conducted in 10 countries in four geographical Patients who presented with SARS-CoV-2 associated cardiac complications were, on average, 10 years older 120 than in those who did not (Table 2) . In a pooled analysis, chronic respiratory illness (odds ratio (OR): 1.67, 95% confidence interval (CI) ( Fig. 6) , were each associated with a higher risk of SARS-CoV-2 associated cardiac complications. Neither 5 primarily situated in the U.S.A Arentz et al., 2020; Lala et al., 2020; Raad et al., 2020; 136 Shah et al., 2020) , the Middle East Shahrokh et al., 2020; Szekely et al., 2020) , Europe 137 (Bertini et al., 2020; Linschoten and Asselbergs, 2020; Duerr et al., 2020; Ferrante et al., 2020; Ghio et al., 138 2020; Lairez et al., 2020; Lombardi et al., 2020; Lorente-Ros et al., 2020; Pagnesi et al., 2020; Sala et al., 2020) , and China Shi et al., 2020; Liu et al., 2020; Ma et al., 2020; Song et al., 140 2020; Toraih et al., 2020; Wei et al., 2020; Xie et al., 2020; Xu G. et al., 2020; Xu H. et al., 2020) . Regionally-pooled sub-analysis of chronic respiratory illness found it to be associated with a higher incidence of 143 SARS-CoV-2 associated cardiac complications in cohorts from the U.S.A. but not the Middle East (Fig. 7 , B). Regional subdivision accounted for the high heterogeneity amongst all but 146 the Middle Eastern cohort. Regionally-pooled sub-analysis of pre-existing CVD found its association with a higher incidence of SARS- Regionally-pooled sub-analysis of hypertension found its association with a higher incidence of SARS-CoV-2 155 associated cardiac complications to be similarly conserved across all cohorts from the U.S.A. ( (Fig. 9 , D), although regional subdivision 158 could not account for high heterogeneity amongst the American and European cohorts. The association between DM and a higher incidence of SARS-CoV-2 associated cardiac complications was also 161 conserved across all cohorts from the U.S.A. Finally, regionally-pooled sub-analysis of male sex found it to be associated with a higher incidence of SARS- Our meta-analysis shows that older age, male sex, and pre-existing chronic respiratory disease, CVD, 177 hypertension and DM are all associated with the development of cardiac complications associated with SARS- CoV-2 infection, while our regional sub-analysis indicates these associations may depend on geographic region. At present the reasons for each of these association are unclear; each is a respiratory risk factor and thus might 180 cause an indirect cardiac effect, however it could equally be the case that they exert their own direct catalytic 181 effect on cardiac complications. Our analysis identified a significant association between pre-existing CVD and the risk of SARS-CoV-2 184 associated cardiac complications, which was conserved across global geographical regions. This is consistent 185 with previous observations that 30% of patients with SARS-CoV-2 cardiac injury had a history of coronary 186 heart disease Shi et al., 2020) . The reason for this association remains unclear. These data 187 may be the result of pre-existing CVD leading to an altered immune response, excessive cytokine release 188 , endothelial dysfunction, increased procoagulant blood activity, rupturing of coronary 189 atherosclerotic plaques (Madjid et al., 2007) , and the formation of an occlusive thrombi (Corrales-Medina et al., 190 2013) . However, further investigations are required to validate this hypothesis. The meta-analysis performed herein also found that chronic respiratory illness was also associated with an 193 increased incidence of SARS-CoV-2 associated cardiac complications. It is possible that these data reflect the CoV-2 ARDS and hypoxemia (Halpin et al., 2020) , and thus this is unlikely to be the sole explanation for the 199 association of cardiac complications in patients with chronic respiratory illness in the present analysis. The association between underlying DM and cardiac complications from SARS-CoV-2 may be attributable to a 202 multitude of other effects induced by abnormal circulating substrates, including hyperglycaemia, and/or the co-203 existence and complex interactions with other, even subclinical, conditions in this patient group (Heather and 204 Clarke, 2011) . In response to changes in substrate availability, for example, the diabetic heart becomes 205 increasingly dependent on fatty acids as a fuel source, which decreases work efficiency, and dysregulates 206 responses to hypoxia (Iqbal et al., 2014) . These metabolic changes may predispose individuals with DM to an 207 increased risk of ischemic cardiac injury upon SARS-CoV-2 infection. The contribution of underlying DM to 208 the risk of SARS-CoV-2 associated cardiac complications, however, depends largely on the duration of pre-209 existing disease (Rask-Madsen and King, 2013). There are several limitations in our review. Firstly, despite a lack of evidence found for publication bias (see 214 Figures S1-S5) the exclusion of 55 eligible studies due to lack of response from the original authors inserts a 215 critical bias in the meta-analysis. Secondly, the limited number of studies that met the pre-defined selection 216 criteria disallowed correction for other variables that may confound these results. For example, it is possible that 217 our observations were confounded by the strong effect that age has on cardiovascular health. Thus, it is not 218 possible to conclude if people with these pre-existing conditions are just more susceptible to severe COVID-19 219 and thus the heart complications associated with this increased severity, or if there is indeed a cardiac-specific 220 effect occurring. Similarly, we cannot exclude the possibility that the associations observed herein are due, at 221 least in part, to treatments for severe COVID-19 that may affect the heart, or treatments for underlying 222 conditions. Information regarding which, if any, therapeutics used in these cohorts of patients was not 223 consistently available. We anticipate that as more data on the cardiac complications become available it will be 224 possible for future analyses to correct for these and other confounders; however, it would also be worthwhile 225 testing the effects of each these pre-existing chronic conditions in one of the recently developed murine models 226 of SARS-CoV-2. Another limitation is that in our analysis for the source of heterogeneity, data was not 227 sufficiently available to perform sub-analysis based on other factors such as stage of disease. Global region did 228 not always account for the observed heterogeneity, which may instead be due to clinical and methodological 229 differences between each study. Furthermore, the adjustment of confounding variables may have differed across 230 studies, with studies possibly deploying different multivariate models in the analyses, also contributing to 231 heterogeneity. However, adjusted odds ratios relevant to our outcome were not readily available from the 232 included studies. Fixed effect models apply when I 2 <50% and random effects models apply when I 2 >50%. Fixed effect models apply when I 2 <50% and random effects models apply when I 2 >50%. 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