Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality: a prospective cohort in UK Biobank

Abstract

Aims

This study aims to evaluate the short- and long-term associations between COVID-19 and development of cardiovascular disease (CVD) outcomes and mortality in the general population.

Methods and Results

A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021. Based on age (within 5 years) and sex, each case was randomly matched with up to 10 participants without COVID-19 infection from two cohorts—a contemporary cohort between 16 March 2020 and 30 November 2020 and a historical cohort between 16 March 2018 and 30 November 2018. The characteristics between groups were further adjusted with propensity score-based marginal mean weighting through stratification. To determine the association of COVID-19 with CVD and mortality within 21 days of diagnosis (acute phase) and after this period (post-acute phase), Cox regression was employed. In the acute phase, patients with COVID-19 (n = 7584) were associated with a significantly higher short-term risk of CVD {hazard ratio (HR): 4.3 [95% confidence interval (CI): 2.6– 6.9]; HR: 5.0 (95% CI: 3.0–8.1)} and all-cause mortality [HR: 81.1 (95% CI: 58.5–112.4); HR: 67.5 (95% CI: 49.9–91.1)] than the contemporary (n = 75 790) and historical controls (n = 75 774), respectively. Regarding the post-acute phase, patients with COVID-19 (n = 7139) persisted with a significantly higher risk of CVD in the long-term [HR: 1.4 (95% CI: 1.2–1.8); HR: 1.3 (95% CI: 1.1– 1.6)] and all-cause mortality [HR: 5.0 (95% CI: 4.3–5.8); HR: 4.5 (95% CI: 3.9–5.2) compared to the contemporary (n = 71 296) and historical controls (n = 71 314), respectively.

Conclusions

COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality. Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease.

1. Introduction

SARS-CoV-2 infection leading to COVID-19 is increasingly associated with cardiovascular dysfunction and complications,^1,2 in addition to respiratory and other systemic diseases.³ Prior studies reported the incidence of cardiovascular pathologies such as myocarditis, pericarditis, ischaemic stroke, arrhythmias, and cardiomyopathy in COVID-19 patients, manifesting at different time points during the acute and post-acute phase of infection.^1,4 These cardiovascular disease (CVD) symptoms were notably persistent in more than half of the patients (∼57%) recruited for observational studies, complaining of cardiac symptoms many weeks post recovery⁵ with evidence of cardiac structural and functional abnormalities such as myocardial injury.^6,7 This persistence of ongoing COVID-19 signs and symptoms, including CVD-associated symptoms, beyond 4 to 12 weeks after recovery from COVID-19 has been internationally recognized as ‘long-COVID’^8,9 or post-acute sequelae SARS-CoV-2 infection. The exact pathophysiology of long-COVID is not yet understood, however, the possibility of COVID-19 in accelerating the risk for cardiovascular complications over time has been proposed from preliminary clinical data, warranting more conclusive evidence.¹⁰ Interestingly, clinical reports found that severe cardiac complications were evident even in healthy individuals such as high-performance athletes,^6,11,12 and in those exhibiting asymptomatic/mild COVID-19 symptoms^13–15 after infection, highlighting the need to evaluate the overall long-COVID-associated cardiovascular risks in the general population through comparison of infected vs. uninfected individuals.

Prior studies have analysed the relationship between CVD and COVID-19 in infected/recovered patients by examining the cardiovascular effects of COVID-19 largely based on the prevalence of CVD-associated clinical characteristics and symptoms, particularly cardiac injury (identified from elevated cardiac-troponin levels).^16,17 Limited evidence on the development of short- and long-term cardiovascular outcomes and their incident risks in patients during infection and post recovery through follow-up studies is available.^1,17 The scope of such evidence is further limited by short follow-up durations averaging at 3 months,^18,19 small sample sizes, and/or being exclusively restricted to hospitalized patients with severe COVID-19 infection²⁰ or to those with pre-existing myocardial complications due to underlying CVD.^21–23 Only one large-scale study has extended the analysis to report the 1 year risks and burdens of cardiovascular outcomes in infected vs. uninfected COVID-19 patients.¹ However, the generalizability of the findings was compromised owing to the recruitment of participants from the male-dominant US Department of Veterans Affairs database. Further, their analysis was focused on evaluating only the long-term cardiovascular outcomes of COVID-19.

