Aortic stenosis (AS) is a progressive aortic valve disease that can lead to heart
failure, syncope and sudden death if not treated. Severe AS currently affects more
than 2 million people over 65 years of age in the USA. The only treatment option for
AS is valve replacement by either surgical aortic valve replacement (AVR) or the less
invasive transcatheter aortic valve replacement (TAVR), also called transcatheter
aortic valve implantation (TAVI). AVR requires intensive care unit (ICU) admission,
whereas TAVR can be performed in a non-ICU setting. Both procedures are commonly associated
with complications, such as stroke.1 Bleeding and thrombosis are also potential complications
of these procedures. Given the considerable morbidity and mortality, patients with
these postoperative complications are admitted to the ICU for management.
SARS-CoV-2, which causes COVID-19, has become a pandemic and has caused high mortality
rates among the elderly. Currently, there is no vaccine against SARS-CoV-2, and there
is no effective treatment to treat patients with severe COVID-19. More than 730 000
people worldwide and over 160 000 in the USA have died from COVID-19 as of 10 August
2020 according to Johns Hopkins Coronavirus Resource Center; these figures are expected
to continue to rise until there are effective vaccines and therapies. Treating patients
with COVID-19 during this pandemic requires many medical resources. Importantly, acute
respiratory distress syndrome and multiorgan failures, believed to be due to systemic
and pulmonary thrombosis,2 3 are common symptoms of severe COVID-19 that require treatment
in the ICU. Therefore, government officials have recommended ceasing almost all elective
surgeries until the COVID-19 pandemic is under control.4 Although many patients with
symptomatic AS can delay procedures intended to alleviate their symptoms, some may
require life-saving procedures. In cases where life-saving procedures (AVR or TAVR)
are required, SARS-CoV-2 infection can be an additional and very dangerous comorbidity.
Therefore, I suggest that the following points should be considered:
Low-risk, asymptomatic patients who can delay their procedures must stringently avoid
infection, for instance by following guidelines for hygiene and wearing masks, and
should continue to maintain strength and endurance as much as possible by routine
exercise.
Patients with severe symptomatic AS should discuss the potential benefits and risks,
including the new risk of comorbidities with COVID-19 that can be life threatening,
of hospitalisation with their cardiologists. Therefore, physicians should have all
pertinent information to identify the appropriate procedure, considering both AVR
and TAVR approaches. The patient risk assessment typically includes patient age and
surgical risk; however, given the increased general risk of the procedure and that
SARS-CoV-2 infection can be an additional and very dangerous comorbidity, suggesting
the less invasive TAVR should be considered.
COVID-19 may predispose some patients to thrombosis, and there are instances in which
standard heparin-based anticoagulants, even at full dosage, are ineffective in preventing
ongoing thrombosis.5 AS patients therefore may have increased risk for developing
thromboembolic complications during the valve replacement procedure or during subsequent
hospitalisation and recovery if they are infected with SARS-CoV-2. Although most patients
with severe COVID-19 who develop thrombosis develop venous thrombosis, some also develop
arterial thrombosis. In fact, a recent study showed that a prosthetic aortic graft
thrombosis patient died from COVID-19 and that anticoagulant and thrombectomy procedure
were unsuccessful.6 Therefore, the risk of prosthetic valve implantation should be
seriously considered. If this procedure is deemed necessary, then thrombus formation
must be carefully monitored.
Although not approved for treating COVID-19, antiviral drugs (eg, ritonavir/lopinavir)
and the potential antiviral drug hydroxychloroquine are in clinical trials and being
used empirically to treat patients with COVID-19. The use of ritonavir/lopinavir and
hydroxychloroquine are associated with cardiovascular disease. The antiviral drug
remdesivir has shown some initial promise in treating COVID-19 and has received Emergency
Use Authorization from the US Food and Drug Agency to treat patients hospitalised
with severe COVID-19. There are no reports to date assessing the effect of remdesivir
on thrombosis or cardiovascular disease, including AS. However, the effects of these
drugs on valvular disease, thrombosis and other cardiovascular disease cannot be ruled
out.
