Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality

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A new study by researchers from the University of Hong Kong has found that all post COVID individuals have an increased risk of death from cardiovascular issues for at least 18 months after infection or even longer.

The study that involved nearly 160,000 participants showed that SARS-CoV-2 infections irrespective being asymptomatic or even mildly or moderately symptomatic, was associated with higher risks of cardiovascular disease and death in the short- and long-term.

The study findings were published in the peer reviewed journal: Cardiovascular Research, a journal of the European Society of Cardiology (ESC).
https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvac195/6987834?login=false
 

From previous studies and clinical reports, commonly occurring cardiovascular complications in COVID-19 patients include myocardial injury (21% of patients), arrhythmia (10.4% of patients), and heart failure (2.8% of patients) in acute settings; also observed and confirmed by this study.41–44 Over time, these symptoms may persist and develop into a variety of CVD sequelae in the long-term, and a comprehensive list of such probable cardiovascular events or outcomes was identified and analysed.

The findings from this study identify a significant increase in incident risks associated with several cardiovascular complications in patients with COVID-19 (cases) than those without COVID-19 (undiagnosed controls), potentially contributing to the substantially higher risks of CVD mortality and all-cause mortality—found to be associated with infected patients in both phases of infection.

Particularly, patients in the acute phase of infection were associated with ∼4 times higher risk of developing major CVD (composite of stroke, CHD, and heart failure) and at ∼81 times higher risk of all-cause mortality than controls; while in the post-acute phase, infected patients were associated with a ∼50% increase in the risk of major CVD in addition to 5 times the risk of all-cause mortality than uninfected controls, highlighting the long-term cardiovascular sequelae of COVID-19.

Further, consistent with previous studies, patients identified with severe COVID-19 were associated with higher risks of CVD and mortality than those with non-severe disease, although those with non-severe disease also exhibited increased risk associated with these outcomes over uninfected controls.

In addition, risks of cardiovascular outcomes were evident in both male and female patients. In the short-term (acute phase), male patients were generally associated with a relatively higher risk of developing most cardiovascular complications and facing mortality than female patients (consistent with the previous study45); while in the long-term during the post-acute phase, both genders demonstrated a roughly similar likelihood of developing outcomes, including major CVD and mortality.

Altogether, these findings suggest that continuous monitoring for signs and symptoms of CVD and related cardiovascular complications in COVID-19 patients post infection and up till at least a year post recovery, especially in those with severe disease, may be beneficial in potentially reducing COVID-19-associated cardiovascular morbidity and mortality in the short- and long-term.

Strengthened by being consistent with previous studies, this study adds evidence in support of increased short-term risks along with long-term risks of cardiovascular complications spanning several disorders in infected patients, up till at least 12 months post survival and recovery from the acute phase of COVID-19.46 

It concurs with findings of the only previous large-scale longitudinal study conducted in the US1 based on patient records from the US Veteran Health Administration (VHA) database, reporting a 50% increase in overall risk of developing any cardiovascular complication than uninfected controls [HR: 1.63 (95% CI: 1.59–1.68)] during the post-acute phase, specifically demonstrating increased relative risk (in HR) for cerebrovascular outcomes [HR: 1.53 (95% CI: 1.45–1.61)], dysrhythmias [HR: 1.69 (95% CI: 1.64–1.75)], inflammatory diseases of the heart and pericardium [HR: 2.02 (95% CI: 1.77–2.30)], ischaemic heart diseases [HR: 1.66 (95% CI: 1.52–1.8)], thromboembolic disorders [HR: 2.39 (95% CI: 2.27–2.51)] and other cardiovascular disorders including heart failure, cardiac arrest, and cardiogenic shock [HR: 1.72 (95% CI: 1.65–1.79)].

These calculated risks may differ numerically for the same outcomes as in this study, since their analysis majorly represents the demographic of male-dominant US veterans, while this study captures these risks in the (UK Biobank) UKB, comprising both male and female participants, aiming to present findings with higher generalizability.