Hence, this study aims to add to the currently limited body of long-term evidence on cardiac presentation in COVID-19, especially long-COVID, and confirm the findings of previous studies through a longitudinal, retrospective study design with a long follow-up period of 18 months. Moreover, the progressive manifestation of cardiovascular outcomes is captured by identifying CVD and mortality short- and long-term risks in both, male and female patients, at the acute and beyond the acute (post-acute) phase of infection, respectively.

2. Methods

2.1 Study design and population

Participants were recruited from the UK Biobank database, a large prospective cohort, investigating associations of a wide variety of exposures with health-related outcomes, collecting baseline data of 502 616 participants between the ages of 40 and 69, from 2006 to 2010. The use of this rich database for epidemiological analyses is well established.^24–26 To monitor the development of COVID-19 outcomes in patients, participant data from the UK Biobank was further linked to the primary care (GP) data from The Phoenix Partnership and Egton Medical Information Systems Health GP system of England up to 31 August 2021; and the hospital inpatient data, sourced from National Health Service (NHS) Digital and Public Health Scotland along with public death-registration records, was linked with the data recorded by NHS England and Wales and NHS Scotland of UK Biobank participants.²⁷

For identifying severe COVID-19 patients, critical care data along with information on the type of support provided to each patient was sourced from the UK Biobank database, specially curated and provided as part of the inpatient data. The inclusion criteria for respiratory support in defining severe COVID-19 included the following treatments: (i) invasive ventilation; (ii) continuous positive airway pressure; (iii) non-invasive ventilation; (iv) unspecified oxygen therapy; (v) other specified oxygen therapy; (vi) other specified ventilation support; (vii) unspecified ventilation support; (viii) other specified oxygen therapy support; and (ix) unspecified oxygen therapy support. OPCS Classification of Interventions and Procedures version 4 (OPCS-4) system was used to identify these treatments (see Supplementary material online, Table S1).

Since vaccine records were unavailable for this study, the inclusion period was restricted to the period when no vaccines were available in the UK—before December 2020. Hence, the case cohort comprised patients diagnosed with COVID-19 between 16 March 2020 and 30 November 2020. To evaluate the short- and long-term effects of COVID-19, the observation period was divided into acute and post-acute phase. For the acute phase, the index date was defined by the date of the first COVID-19 infection during the inclusion period. For the post-acute phase, the index date was defined by 21 days after the date of the first COVID-19 infection during the inclusion period. Two control cohorts—contemporary and historical—differing in their inclusion periods were used for comparative analysis with the cases to determine the effects of COVID-19. A comparison with the historical control cohort ruled out the indirect effect of COVID-19—an overall deterioration in public health with an increase in mortality even in those with non-COVID-19 illnesses, attributed to reduced availability/suspension of routine healthcare services during the pandemic.²⁸

The contemporary cohort analysis included individuals diagnosed with COVID-19 between 16 March 2020 and 30 November 2020 as cases and those without COVID-19 diagnosis during this whole study period (e.g. 16 March 2020 and 31 August 2021) as controls. Based on age (±5 years) and sex, each case was randomly matched with up to 10 controls. Further, the index date of each control was matched and assigned to a corresponding case with an identical index date. The selection procedures remained the same for the historical cohort, and uninfected controls were identified from 16 March 2018 to 30 November 2018. The difference lies in the index date for each matched control being defined as 2 years prior to the index date of the corresponding case. For example, if the index date of a case (e.g. the date of COVID-19 infection) was 1 May 2020, hence, the index date of matched controls in contemporary and historical cohorts would be 1 May 2020 and 1 May 2018, respectively. For each patient, the follow-up period was until the first date of outcome, mortality, or 31 August 2021 for contemporary cohort and 31 August 2019 for historical cohort (or until 21 days after the index date for the acute phase), whichever occurred first.

