Enhanced ACE1/ACE2 imbalance in comorbidities that
influence COVID-19 morbidity and mortality
Why do some patients, with comorbidities have increased susceptibility
to morbidity and mortality from COVID-19? Our model for pulmonary and
cardiac injury implies a role for crosstalk between ACE2-expressing
cells infected by SARS viruses and other cell types, especially
inflammatory cells (e.g., macrophages and neutrophils) and fibroblasts.
In patients with underlying disease, one or more of these cell types may
be dysfunctional. Superimposed SARS-CoV-2 infection further amplifies
ANG II signaling (which promotes injury) and suppresses ANG (1-7)
signaling (which opposes injurious effects), thus increasing
pathobiology. Multiple clinical conditions may be associated with
elevated vulnerability to COVID-19. Examples include:
Chronic Lung Injury/Disease . Lung injury (e.g., from fibrotic
disease, smoking or radiation) is associated with increased local
inflammatory signaling, predisposing the epithelium to ANG II-promoted
injury. In these settings, epithelial cells and fibroblasts can have
elevated a net increase in pro-inflammatory ANG-mediated responses.
The addition of SARS-CoV-2 further increases this imbalance, thereby
enhancing lung injury.
- Cardiac hypertrophy and remodeling . ANG II regulates cardiac
remodeling in multiple settings, including hypertension. The elevation
in ANG II signaling, derived in part from cardiac RAS, increases
effects of ANG II in the heart (Forrester et al., 2018). Patients with
cardiac pathologies associated with remodeling are thus particularly
susceptible to an acute imbalance in the RAS pathway caused by
myocardial SARS-CoV-2 infection. Decreased cardiac function,
especially in patients with left heart failure, may also increase the
likelihood of pulmonary edema, accompanying pulmonary infection and
complications.
- Diabetes, obesity, metabolic syndrome and chronic inflammatory
disease . Advances in the understanding of the immune system and
chronic inflammation have led to the concept of ‘inflammageing’,
whereby aging is associated with the advent of chronic inflammation,
and the presence of inflammation-associated illnesses, including
Type-2 diabetes (Ferruci and Fabbri, 2018; Fulop et al., 2018;
Castelo-Branco, 2013). Chronic inflammation is also predicted to rise
with obesity (Ferruci and Fabbri, 2018), a risk factor for COVID-19
morbidity. Inflammation is a key mechanism by which elevated ANG II
signaling and ACE1/ACE2 imbalance causes injury (Figures
3-5 ). Certain patients with Type 2 diabetes and obesity also have
hypertension and hypercholesterolemia; together, these features
characterize the metabolic syndrome. The metabolic syndrome is
associated with chronic inflammation, which may be a causative feature
of this syndrome (Monteiro & Azevedo, 2010; Donath et al., 2019).
Increased RAS activity appears to be a pathogenic factor in metabolic
syndrome (Skov et al., 2014). Patients with the metabolic syndrome are
‘pre-sensitized’ to RAS-mediated effects and hence, more vulnerable to
dysregulation of RAS by COVID-19.
- Weakened adaptive immune response . Within the inflammageing
paradigm, aging-associated chronic inflammation via the innate immune
system is coupled with a weakened adaptive immune response. The
adaptive immune system thus has a reduced ability to establish a
defense against SARS-CoV-2, allowing greater viral infectivity and
opportunities for tissue injury. Immune-compromised subjects from
other causes (e.g. those on immune-suppressive medications) would also
be more vulnerable to SARS-CoV-2/COVID-19.
- ACE polymorphisms . ACE1 insertion/deletion polymorphisms (I/D)
have been widely studied. The D-allele is associated with higher ACE1
activity. Patients with the D allele, especially those with the D/D
genotype, are at higher risk of morbidity and mortality from ARDS
(Adamzik et al., 2007) and certain cardiac, pulmonary and inflammatory
conditions (Gard, 2010; Zhou et al., 2010). The ACE1/ACE2 imbalance
hypothesis predicts that patients with the D allele of ACE1, in
particular the D/D genotype, will have elevated severity of COVID-19,
as was seen in patients with SARS-1 (Itoyama et al., 2004).
Therefore, the ACE1/ACE imbalance model for SARS-CoV-2 pathobiology can
help explain how/why patients with certain underlying
conditions/comorbidities are at greater risk if infected with
SARS-CoV-2/COVID-19. Elderly individuals are at particular risk, since
many of the comorbidities are age-associated. Those with health
conditions such as immune deficiencies, diabetes, or cardiac disease
will likely be at greater risk for more severe COVID-19 infections and
ACE1/ANGII-mediated pathology. By contrast, children (who lack
comorbidities associated with ACE1/ACE2 imbalance) are predicted to have
less morbidity and mortality from COVID-19.