Increased complications of COVID-19 in people with cardiovascular disease: Role of the renin-angiotensin-aldosterone system (RAAS) dysregulation

Abstract

The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has had a dramatic negative impact on public health and economies worldwide. Recent studies on COVID-19 complications and mortality rates suggest that there is a higher prevalence in cardiovascular diseases (CVD) patients. Past investigations on the associations between pre-existing CVDs and susceptibility to coronavirus infections including SARS-CoV and the Middle East Respiratory Syndrome coronavirus (MERS-CoV), have demonstrated similar results. However, the underlying mechanisms are poorly understood. This has impeded adequate risk stratification and treatment strategies for CVD patients with SARS-CoV-2 infections. Generally, dysregulation of the expression of angiotensin-converting enzyme (ACE) and the counter regulator, angiotensin-converting enzyme 2 (ACE2) is a hallmark of cardiovascular risk and CVD. ACE2 is the main host receptor for SARS-CoV-2. Although further studies are required, dysfunction of ACE2 after virus binding and dysregulation of the renin-angiotensin-aldosterone system (RAAS) signaling may worsen the outcomes of people affected by COVID-19 and with preexisting CVD. Here, we review the current knowledge and outline the gaps related to the relationship between CVD and COVID-19 with a focus on the RAAS. Improved understanding of the mechanisms regulating viral entry and the role of RAAS may direct future research with the potential to improve the prevention and management of COVID-19.

Keywords: ACE2; COVID-19; Cardiovascular diseases; Coronavirus; RAAS; SARS-CoV-2.

Graphical abstract

Fig. 1

Mortality incidence of COVID-19 patients with pre-existing diseases. Patients with pre-existing heart diseases had the highest mortality rate of 10%. Diabetes was associated with the second-highest fatality rate of ∼7%. Approximately 6% mortality was observed in those with underlying hypertension. Thus, ∼16% of mortality of COVID-19 patients was associated with some form of pre-existing CVDs or the risk factors for CVD. Data adapted from the Chinese Center for Disease Control and Prevention [65].

Fig. 2

Major complications associated with SARS-CoV-2 infection in CVD patients. The manifestations of COVID-19 in CVD patients begin soon after the entry of the virus through ACE2 receptor (myocardial cell damage, ACE/ACE2 imbalance) and can result in myocardial infarction, hypertension or DIC. Respiratory infections due to SARS-CoV2 can results in hypoxia, ARDS and higher myocardial demand in CVD patients. These can result in hypoxia-induced cardiomyocyte or endothelial cell death. Further, SARS-CoV2 associated systemic inflammation can result in disrupted immune response, endothelial dysfunction and cytokine mediated myocardial injury.

Fig. 3

Links between SARS-CoV-2 infection and highly abundant Angiotensin II leading to various pathogenic downstream effects. Binding of SARS-CoV-2 to the ACE2 receptor on the cell surface decreases ACE2 abundance and increases the level of Angiotensin II whilst reducing Ang 1–9 and Ang 1–7. This can lead to inflammation, oxidative stress, fibrosis, thrombosis, cell proliferation, salt and water retention and vasoconstriction, hence inducing cell injury. Adapted from Ref. [167] with the permission of Elsevier.

Fig. 4

In healthy individuals, Angiotensin II is converted into Angiotensin (1–7) via ACE2. However, in COVID19, ACE2 may be dysfunctional due to the binding of SARS-CoV-2, which can affect the conversion of Angiotensin II to Angiotensin (1–7). This results in the accumulation of Angiotensin II in the infected person and induces proinflammatory, prothrombotic, fibrotic and vasoconstrictive downstream effects. In the presence of CVD, however, the RAAS could be impaired. Consequently, upon infection with SARS-CoV-2, more Angiotensin II could accumulate resulting in serious cardiovascular complications.