Cardiovascular Risk and Effects of Cardiovascular Drug Therapy During nCoV-19 Infection

Background

COVID-19 has shown a lower case-fatality rate compared to other major viral outbreaks in contemporary history, including severe acute respiratory syndrome (SARS) of 2002-2003. However, the relative susceptibility to symptomatic infection and the case fatality risk increase substantially after 60 years of age, in men, and in overweight patients, raising questions about the underlying biology of host responses. This includes possible genetic derterminants of sex bias. Cardiac involvement, as characterized, by elevation of cardiac Troponin I and brain-type, natriuretic peptide, is frequent in COVID-19 and it is associated with worse prognosis. Myocardial injury and heart failure accounted for 40% of deaths in a Wuhan cohort, either exclusively or in conjunction with respiratory failure. Thus, it seems that cardiac involvement is both prevalent and of prognostic significance in COVID-19. However, both the actual incidence of myocardial injury (biomarkers elevation may simply reflect systemic illness in critically-ill patients) and the pathophysiology of cardiac involvement remain to be clarified. The SARS-CoV-2 virus interacts through the structural glycopeptides of the "crown" spikes with its cellular target that, in humans, is the angiotensin2 (ACE2) converting enzyme, expressed in particular in the heart and lungs. ACE2 is used by SARS-CoV-2 to be internalized by alveolar epithelial cells. Therefore, chronic intake of ACE inhibitors, or sartans, may influence the course of the COVID-19 disease because an increased expression of ACE2 (such as that induced by ACEi therapy) could facilitate the internalization of the virus and the progression of infection. However, the infection by the virus leads to the down-regulation of ACE2. The imbalance between ACE and ACE2 leads to an increase in angiotensin II, which binds AT1R, which increases pulmonary vascular permeability and lung damage. Thus, the role ACEi and ARBs on the susceptibility to SARS-COv-2 infection remain to be clarified.

COVID-19 is characterized by changes in heart rate and cardiac autonomic modulation, systemic activation of inflammatory processes, with endothelial damage and involvement of cardiovascular (CV) and respiratory systems. Although most patients remain asymptomatic or mildly symptomatic, in a subset of them the host inflammatory response continues to amplify with progressive lymphocytopenia, high white blood cells and neutrophil counts, to end-up with a systemic inflammation characterized by multiple organ failure and elevation of key inflammation markers (e.g. interleukin, tumor necrosis factor, interferon-y inducible protein, etc.). These biomarkers are not just indicators of inflammation, but are also associated with prognosis. Patients who died of COVID-19 showed higher levels of IL-6, ferritin and CRP. Moreover, biomarkers of myocardial injury and ECG abnormalities were associated with elevated inflammatory markers suggesting an indirect mechanism of cardiac injury. However, recent data have demonstrated the presence of the virus within the myocardium of some COVID-19 pts, implicating also direct myocardial injury. Also low Vit.D, with immunomodulating action, is associated with poor outcome. Another interesting aspect of the complex pathophysiology of COVID-19 is the finding that 71.4% of nonsurvivors and 0.6% of survivors in a Wuhan hospital showed overt disseminated intravascular coagulation (DIC). It is well known that sepsis is a common cause of DIC and inflammatory cytokines can promote the activation of blood coagulation in many ways. However, whether SARS-Cov-2 is more prone to DIC development and the role of anticoagulation in determining the prognosis in COVID-19 need to be established. Finally, no data is available on the short-term sequelae in COVID-19 pts after discharge, in terms of residual structural and functional cardiorespiratory damage and its determinants (viral, inflammatory, metabolic and pro-thrombotic factors).

Hyphotesis and Significance

We hypothesize that COVID-19 could represent a "new" CV risk factor inducing acute and chronic CV changes able to affect clinical evolution and long term prognosis. Suggested important mechanisms of COVID-19 severity related to injury of CV and respiratory systems include: 1) a pro-inflammatory cytokine storm, with endothelial damage and DIC; 2) patients' demographic and clinical features (age, sex, body mass index, genetic factors, autonomic cardiac modulation, medical history in particular diabetes and CV diseases, sleep disordered breathing, low vitamin D levels, thyroid dysfunction, and current drug treatment); 3) evidence of cardiac damage during course of the disease. All these possible determinants of COVID-19 severity need to be systematically evaluated according to an integrated approach in a large number of patients developing COVID-19 of different severity, including inpatients and outpatients. Given the complexity of the hypothesized multifold pathogenetic mechanisms, also approaches to data analysis through artificial intelligence (machine learning algorithms) may allow to develop multivariable models to 1) effectively risk stratify patients to identify those at highest risk requiring more intensive support; 2) Promptly recognize patients most vulnerable for adverse outcomes, to prioritize palliative care and improve cost/effectiveness of healthcare resources deployed. Finally, no information is yet available on the short term residual structural and functional consequences on the immune, CV and respiratory systems following discharge of COVID-19 patients who have recovered from acute disease.