key: cord-0776147-g9szoh3g authors: Bartoloni, Elena; Perricone, Carlo; Cafaro, Giacomo; Gerli, Roberto title: Hypertension and SARS-Cov-2 infection: is inflammation the missing link? date: 2020-09-23 journal: Cardiovasc Res DOI: 10.1093/cvr/cvaa273 sha: 8a1f354bb5ba544573c1e35c606d3d1d64d67b11 doc_id: 776147 cord_uid: g9szoh3g nan The dramatic emergence of the pandemic coronavirus disease COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) raised significant medical and public health concerns for the high disease mortality rate ranging from 1% to more than 5%. In this setting, patients with severe disease exhibit high serum levels of pro-inflammatory cytokines, including interleukin (IL)-1 and IL-6, and their elevated concentrations closely relates to worse outcome. 1 In addition to respiratory failure, cardiovascular system involvement and myocardial damage are associated with a significant increase of mortality rate in infected patients. 2 In fact, pre-existing cardiovascular comorbidities, including hypertension (HTN), diabetes mellitus, cerebrovascular and coronary heart disease, enhance susceptibility to SARS-CoV-2 infection and are associated with increased risk of severe disease, myocardial injury and short-term mortality rate. 3 In particular, HTN emerged as the most common comorbidity among patients with COVID-19 and hypertensive patients display more than three-fold higher mortality risk in comparison to normotensive. 4 However, due to the high prevalence of hypertension in the general population, concerns raised as to whether hypertension represents merely a concomitant risk factor or a pivotal pathogenic trigger of cardiac injury in patients with SARS-CoV2 infection. As reported by Kreutz et al in their interesting review article, the identification of angiotensin-converting enzyme 2 (ACE2), highly expressed in cardiac and pulmonary tissue, as a functional receptor for the spike SARS-CoV-2 glycoprotein, focalized considerable attention around the pathophysiologic and clinical consequences of ACE2 upregulation in hypertensive patients with COVID-19 infection. 5 However, as reported, concomitant mechanisms related to inflammatory dysregulation may be advocated to take part in this process. 5 Indeed, the contribution of aberrant innate immune system activation and consequent downstream signalling cascade leading to pro-inflammatory cytokine release has been recognized in various experimental models of HTN. 6 In particular, persistent activation of toll-like receptor (TLR) 4 signalling pathway by different hypertensive stimuli and endogenous damageassociated molecular patterns (DAMPs) emerged as a pivotal immunopathogenic mechanism underlying HTN. 6 Interestingly, TLR 4 has been localized in multiple sites including vessel wall and alveolar macrophage of severe acute respiratory syndrome mice models. Interestingly, in alveolar macrophage, viral pathogen-associated MP (PAMP) activation of TLR4 signalling may induce oxidative stress and subsequent development of acute lung injury. 7 In particular, activation of macrophage TLR4 leads to induction of two distinct intracellular signalling pathways (MyD88 and TRIF) and rapid cytokine production. In this setting, it may be hypothesized that COVID-19associated PAMPs may act as exogenous triggers of TLR4 signalling pathway leading to inflammasome activation and inflammatory cytokine release, including interleukin-1 (Figure) . 8 We believe that this common activation of innate immune mechanisms may, at least in part, explain the dramatic systemic inflammatory response associated with worse outcome in COVID-19 hypertensive patients. COVID-19: Consider cytokine storm syndromes and immunosuppression COVID-19 and the cardiovascular system COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options Arterial hypertension and risk of death in patients with COVID-19 infection: Systematic review and meta-analysis Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19 Hypertension as a cardiovascular risk factor in autoimmune rheumatic diseases Identification of oxidative stress and Toll-like Receptor 4 signalling as a key pathway of acute lung injury Induction of proinflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies Funding: No fundings to declare.