2.2 Definition of COVID-19 infection

Infection with COVID-19 was defined as those having a positive COVID-19 polymerase chain reaction (PCR) test result²⁹ or a hospital-admission code for a COVID-19-related diagnosis (U07.1 and U07.2). Public Health England (PHE), Public Health Scotland, and Secure Anonymized Information Linkage were linked with the UK Biobank to provide the COVID-19 test results,³⁰ which were from pillar 1 (swab-testing conducted in PHE laboratories and NHS hospitals for those with a clinical need or working as healthcare professionals) and pillar 2 (swab-testing conducted for the wider population).³¹

Since solely using hospitalization records as a proxy for severity of infection was noted not to be a very reliable or sophisticated indicator,³² cases of severe COVID-19 were defined based on a previous study as patients with records of critical care admission within 7 days after COVID-19 diagnosis and/or receiving treatment with invasive or non-invasive mechanical ventilation or other respiratory support.³³

2.3 Outcome measures

The outcomes include (i) major CVD: the composite outcome of heart failure, stroke, and coronary heart disease (CHD); (ii) stroke; (iii) transient ischaemic attack (TIA); (iv) atrial fibrillation (AF); (v) atrial flutter; (vi) pericarditis; (vii) myocarditis; (viii) CHD; (ix) acute coronary disease; (x) myocardial infarction (MI); (xi) ischaemic cardiomyopathy; (xii) stable angina; (xiii) unstable angina; (xiv) heart failure; (xv) non-ischaemic cardiomyopathy (NIC); (xvi) cardiac arrest; (xvii) cardiogenic shock; (xviii) deep vein thrombosis; (xix) superficial vein thrombosis; (xx) CVD mortality; and (xxi) all-cause mortality. All these outcomes were defined using the 10th revision of the International Classification of Diseases (see Supplementary material online, Table S2).

2.4 Baseline characteristics

The baseline characteristics included age, sex, smoking, diabetes mellitus, hypertension, Charlson Comorbidity Index,³⁴ baseline body mass index (BMI), ethnicity, index of multiple deprivation, and history of outcome measures listed above. All the disease definitions of baseline characteristics and Charlson Comorbidity Index are listed in Supplementary material online, Table S1.

2.5 Ethics approval

Ethical approval was given by the North West Multi-Centre Research Ethics Committee and the application number of the resource under UK Biobank for this study is 65688. All participants in UK Biobank provided their written consent and those who withdrew from the study were removed from the analysis.

2.6 Statistical analysis

The marginal mean weighting through stratification (MMWS) method was employed to adjust for the selection bias among patients in the case, contemporary and historical groups.³⁵ An extension of the propensity score method (which conducts weighting on the basis of propensity score stratification), this statistical approach utilizes propensity scores based on fixed quantiles to create the fine strata, as a measure to avoid extreme weights (in the case of the exposure prevalence being low or any propensity score distribution being skewed).³⁵ This method was applied by using the ‘MMWS’ package in Stata³⁶ with 75th quantile categories of propensity score, based on age, sex, smoking, diabetes mellitus, hypertension, Charlson Comorbidity Index, baseline BMI, ethnicity group (White and others), index of multiple deprivation, and history of outcome measures. Post weighting, the baseline characteristics were summarized using descriptive statistics. The standard mean difference (SMD) between the case group and the two control groups was described and an SMD of <0.2 was deemed as a sufficient balance between the groups.³⁷

The observation period for following up on the outcomes was divided into the acute and post-acute phase, evaluating the short- and long-term effects of COVID-19. Those outcomes occurring within 21 days from the index date were included in the acute phase and incidence was defined by the number of patients having a first event of an outcome of interest in this period while the incidence rate was calculated by dividing the number of such patients by the total number of people at risk during this time period; whereas the post-acute outcomes were selected based on the outcomes observed in patients surviving this initial 21-day period and incidence was defined by the number of patients having the first event of an outcome at least 21 days after the index date, with the incidence rate being determined by dividing the number of such patients with the total number of patients at risk in this time period.^38,39 The incidence rates and their corresponding 95% confidence intervals (CIs) were assessed based on their Poisson distribution. The association between COVID-19 infection and each of the outcomes in comparison with the contemporary and historical control groups was evaluated using the Cox proportional hazard regression. Patients who had a history of a particular outcome were excluded from the corresponding analyses while evaluating the incidence and relative risk associated with each outcome. Further, two subgroup analyses were included in this study: (i) subgroup analysis of gender (male vs. female) (ii) subgroup analysis of the severity of COVID-19 (COVID-19 cases with records of critical care admission within 7 days after COVID-19 diagnosis and/or receiving treatment with invasive or non-invasive mechanical ventilation or other respiratory support, defined by using OPCS-4 codes listed in Supplementary material online, Table S2).³³

