Hypertension and COVID-19: hyperinflammation is a mediator of increased disease risk

Hypertension and COVID-19: hyperinflammation is a mediator of increased disease risk

Early in the coronavirus disease 2019 (COVID-19) pandemic, it became apparent that patients with hypertension and other cardiovascular diseases were more frequently affected by a critical disease course. Two main classes of therapeutics, namely angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that both modulate blood pressure by acting on the renin-angiotensin-aldosterone system (RAAS) are commonly used to treat hypertension. As the angiotensin-converting enzyme II (ACE2), a member of RAAS, emerged as the main cellular entry factor for the COVID-19-inducing SARS-CoV-2 virus, concerns grew that anti-hypertensive treatment might contribute to increased infectivity by SARS-CoV-2 and a worse clinical outcome of COVID-19 for patients treated with either ACEi or ARB. In our study, we combined clinical data with single-cell sequencing of airway samples and in vitro experiments, to address this urgent question. Our initial observation was that patients with hypertension not treated with either ACEi or ARB were at a higher risk for a critical COVID-19 progression compared to patients without a co-existing cardiovascular disease. While in ARB treated patients this risk was still increased, patients treated with ACEi did not show a risk increase for critical COVID-19 compared to patients without cardiovascular disease. In line, ARB-therapy was associated with delayed clearance of the virus as evaluated by qPCR analysis of patients’ nasal swab samples. To explore the possible underlying mechanism of these phenomena we analyzed the single-cell transcriptome landscape of the airways of 32 COVID-19 patients and 16 SARS-CoV-2 negative control patients with or without ACEi/ARB treatment (Fig. 1).

Figure 1. Single cell transcriptome analysis of airway samples from hypertensive patients comparing ACE inhibition to angiotensin receptor blockade.

Importantly, anti-hypertensive treatment did not induce elevated expression of the SARS-CoV-2 entry receptor ACE2 between patients without hypertension and ACEi or ARB treated hypertensive patients, neither in non-infected nor in SARS-CoV-2 infected patients. When disentangling the antiviral responses of epithelial cells, which can be either cell-intrinsic or cell-extrinsic, we observed that in SARS-CoV-2-positive patients, the cell-intrinsic antiviral response genes were activated in secretory cells of ACEi but not ARB treated patients. This seems to be particularly important, as the secretory cells are among the cells preferentially targeted by the virus and there is mounting evidence that cell-intrinsic antiviral signaling plays a substantial role in controlling SARS-CoV-2 replication. We think that this deviating antiviral response of both treatment groups contributes not only to the delayed viral clearance in ARB treated patients but also to the higher risk of a critical COVID-19 progression of these patients.

Similarly, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. Compared to non-hypertensive and ACEi-treated patients with COVID-19, ARB treatment was associated with an even stronger hyperactivated inflammatory phenotype of immune cells. In particular under ARB treatment, immune cells exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1 (Fig. 2), underlining the importance of this signaling axis and supporting the potential of CCR1 as a therapeutic target in critical COVID-19, as our previous study has already indicated (Chua et. al., Nature Biotechnology, 2020, https://www.nature.com/articles/s41587-020-0602-4).

Figure 2. The left panel summarizes all genes related to immune mediators and receptors that we found to be elevated in hypertensive patients negative for SARS-CoV-2 compared to patients without hypertension independent of ACEi/ARB treatment. The right panel shows those genes significantly upregulated in COVID-19 patients when comparing ACEi (light blue colored genes) to ARB (dark blue colored genes). Genes associated with critical COVID-19 are highlighted in red.

Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEi treatment in patients with COVID-19 who have hypertension warrant further investigation.