However, both studies agree on evidence in support of the increased likelihood of COVID-19 patients in developing a variety of CVD outcomes over time. Results from a UK-based short follow-up study up to 4 months also concur with these findings. Building a cohort of 47 780 hospitalized COVID-19 patients (mean age 65 years, 55% men), they report a three-fold increase in risk over uninfected controls for major adverse cardiovascular events up to 4 months from diagnosis with COVID-19.19

On the contrary, another short follow-up (60 days) retrospective study comparing CVD events (ischaemic/haemorrhagic stroke, heart failure, and early MI) and new-onset heart disease in 77 364 COVID-19-positive testing vs. COVID-19-negative testing women veterans using clinical data from the US VHA database reported infected patients to be at a lower risk of experiencing cardiovascular events and developing new-onset CVD within 60 days, although at a 4 times higher risk of mortality, than the uninfected controls.18 

The authors of the study acknowledged that the risks in the women veteran population, similar to the male veteran population, do not accurately capture the risks for the general population due to demographical differences including median age, prevailing comorbidities, access to healthcare, etc.

Further, the discrepancy between these findings from the current study and the previous longitudinal studies implies that CVD outcomes are indeed more likely to develop and manifest over a long period of time after the acute phase of infection, highlighting the advantage of long-term follow-up studies in assessing the true risk of CVD and associated mortality.

Thus, infected patients should undergo continuous follow-up monitoring up till at least a year post recovery for detection of any long-term cardiovascular complications and CVD outcomes, to ensure that these complications do not go undiagnosed and untreated due to premature assessment when their manifestation is not apparent.

No conclusive mechanism can currently explain the pathophysiology of long-COVID resulting in cardiovascular sequelae. Probable mechanisms include direct effects mediated via direct interaction of SARS-CoV-2 with the angiotensin-converting enzyme 2 (ACE2) receptor, given that this receptor is highly expressed in the heart (more so than the lungs) and its blood vessels such as the coronary arteries.47 

The virus may be directly infecting the myocardium and other cardiovascular cell types, supported by the histological finding of a marked increase in macrophage infiltration in infected patients with myocardial damage.48 Further, consumption of ACE2 for SARS-CoV-2 cellular entry causing increased angiotensin II level is believed to induce vasoconstriction, reducing blood flow and promoting coagulation, leading to AF and consequent thromboembolic events.49 

However, incident myocarditis is uncommon in the acute phase of COVID-19,50 as is evident in this study, increasing the likelihood that the cardiovascular outcomes result from the indirect effects of uncontrollable SARS-CoV-2 replication, triggering a cytokine storm including interleukin-6 and tumour necrosis factor-α, causing systemic inflammation.51,52 

This results in organ damage, including myocardial injury, known to be independently associated with an increased risk of mortality.53 Inflammation also exacerbates any pre-existing CVDs and/or activates them in those with a dormant risk for CVD outcomes, demonstrated in a mouse model.54 

Moreover, a bidirectional relationship associating long-COVID with increased risk for cardiovascular complications has also been proposed,10 based on clinical reports demonstrating a higher prevalence of underlying cardiovascular comorbidities in patients suffering an outcome of COVID-19-associated mortality (attributable to an increased expression of ACE2-receptor in failing hearts promoting severe SARS-CoV-2 infection55), along with an increase in the incidence of cardiovascular disorders in infected patients.39

Therefore, increased CVD risks in patients with COVID-19, even post recovery, are an amalgamation of both direct and indirect effects of SARS-CoV-2 infection at different time points, which are further enhanced by the bidirectional relationship between COVID-19 and cardiovascular complications.

Indeed, this study finds a higher incidence and relative risk of cardiovascular outcomes other than major CVD in infected patients over controls, with propositions of direct and indirect mechanisms of SARS-CoV-2 infection underlying their manifestation.56–58 While a ∼7.5-fold increased risk is associated with AF (possibly explaining the ∼10-fold associated risk of stroke and a five-fold risk of heart failure, since AF is independently associated with both59) and a ∼22-fold risk is associated with DVT during the acute phase60; in the post-acute phase the emergence of a ∼five-fold increased risk associated with pericarditis and superficial vein thrombosis, in addition to the persistent (but reduced from acute phase) ∼1.5-fold risk of DVT, is observed.

