Discussion
To our knowledge, this study represents the first case series of consecutive hospitalised confirmed COVID-19 patients in the UK describing cardiovascular outcomes. In-hospital mortality rate was 30.9% with 14.7% of patients being admitted to ICU. Our in-hospital mortality rate is comparable with published inpatient mortality of 28.2% in China and 21%–30% in the USA.2 6 7
We found that acute myocardial injury and history of hypertension significantly increased the odds of in-hospital mortality once other variables were accounted for.
CVD and myocardial injury
In our cohort, patients who died of COVID-19 had increased underlying CVD (78.6% vs 57.6%). Hypertension was the most common cardiovascular comorbidity present in 53.4% of patients and significantly predicted outcome. A large report from Chinese Center for Disease Control and Prevention looking at outcomes in 44 672 confirmed COVID-19 cases, reported overall mortality increasing from 2.3% to 10.5% in patients with CVD.8
Acute myocardial injury occurred in 43.2% of patients with raised hs-TnI levels. Patients who died from COVID-19 had higher rates of myocardial injury compared with those who survived (66.2% vs 32.8%) regardless of underlying CVD status. Chinese data has shown the SARS-CoV-2 infection causes myocardial injury and is associated with worse outcomes.3 4 One cohort of 416 COVID-19 patients showed that 82 (19.7%) patients had evidence of myocardial injury. Those with myocardial injury had a significantly higher associated in-hospital mortality (51.2%), compared with those without myocardial injury(4.5%).3 Guo et al reported 52 of 187 patients(27.8%) had raised troponin T (TnT) levels. In-hospital mortality was 59.6% (31 of 52) in those with raised TnT compared with those with normal levels, 8.9% (12 of 135).4 We have seen similar increased mortality of 47.4% in those with myocardial injury compared with 18.4% in those with normal troponin levels. The highest mortality rates were observed in those who had underlying CVD and raised TnT levels(69.4%).
Mechanisms of cardiac injury and impact on cardiovascular system
Patients with CAD and cardiovascular risk factors are at greater risk of cardiac events during acute infections and acute inflammatory conditions due to an increase in myocardial demand, causing myocardial injury or infarction in a type 2 myocardial infarction (MI) pattern.9–11 This is likely to be exacerbated by dehydration and acute kidney injury seen in many of the sickest patients in our cohort. Although severe inflammatory stress has been suggested to cause atherosclerotic plaque instability and rupture, we saw very little in the way of classical ACS or coronary artery plaque rupture in our patient cohort. Thromboembolic phenomena are thought to be associated with COVID-19 pathogenesis due to coagulopathy and endothelial dysfunction. This is reflected in raised troponin and D-Dimer levels. There have been suggestions that these may lead to coronary thromboembolism and present as ACS cases.12 In our cohort, only three STEMI cases had invasive coronary angiography and none were felt to be related to this phenomenon. One had normal coronary arteries. The two other cases had diffuse CAD, likely related to underlying atherosclerotic disease than acute thrombotic COVID-19-related pathology. Their underlying atherosclerotic disease could have been exacerbated by their acute infection. Italian data have suggested that up to 40% of COVID-19 STEMI patients have no identifiable coronary culprit lesion to explain abnormal ECG and troponin rise.13
Thirty-four patients (6.8%) were reported to have inpatient arrhythmias with atrial fibrillation being the most frequently observed rhythm, which is lower than the previously reported incidence of 16.7% by a Chinese group.14 As there appears to be no clear associated underlying ACS or LV dysfunction, these arrhythmias could be a consequence of severe underlying metabolic disturbances, hypoxia or severe inflammatory response.
Only 35 patients (7.0%) underwent focused echocardiography during their admission. These were focused scans in order to minimise contact with patients and reduce exposure to staff. Eighteen (51.4%) echocardiograms were normal (online supplemental table 3). Only four (0.8%) patients had moderate-severe LV impairment in our cohort. Despite significant number of patients with myocardial injury, there were no corresponding echocardiographic changes observed, suggesting troponin rise more likely related to inflammatory response than direct involvement of the myocardium. A Chinese study similarly reported that cardiac involvement was secondary to systemic involvement as patients failed to show any typical echocardiographic or ECG changes of myocarditis15
Due to the respiratory deterioration, some patients have shown radiological findings that may be consistent with pulmonary oedema. However, despite these patients having raised cardiac biomarkers, we have not seen the development of acute LV failure on echocardiography. Despite patients having no echocardiographic ventricular impairment, BNP was significantly raised in patients who died. This possibly indicates myocardial dysfunction that contributes to overall mortality.