Moreover, three sensitivity analyses were conducted in this study. (i) A competing risk Cox regression using the Fine and Gray⁴⁰ method to adjust for mortality as a competing risk while evaluating associations. (ii) A multivariable Cox proportional hazard regression adjusted by age, sex, smoking, diabetes mellitus, hypertension, Charlson Comorbidity Index group, baseline (BMI), ethnicity, index of multiple deprivation, and history of outcome measures before weighing. (iii) A multivariable Cox proportional hazard regression adjusted by age, sex, smoking, diabetes mellitus, hypertension, Charlson Comorbidity Index, baseline BMI, ethnicity, index of multiple deprivation, and history of outcome measures after weighting.

Two-tailed tests were adopted for analysing results from this study and a P-value <0.05 was inferred as a statistically significant result. All statistical analyses were conducted using Stata version 15.1.

3. Result

The selection of patients with and without COVID-19 infection is depicted in Figure 1. The acute phase analysis involved a total of 7584 cases, matched with 75 790 contemporary controls and 75 774 historical controls, after weighting. For the post-acute phase analysis, 7139 cases and 71 296 matched-contemporary controls, and 71 314 matched-historical controls were identified. Table 1 summarizes the baseline characteristics with SMD after weighting, while the baseline characteristics with SMD before weighting are shown in Supplementary material online, Table S3. The SMD for all characteristics among the three groups was <0.2, indicating a good balance in all characteristics between subgroups.

3.1 Acute phase

The incidence rate of COVID-19-related mortality is found to be 699.7 (95% CI: 620.7–791.6). In Figure 2, the incidence rate and hazard ratio (HR) for each of the CVD outcomes is reported. In general, in the acute phase patients with COVID-19 demonstrated a higher incidence and increased risk for most CVD outcomes and all-cause mortality than both the uninfected control groups (contemporary and historical). COVID-19 patients showed a substantially higher incidence rate of major CVD as well as all-cause mortality compared to the two control groups. Adjustment in the regression analysis also revealed the same findings: patients with COVID-19 infection were more likely to develop CVD and mortality compared to the contemporary controls [HR of major CVD: 4.3 (95% CI: 2.6–6.9); all-cause mortality: 81.1 (95% CI: 58.5–112.4)] and historical controls [HR of CVD: 5.0 (95% CI: 3.0, 8.1); HR of all-cause mortality: 67.5 (95% CI: 49.9–91.1)]. Notably, risks of stroke, AF, and deep vein thrombosis (DVT) were also significantly higher than the contemporary controls [stroke: 9.7 (3.8, 24.9); AF: 7.5 (95% CI: 4.1–13.6); DVT: 22.1 (95% CI: 6.6–74.0)] and the historical controls [stroke: 5.0 (95% CI: 2.2–11.4); AF: 5.9 (95% CI: 3.3–10.4); DVT: 10.5 (95% CI: 4.0–27.7)].

3.2 Post-acute phase

The incidence rate of COVID-19-related mortality is 11.6 (95% CI: 9.2–14.7) in the post-acute phase (21 days after infection). The incidence rate and HR of the outcomes in this phase among patients with and without COVID-19 infection can be referred to in Figure 2. Higher incidence rates of certain cardiovascular sequelae persisted in infected patients—particularly outcomes of major CVD. Further, the incidence rate of all-cause mortality remained substantially lower in the contemporary and historical controls than in patients with COVID-19. Similar results were identified after adjustment in regression analysis. Patients with COVID-19 maintained significantly higher risks from the acute phase for some outcomes, particularly major CVD [HR: 1.4 (95% CI: 1.2–1.8)] and all-cause mortality [HR: 5.0 (95% CI: 4.3–5.8)], compared to the contemporary controls; while risks of some others returned to baseline (including TIA, AF, acute coronary disease, stable angina, and NIC). A comparison with the historical cohort confirmed this result, also demonstrating relatively higher risks of major CVD [HR: 1.3 (95% CI: 1.1–1.6)] and all-cause mortality [HR: 4.5 (95% CI: 3.9–5.2)] in infected patients over controls. Notably, unlike the acute phase, the emergence of pericarditis associated with a significant increase in relative risk was observed in infected patients over contemporary [HR: 4.6 (95% CI: 2.7–7.7)] and historical [HR: 4.5 (95% CI: 2.7–7.7)] controls.

