Coronaviruses and the cardiovascular system: acute and long-term implications.

The recent outbreak of coronavirus disease 2019 (COVID-19) provides a further challenge in the battle against outbreaks of novel virus infections and has been declared a public health emergency of international concern. Much has been learnt in the course of preceding epidemics, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and H1N1 influenza, and it is now recognized that their overall health burden may be under-estimated since extra-pulmonary manifestations are frequent. Acute and chronic cardiovascular complications of pneumonia are common and result from various mechanisms, including relative ischaemia, systemic inflammation, and pathogen-mediated damage. There is, however, only limited published data concerning cardiovascular presentations in the wake of viral epidemics. The present COVID-19 outbreak emphasizes the need for greater awareness of the immediate and long-term cardiovascular implications of viral infection and the significant gaps in knowledge that future research will need to address.

Epidemiological overview of recent outbreaks of respiratory virus infection

Respiratory virus infection is a major source of global pandemics as a consequence of swift human-to-human respiratory tract transmission. Within the past two decades, coronaviruses and influenza viruses have hit the world several times, causing significant mortality, economic loss, and global panic. The SARS outbreak in 2002 triggered 916 deaths among more than 8000 patients in 29 countries, followed by the emergence of MERS in 2012, which resulted in at least 800 deaths among 2254 patients in 27 countries. Besides coronaviruses, avian and swine influenza remain a concern for global public health—in the 2009 H1N1 pandemic alone, there were 18 500 laboratory-confirmed deaths and more than 200 000 deaths from respiratory disease worldwide (based upon epidemiological modelling).

In late 2019, a cohort of patients presenting with pneumonia of varying acuity and unknown aetiology in Wuhan, China heralded the outset of COVID-19. As of 16 March 2020, a total of 167 511 confirmed cases (including 6606 deaths in 152 geographical territories) have been reported to the World Health Organization (), and this number is still increasing. Although COVID-19 appears to have greater infectivity and lower mortality than SARS and MERS, many uncertainties (including route of infection, viral evolution, epidemic dynamics, appropriate anti-viral treatment, and strategies for disease control) remain.

Current global distribution of COVID-19 and cardiovascular consequences of respiratory virus infection. (A) The global distribution of COVID-19 on 16 March 2020 (figure source: COVID-19 situation reports from World Health Organization). (B) Direct and indirect cardiovascular consequences of respiratory virus infection.

Cardiovascular complications of respiratory virus infection

Cardiovascular complications of influenza infection, including myocarditis, acute myocardial infarction, and exacerbation of heart failure have been well-recognized during previous historical epidemics and make a significant contribution to mortality. Likewise, previous coronavirus outbreaks have been associated with a significant burden of cardiovascular comorbidities and complications (Table ). Furthermore, the severity of the primary respiratory syndrome and risk of adverse outcomes is increased in patients with pre-existing cardiovascular diseases. Hypotension, tachycardia, bradycardia, arrhythmia, or even sudden cardiac death are common in patients with SARS. Electrocardiographic changes and troponin elevation may signal underlying myocarditis, and echocardiography frequently demonstrates sub-clinical left ventricular diastolic impairment (with a higher likelihood of the need for mechanical ventilation in those with systolic impairment and reduced ejection fraction).,

Early COVID-19 case reports suggest that patients with underlying conditions are at higher risk for complications or mortality—up to 50% of hospitalized patients have a chronic medical illness (40% cardiovascular or cerebrovascular disease). In the largest published clinical cohort of COVID-19 to date, acute cardiac injury, shock, and arrhythmia were present in 7.2%, 8.7%, and 16.7% of patients, respectively, with higher prevalence amongst patients requiring intensive care.

