Commentary on ‘Clinical characteristics of 138 hospitalized patients with 2019 novel
coronavirus-infected pneumonia in Wuhan, China’, by D. Wang et al., JAMA 2020; doi:10.1001/jama.2020.1585
Disclaimer: This commentary was finalized on 24 March 2020, which should be considered
in light of the rapidly developing understanding of COVID-19.
On 31 December 2019, China alerted the World Health Organization (WHO) to several
cases of an uncommon pneumonia in Wuhan, the most populous city in Central China with
>11 million people. The causal pathogen was unknown. In the initial stages, severe
acute respiratory infection symptoms appeared, and some patients also quickly developed
acute respiratory distress syndrome (ARDS), acute respiratory failure, and other additional
problems of a severe nature. On 7 January, a new coronavirus was recognized by the
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample
of a patient,
and then officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
by the WHO. Since then, the disease has quickly spread from Wuhan to other regions.
Now, the WHO has declared the novel coronavirus disease 2019 (COVID-19) a pandemic,
with substantial occurrences in >100 countries around the world, with cases rapidly
increasing at the time of publication of this Commentary.
Understanding the detailed clinical characteristics of hospitalized patients with
COVID-19 is of paramount importance to identify subjects at the highest risk of (i)
being infected and (ii) presenting with a particularly severe clinical presentation
which may lead to death. Recent reports from China, such as a study from Wang et al.,
have demonstrated that old age as well as additional underlying health conditions
significantly increases the risk of dying from infection. Importantly, cardiovascular
disease, including hypertension, appears to be particularly linked to the severity
In a large-scale report from China’s CDC,
patients who needed admission to an intensive care unit were more likely to have comorbidities,
the majority of which were cardiovascular- or diabetes-associated. Even though the
mortality rate remains highly variable depending on the region (currently 2.3% in
China, and >9% in Italy or Spain), the large-scale analysis of 44 672 confirmed COVID-19
cases indicated an increased mortality risk for older patients (14.8% for patients
≥80 years of age), and for those with diabetes (7.3%), hypertension (6%), and cardiovascular
disease (10.5%). Remarkably, the case fatality rate for underlying cardiovascular
disease (10.5%) is larger than for patients with underlying chronic respiratory disease
This is somewhat unexpected as compared with, for instance, the 2009 H1N1 influenza
outbreak, where immunosuppressed patients were primary affected.
As emerging worldwide evidence becomes accessible, studies from international cohorts
will help to stratify the risk for more severe forms of COVID-19 for patients with
pre-existing cardiovascular diseases.
The mechanisms of this association remain unclear. Unquestionably, the disparity between
augmented metabolic demand and reduced cardiovascular reserve may represent one of
the possible mechanisms.
Viral infections are linked to increased metabolic demands by four- to eight-fold
when compared with the normal physiological workload of the heart. This is comparable
to significant exercise. This, in addition to the possible direct effects of pneumonia,
can impair cardiac function. Other possible mechanisms may include high levels of
expression of angiotensin-converting enzyme 2 (ACE2), a membrane-bound aminopeptidase
used by the SARS-CoV-2 virus to invade host cells in cardiac tissues (separate from
In patients with existing cardiovascular conditions, symptoms of COVID-19 appear to
be more severe, which might be related to augmented ACE2 expression in these individuals
compared with healthy humans—although this remains speculative, as evidence of increased
ACE2 in humans is not sufficient. Thus, further understanding of the injury triggered
by COVID-19 to the heart and of the underlying pathways is of the utmost relevance,
so that therapeutic measures delivered to these patients can be precise and effective,
leading to decreased mortality.
If we consider the severe metabolic demand and cardiac dysfunction observed particularly
in patients with co-existent hypertension, diabetes, and cardiac disease, the use
of ACE inhibitors or angiotensin II receptor antagonists might be justified and beneficial.
Experimental evidence, however, suggests that ACE2 used by SARS-CoV-2 to access host
cells may be up-regulated by these medications, raising questions about the therapeutic
use of renin–angiotensin–aldosterone system inhibitors if they promote increased ACE2
levels. Due to the crucial functional relevance of ACE2 to SARS-CoV-2, the possible
effects of antihypertension therapeutics with angiotensin receptor blockers or ACE
inhibitors in patients infected with COVID-19 have to be prudently deliberated.
Reports suggest also that COVID-19 can cause acute cardiac complications. Acute myocardial
injury appeared in 5 of the first 41 humans detected with this virus in Wuhan, who
mostly expressed an increase level of high-sensitivity cardiac troponin I (hs-cTnI;
In another comprehensive case report of 138 hospitalized COVID-19 patients, Wang et
al. demonstrated that 16.7% of them developed arrhythmia and 7.2% developed acute
Unpublished first-hand data also demonstrated the development of fulminant myocarditis.
In fact, in all influenza pandemics, cardiac events exceeded all other causes of death,
The mechanism of acute cardiac injury triggered by COVID-19 described here might be
related to ACE2, as explained before. Other alternative mechanisms comprise a cytokine
storm activated by an excessive reaction by type 1 and 2 T-helper cells,
as well as hypoxaemia and respiratory dysfunction instigated by SARS-CoV-2, causing
damage to myocardial cells.
In line with this, inflammation markers, such as plasma high-sensitivity C-reactive
protein (hsCRP), as well as levels of cytokines linked to cardiovascular risk, are
also related to adverse outcomes and could be used as possible biomarkers of overall
Bats are the source of severe acute respiratory syndrome coronavirus (SARS-CoV)-related
viruses. SARS-CoV-2 may originate from bats or unidentified intermediary hosts and
cross the species barrier into humans. Spike (S) glycoprotein of SARS-CoV-2 binds
to the host cell receptors, angiotensin-converting enzyme 2 (ACE2), which is a crucial
step for virus entrance. SARS-CoV-2 mainly invades alveolar epithelial cells, resulting
in respiratory symptoms. Host factors can also influence vulnerability to infection
and disease evolution. Older patients with underlying diseases are vulnerable to SARS-CoV-2
and tend to progress into severe complications. The severity in patients with cardiovascular
diseases may be associated with increased secretion of ACE2 in these patients compared
with healthy individuals. This figure was created with BioRender.com.
Questions also arise regarding chronic and long-term effects of COVID-19 on the cardiovascular
system. A follow-up survey (12 years) of recovered patients who were previously infected
with SARS-CoV (which has a similar structure to SARS-CoV-2) demonstrated that 44%
had cardiovascular system abnormalities, 60% had glucose metabolism disorders, and
68% had hyperlipidaemia.
No targeted therapies are available, and existing management comprises disease containment
and mitigation on a populational level, including travel limitations, patient quarantine,
and supportive medical care.
COVID-19 is a quickly evolving public health emergency, having spread rapidly since
it was first recognized in Wuhan with a wide spectrum of severity. In early 2020,
the WHO believed that it did not expect a vaccine against SARS-CoV-2 to become available
in less than 1.5 years. In the meanwhile, protocols for the supervision of COVID-19
patients with heart diseases and/or cardiovascular patients with COVID-19 should be
established in detail.
Conflict of interest: none declared.
Rui Adão is supported by Portuguese Foundation for Science and Technology through
project IMPAcT- PTDC/MED-FSL/31719/2017.