Consistent with this study, previous studies also report higher risks of these outcomes in association with COVID-19. Hospitalized infected patients (age ≥ 18) were at higher odds for the onset of AF over COVID-19-negative patients [odds ratio (OR): 1.19 (95% CI: 1.00–1.1)],61 with AF being proposed as a strong predictor of in-hospital all-cause mortality [HR: 1.405 (95% CI: 1.027–1.992)].62 

Patients with COVID-19 were associated with a five-fold increased risk of DVT 30 days post diagnosis (acute phase) and up to 3 months post recovery,63 persisting even after 1 year of recovery [HR: 2.09 (95% CI: 1.94–2.24)], demonstrated in another study.1 Systemic inflammation and consequent endothelial damage are believed to underlie development of pericardial complications, including pericarditis, also demonstrated to be persistent up till at least a year post recovery [HR: 1.85 (95% CI: 1.61–2.13)].

This study has several strengths. By using the vast and rich database of the UK Biobank, a large cohort of patients was built, inclusive of both male and female patients. Rather than analysing the different phases of COVID-19 infection in isolation, the study design involved a long-term follow-up in the same patient cohort, allowed monitoring of the development of an extensive list of pre-specified cardiovascular outcomes over 18 months.

The dynamic changes in the incidence and risk of cardiovascular complications and mortality as the disease progressed from the acute to the post-acute phase in patients may give an insight into the underlying mechanisms leading to these outcomes. To ensure the robustness of our results, two control groups were employed to conduct the comparative analysis—a historical and a contemporary cohort—as previous evidence had demonstrated the indirect effect of COVID-19 in deteriorating the health conditions of individuals with non-COVID-19-associated disease due to disruptions in regular healthcare services.28 

Thus, a comparison with the historical control cohort ruled out the indirect effect of COVID-19 infection. In addition, a recent study suggested that COVID-19 vaccination may protect against the complications of COVID-19 infection.64 Since vaccination records for the participants were unavailable for this study, this limitation was overcome by restricting the inclusion period to before December 2020, when vaccines were not available in the UK (although these findings should be confirmed in a vaccinated cohort in the future to reinforce the effectiveness of vaccination in reducing these CVD and mortality risks identified in the unvaccinated population).

Nevertheless, this study faces some specific limitations. Firstly, being an observational study, only the association between COVID-19 infection and risks for the specific disease outcomes can be established, rather than causality. Secondly, since the mean age of UKB participants tends to be older and is primarily of European ancestry, whether these findings apply across different ethnicities and age groups cannot be determined.

Thirdly, some potential confounders, including lifestyle factors, clinical parameters indicative of disease severity (including heart rate, blood pressure, PCR values, leucocyte, oxygen saturation, etc.), and history of medication (such as prior use of anticoagulant or antiplatelet drugs), were unavailable and thereby unaccounted for in this study, although matching by age and sex and weighting by age, sex, ethnicity, baseline BMI, index of multiple deprivation and a comprehensive list of comorbidities (including Charlson Comorbidity Index score, history of cardiovascular complications, hypertension, and diabetes) were used to minimize selection and confounding biases. Further, subgroup analyses were employed to account for confounding by severity of infection or gender differences on the risks of cardiovascular complications.

Owing to the limited sample size of severe COVID-19 cases and inconsistency in the definition of severe COVID-19 in the current literature, further analysis in future studies is warranted. Fourthly, since the cases were distinguished from controls based on the latter not having a positive COVID-19 PCR test result and/or not being hospitalized with a COVID-19-related diagnosis admission code, the possibility of asymptomatic, undiagnosed COVID-19 infected individuals being included in the contemporary control group and/or excluded from recruitment into the COVID-19 patient cohort still remains.

However, this should only bias the results towards the null; moreover, since the results for the contemporary cohort were comparable with the historical cohort, we perceive that such contamination had minimal effects on the results, ensuring that they remain robust. Lastly, risks of certain complications could not reach statistical significance stemming from the inherent rarity of the outcome and low prevalence in COVID-19 patients, leading to low event rates and high CIs.

Future studies on larger cohorts and across age groups, and ethnicities are warranted to validate these findings. In addition, evaluating whether these risks differ in vaccinated cohorts and/or change(d) with the advent of the second and third wave of the outbreak and beyond, warrants further study.


 

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