Viral pathology and links to the cardiovascular system

Chronic cardiovascular disease may become unstable in the setting of viral infection as a consequence of imbalance between infection-induced increase in metabolic demand and reduced cardiac reserve. Patients with coronary artery disease and heart failure may be at particular risk as a result of coronary plaque rupture secondary to virally induced systemic inflammation, and rigorous use of plaque stabilizing agents (aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors) has been suggested as a possible therapeutic strategy. Pro-coagulant effects of systemic inflammation may increase the likelihood of stent thrombosis and assessment of platelet function and intensified anti-platelet therapy should be considered in those with a history of previous coronary intervention.

The beta-coronavirus virus underlying COVID-19 strains from the same species as SARS and has recently been named SARS-CoV-2. SARS-CoV binds to cells expressing appropriate viral receptors, particularly angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme 2 is also expressed in the heart, providing a link between coronaviruses and the cardiovascular system. Murine models and human autopsy samples demonstrate that SARS-CoV can down-regulate myocardial and pulmonary ACE2 pathways, thereby mediating myocardial inflammation, lung oedema, and acute respiratory failure. Pro-inflammatory cytokines are up-regulated in the lungs and other organs of SARS patients, and the systemic inflammatory response syndrome provides a possible mechanism for multi-organ failure (usually involving the heart) in severe cases.

Does the risk of cardiovascular disease persist?

Heightened systemic inflammatory and pro-coagulant activity can persist in survivors of hospitalization for community-acquired pneumonia long after resolution of the index infection. The clinical effects of pneumonia have been linked to increased risk of cardiovascular disease up to 10-year follow-up and it is likely that cases infected via respiratory virus outbreaks will experience similar adverse outcomes. Therapeutic use of corticosteroids further augments the possibility of adverse cardiovascular events. However, long-term follow-up data concerning the survivors of respiratory virus epidemics are scarce. Lipid metabolism remained disrupted 12 years after clinical recovery in a metabolomic study amongst 25 SARS survivors, whereas cardiac abnormalities observed during hospitalisation in eight patients with H7N9 influenza returned to normal at 1-year follow-up. Whilst viral phenotype, baseline clinical characteristics, initial disease severity, and immediate management impact on short-term survival, long-term prognosis following outbreaks of respiratory virus infection may equally depend upon the extra-pulmonary manifestations. Serial follow-up studies amongst the survivors of acute infection are sorely needed.

Conclusions

Increased human mobility and ready access to international travel have accelerated the rate of microbial transmission around the world and global pandemics are a persistent threat. Outbreaks of viral respiratory illness threaten public health but the associated extra-pulmonary manifestations and their prolonged consequences are frequently overlooked. COVID-19 is a rapidly evolving epidemic with uncertain clinical characteristics and further acceleration seems likely. Pre-existing cardiovascular disease may contribute to adverse early clinical outcomes and infection may have longer-term implications for overall cardiovascular health (Take home figure). Inter-disciplinary management of severe cases (with priority for those with pre-existing cardiovascular disease) and prolonged clinical follow-up are therefore essential.

Conflict of interest: none declared.

Table 1

Representative studies addressing the acute cardiovascular manifestations of coronavirus infection and their clinical implications

Outbreaks	First author and cohort size	Cardiovascular manifestations	Outcomes
SARS	Yu et al.5 (n = 121)	Hypotension, tachycardia, bradycardia, cardiomegaly, and arrhythmia	Mostly transient
	Pan et al.6 (n = 15)	Cardiac arrest	Death
	Li et al.7 (n = 46)	Sub-clinical diastolic impairment without systolic involvement on echocardiography	Reversible on clinical recovery
MERS	Alhogbani8 (n = 1)	Acute myocarditis and acute-onset heart failure	Recovered
COVID-19	Huang et al.9 (n = 41)	Myocardial injury (manifesting with increased high-sensitivity cardiac troponin I) in five patients	Four patients required intensive care
	Wang et al.10 (n = 138)	Acute cardiac injury (7.2%), shock (8.7%), and arrhythmia (16.7%)	Most patients required intensive care