There has been one case report in the literature identifying marked biventricular diffuse LGE and interstitial oedema on cMRI, consistent with acute myocarditis.16 Our cMRI findings suggest that there may be multiple modalities of cardiac involvement in COVID-19 rather than typical myocarditis.
In hypertensive patients, there is a higher expression of ACE2 and it has been suggested that this is the mechanism which may increase their susceptibility to SARS-CoV-2 infection. However, there is lacking clear evidence linking any direct causation.
ACEi and outcomes
SARS-CoV belongs to the β-CoVs group and binds to the zinc peptidase ACE2, a surface molecule to enter the host cell.17 18 Suppression of the ACE2 expression during SARS-CoV infection has been proposed to be involved in the pathogenesis of the disease in the lung, leading to severe infection and lung failure. ACEi/ARB can lead to increased upregulation of ACE2 receptors in the lungs which may contribute to lung pathology. Influenza A uses the same ACE2 receptor to mediate lung injury. A large UK analysis showed angiotensin blockade had no effect on influenza incidence or a lower incidence, depending on the duration of use.19 These observations for influenza may also apply to SARS-CoV-2. There are some suggestions that renin–angiotensin–inhibitors (ACEi/ARBs) may have a theoretical benefit, but clinical data is lacking.20 21 There have been concerns regarding the role renin–angiotensin–aldosterone system inhibitors have in COVID-19 patients. However, data from the USA, China and Italy have shown no association between ACEi/ARBs and COVID-19 mortality.22–25 Furthermore, there is at least one randomised control trial investigating the role of ACEi in COVID-19 (NCT04312009).
Although we found no mortality difference in patients on ACEi/ARB as a group, being on ACEi was linked to worse outcomes. Once this was adjusted for hypertension and myocardial injury, we found no increased mortality risk. However, we recognise our data represent a small patient group and current advice from international cardiology societies states that patients should remain on their medications until further definitive evidence is available. The role these medications play in the severity of lung disease is complex and not completely understood.
Cardiac management in COVID-19 patients
The mainstay of COVID-19 management has been respiratory support, predominantly in the form of intubation and ventilation.24 There has been very limited success to date in identifying any antiviral drugs or vaccines to target SARS-CoV-2.
Patients with CVD are at greater risk of myocardial injury and adverse outcomes. Cardiac biomarkers should be performed on all patients admitted with COVID-19 routinely, particularly those with underlying CVD. Despite these patients needing limited cardiac intervention, the cardiovascular system is significantly associated with mortality in COVID-19 patients. Increased troponin levels may help identify high-risk patients and may lead to modification in treatment strategy.
Importantly, cardiac issues may be masked as patients who present with significant respiratory symptoms can deteriorate rapidly before cardiac issues become apparent.
There were initial concerns that infected patients may present with a varied range of cardiac complications, including STEMI, arrhythmias and cardiomyopathy.26 In our cohort of patients, despite in-hospital mortality being associated with underlying CVD and myocardial injury, we did not observe high numbers of patients requiring catheter laboratory procedures as initially expected. Despite the numbers requiring intervention being low, we need to be aware that these patients may have underlying cardiac disease that needs intervention without which their prognosis may be worse. The two cases that needed PCI in our cohort had severe underlying three vessel disease which required intervention.
Our low number of cardiology interventions is likely to reflect the need to minimise patient contact due to the highly infectious nature of SARS-CoV-2. More importantly, patients presenting in a critical clinical status would not have benefited from cardiac intervention. Many institutes like ours have written thrombolysis protocols for STEMIs in COVID-19 positive patients. In our cohort of patients, only one case was administered thrombolysis (online supplemental table 1). The long-term consequences of conservative management in such patients is unknown, and this will require long term follow-up to ascertain potential long-term sequelae.