Clearly, patients with COVID-19 are highly prothrombotic with unknown aetiology. D-dimer
is markedly elevated in many patients, and meta-analysis revealed its association
with disease severity and mortality.7 Therefore, it is critical to determine which
anticoagulant should be used in addition to the normal prophylaxis regimens, since
these are not very effective in patients with COVID-19. Recent data from our group,
showed a superior effect of the direct thrombin inhibitor, argatroban in reducing
circuit thrombosis and D-dimer, whereas therapeutic dosage of heparin failed to prevent
thrombosis.5 Therefore, direct thrombin inhibitors should be considered for AS patients
who test positive for SARS-CoV-2, since both COVID-19 and AS procedure can increase
the risk of thrombosis.
If AS patients have COVID-19 and shortness of breath, the risk of morbidities is increased,
as shortness of breath can be caused by either COVID-19 or AS. Under such circumstance,
echocardiography is important for accurate diagnosis of the status of the patient’s
AS. If the shortness of breath is not caused by AS, markers for COVID-19, such as
interleukin-6, D-dimer and complement proteins and white cell counts, and acute white
cell counts should be examined, as these levels should not rise in stable AS patients.
If, however, the respiratory symptom is the result of AS, which can be fatal in itself,
TAVR may be a better option than AVR considering the very high-risk status of patients
with COVID-19 comorbidities. Concurrent monitoring of the status of AS by echocardiography
will avoid the complicating comorbidity of thrombosis, for which there are currently
no clear treatment guidelines for patients with COVID-19.
SARS-CoV-2 enters human cells by binding of the viral spike protein to the membrane-bound
form of the aminopeptidase ACE2 on cells. ACE2 plays an important regulatory role
in the renin–angiotensin system, which regulates normal and pathological vascular
tone and blood pressure. Various types of medications that inhibit this system are
used to treat patients suffering from cardiovascular disease, including those with
AS, although none successful in clinical trial for AS. Studies in animals have suggested
that inhibitors of this system can upregulate ACE2 expression, which led some investigators
to postulate that patients receiving those inhibitors may be at high risk of contracting
a SARS-CoV-2 infection, which needs to be validated experimentally.8 Therefore, it
is critical to carefully assess and differentiate symptoms in acute AS versus COVID-19
cases wherein comorbidities and risk always rise. If the AS patient cannot delay life-saving
procedures and are taking the ACE inhibitors, which can be discontinued but, as discussed
above, other challenges, such as management of thrombosis, also need careful consideration.
The disease-causing mechanisms of both AS and COVID-19 are not well known. Both are
associated with high-risk underlying conditions, including age, obesity, diabetes,
hypertension and male gender, which increases the complexity of comorbidities and
decision making, especially in the ICU setting when patients are on ventilators and
oral treatments are not an option. Thus, understanding the mechanisms of these two
diseases is required to improve treatments of these diseases separately as well as
when they occur together. Because it is almost impossible to test the mechanism of
AS or COVID-19 in humans, other than correlative studies, animal studies are needed.
We have established a new robust mouse model of AS that simulates AS in human and
identified platelet transforming growth factor beta-1 as a major driver of AS progression.9
The new SARS-CoV-2 animal models10 can be adapted to comorbid disease models, such
as AS, to facilitate the identification of underlying mechanisms. These models will
potentially inform the development of therapies for AS and COVID-19. Finally, COVID-19
may pose an additional risk for other life-saving procedures where thromboembolic
events are common, such as cardiac catheterization, implantation of permanent pacemaker
and left ventricular assist device in heart failure patients or thrombus removal in
stroke patients. Thus, caution should be taken if these procedures are deemed necessary;
in particular, thrombosis and the effects of anticoagulants on bleeding must be carefully
monitored.