Delayed viral clearance and exacerbated airway hyperinflammation in hypertensive COVID-19 patients

Abstract

In COVID-19, hypertension and cardiovascular diseases have emerged as major risk factors for critical disease progression. Concurrently, the impact of the main anti-hypertensive therapies, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), on COVID-19 severity is controversially discussed. By combining clinical data, single-cell sequencing data of airway samples and in vitro experiments, we assessed the cellular and pathophysiological changes in COVID-19 driven by cardiovascular disease and its treatment options. Anti-hypertensive ACEi or ARB therapy, was not associated with an altered expression of SARS-CoV-2 entry receptor ACE2 in nasopharyngeal epithelial cells and thus presumably does not change susceptibility for SARS-CoV-2 infection. However, we observed a more critical progress in COVID-19 patients with hypertension associated with a distinct inflammatory predisposition of immune cells. While ACEi treatment was associated with dampened COVID-19-related hyperinflammation and intrinsic anti-viral responses, under ARB treatment enhanced epithelial-immune cell interactions were observed. Macrophages and neutrophils of COVID-19 patients with hypertension and cardiovascular comorbidities, in particular under ARB treatment, exhibited higher expression of CCL3, CCL4, and its receptor CCR1, which associated with critical COVID-19 progression. Overall, these results provide a potential explanation for the adverse COVID-19 course in patients with cardiovascular disease, i.e. an augmented immune response in critical cells for the disease course, and might suggest a beneficial effect of clinical ACEi treatment in hypertensive COVID-patients.

Hypertension, a Moving Target in COVID-19

“…In airway cells, the SARS-CoV-2 infection itself associates with increased ACE2 mRNA expression. 56 – 58 Hence, in epithelial cells obtained from nasopharyngeal and bronchial samples in patients with COVID-19, an average 3-fold increase in ACE2 expression was found in epithelial cells. 57 This correlated with INF (interferon) signals by immune cells 57 in agreement with a study that revealed the induction of ACE2 mRNA expression by interferon in human nasal epithelial and lung tissue (Figure 1 D).…”

“… 21 Treatment with RAS-blockers may protect against organ injury, for example, in the lung, by inhibiting the damaging Ang II/AT1R axis and by activation of the protective axis, particularly via the ACE2/Ang 1-7/MasR axis. Available data indicate that ACE2 mRNA 58 and importantly also ACE2 protein expression 53 are not increased in airway cells of patients treated with ACEIs or angiotensin receptor blockers (ARBs) suggesting that these drugs do not impact on the infectivity of SARS-CoV-2.…”

Epidemiological Impact of Myocarditis

“…Moreover, it has been suggested that underlying cardiovascular disease may promote a more severe course of COVID-19 infection [ 141 , 142 , 155 , 156 , 157 , 158 ]. In this context, a meta-analysis of 1527 COVID-19 patients showed that 17.1% of these patients were hypertensive and 16.4% had pre-existing heart disease [ 159 ].…”

Severe COVID-19 associated variants linked to chemokine receptor gene control in monocytes and macrophages

“…Elevated CCR1 expression may enhance lung infiltration by monocytes and macrophages upon viral infection 16 , provoking a rapid and deleterious hyperinflammation as observed in COVID-19 patients suffering from severe disease 2 , 21 ( Fig.2e ). In support of this notion, single cell RNA-sequencing revealed increased levels of CCR1 and its ligands CCL2 / CCL3 in pulmonary macrophages from critical COVID-19 patients 22 , 23 . Additionally, CCL2 plasma levels showed the highest predictive value for mortality in a COVID-19 patient cohort 21 .…”