3.3 Sensitivity and subgroup analyses

Supplementary material online, Tables S4–S8 summarize the results from the sensitivity analyses, with results of the associations found to be largely consistent with the main analysis.

Results of the subgroup analyses are shown in Supplementary material online, Table S9–S16. The subgroup analysis comparing risks of cardiovascular outcomes in patients with severe COVID-19 vs. those with non-severe COVID-19 is reported in Supplementary material online, Table S13–S16. A higher long-term risk of major CVD persisted in both severe and non-severe cases over contemporary controls [HR of severe COVID-19 cases: 5.8 (95% CI: 2.1–16.2); HR of non-severe COVID-19 cases: 1.4 (95% CI: 1.1–1.7)] and historical controls [HR of severe COVID-19 cases: 5.1 (95% CI: 1.8–14.1); HR of non-severe COVID-19 cases: 1.3 (95% CI: 1.0–1.6)]. In addition, both severe and non-severe COVID-19 cases demonstrated a higher likelihood of all-cause mortality, persistent even in the post-acute phase, over contemporary controls [HR of severe COVID-19 cases: 8.8 (95% CI: 4.0–19.5); HR of non-severe COVID-19 cases: 4.8 (95% CI: 4.1–5.7)] and historical controls [HR of severe COVID-19 cases: 10.9 (95% CI: 4.8–24.6); HR of non-severe COVID-19 cases: 4.1 (95% CI: 3.5–4.8)]. Overall, patients with severe COVID-19 were more likely to develop major CVD and face all-cause mortality than non-severe cases, although both subgroups demonstrated increased risks over the uninfected control groups. Subgroup analysis by gender (depicted in Supplementary material online, Table S9–S12) identified male patients to be associated with higher risks of developing cardiovascular outcomes in the acute phase than the subgroup of female patients and the main analysis, while the risks observed in the post-acute phase remained largely similar in both genders and were consistent with the main analysis.

4. Discussion

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.

5. Conclusion

This study demonstrates patients with COVID-19 to be associated with increased risks of CVD and mortality post infection (acute phase). These risks remain increased even up till a year post recovery and are associated with long-COVID. Ongoing monitoring of signs and symptoms of CVD in the short- and long-term may be beneficial in patients post infection and recovery. Further study is warranted to compare the findings in a vaccinated cohort.

Supplementary material

Supplementary material is available at Cardiovascular Research online.

Authors’ contributions

Concept and design by E.Y.F.W. and I.C.K.W. Acquisition by E.Y.F.W. Analysis or interpretation of data by E.Y.F.W., S.M., R.Z., V.K.C.Y., F.T.T.L., C.S.L.C., X.L., C.K.H.W., E.W.Y.C., K.H.Y., and I.C.K.W. Drafting of the manuscript by E.Y.F.W., S.M., and R.Z. Critical revision of the manuscript for important intellectual content by all authors. Statistical analysis by E.Y.F.W., R.Z., and V.K.C.Y. Administrative, technical, or material support by E.Y.F.W. and I.C.K.W. Supervision by E.Y.F.W. and I.C.K.W.

Acknowledgements

The authors wish to acknowledge the UK Biobank participants who provided the sample that made data available; without them, the study would not have been possible. The computations were performed using research computing facilities offered by Information Technology Services, at the University of Hong Kong.

Funding

This work was funded by Collaborative Research Fund from University Grants Committee of The Government of the Hong Kong Special Administrative Region, China (Ref. No. C7154-20GF), and the start-up fund from the University of Hong Kong. The funders did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. I.C.K.W. and F.T.T.L. are partially supported by the Laboratory of Data Discovery for Health (D24H) funded by AIR@InnoHK administered by the Innovation and Technology Commission.

Data availability

Data in this study are available from the corresponding author upon reasonable request.

References

Author notes